PRINCIPLES OF NANO-SIZED DRUG DELIVERY SYSTEMS

By,

Melis Nur YILMAZ

Ayşe Şevval ÇAKIR

Submitted to the Department of Chemical Engineering

in partial fulfillment of

the requirements for the degree of

Bachelor of Science

Faculty of Engineering

Yeditepe University

2021
 PRINCIPLES OF NANO-SIZED DRUG DELIVERY SYSTEMS

APPROVED BY:

DATE OF APPROVAL: …./….

ACKNOWLEDGEMENTS
 ABSTRACT

Drug delivery is a concept that includes; the therapeutic drug, the carrier that delivers
the drug, the route that carrier went through, and the methods that make the carrier go to the
diseased area. The main idea about drug delivery is bringing the drug effectively to injured
cell or tissue and releasing it properly. Drugs are used to repair the injured areas which are
form due to diseases. Number of carriers is many, but they are chosen according to their
properties, availabilities, and aligning with the drug. In order to bring the drug to the diseases
sites there are lots of routes. Some of them are oral, pulmonary, transdermal, injectable and
ocular. Each route has their own related diseases and own advantages/obstacles. In order to
target the injured areas, some targeting strategies are present. Drugs can be released by active
or passive targeting methods. In active targeting, cell specific ligands and some stimuli
properties that trigger the drug release are used. Whereas in passive targeting, the nanoparticle
is coated with some materials, most known material to hide the carrier is polyethylene glycol.
Furthermore, in human body, there are several biological barriers. For instance; there is blood
brain barrier in brain, stratum corneum inside the layers of the skin and pre-corneal, dynamic
and static ocular barriers in the eye. Not the whole drug carriers are able to cross these
barriers. Therefore, to overcome these barriers and other issues such as the size of the carrier,
toxicity and incompatibility with the drug or tissue, nanotechnology and drug delivery are
held together. That’s why, nano-carriers are used in order to deliver the drug deep down in the
body as possible. Nano-carriers are particles that size ranges between 1 and 100 nm. Hence,
they can move freely in the human body compared to bigger materials. Some carriers are used
in both manner; regular and nano-sized. Liposomes and dendrimers are examples for these
category. Nano-sized drug delivery systems have advantages and wider applications
compared to regular sized drug delivery systems. Also they have disadvantages such as higher
costs and complex form of nanoparticles as multi-component three dimensional constructs
which demand careful design and engineering. In addition, several fields of science should
come together in order to accomplish the drug delivery. Biology, chemistry and medicine are
the main ones. From engineering perspective, drug delivery should be conducted compatible
with these fields, cost of the drug delivery and patient compliance also should be taken into
account.
 ÖZET

İlaç teslimi; tedavi edici ilaç, ilacı teslim eden taşıyıcı, taşıyıcının geçtiği yol ve
taşıyıcıyı hastalıklı bölgeye ulaştıran yöntemleri içeren bir kavramdır.İlaç dağıtımı ile ilgili
ana fikir, ilacı yaralı hücre veya dokuya etkili bir şekilde getirmek ve uygun şekilde
bırakmaktır. İlaçlar, hastalıklara bağlı olarak oluşan yaralı bölgeleri onarmak için kullanılır.
Taşıyıcıların sayısı çoktur, ancak özelliklerine, bulunabilirliklerine ve ilaca uygunluklarına
göre seçilirler. İlacı hastalık bölgelerine getirmenin birçok rotası vardır. Bunlardan bazıları;
ağızdan, akciğerden, deriden, enjekte halinde ve gözden oluşur. Her rotanın kendine özgü
hastalıkları ve avantajları/engelleri vardır. Yaralı bölgeleri hedeflemek için bazı hedefleme
stratejileri mevcuttur.İlaçlar, aktif veya pasif hedefleme yöntemleri ile serbest bırakılabilir.
Aktif hedeflemede hücreye özgü ligandlar ve ilaç salınımını tetikleyen bazı uyarıcı özellikler
kullanılır. Pasif hedeflemede nano-parçacık bazı malzemelerle kaplanırken, taşıyıcıyı
gizlemek için en bilinen malzeme polietilen glikoldür. Ayrıca, insan vücudunda birkaç
biyolojik engel vardır. Örneğin; beyinde kan beyin bariyeri, deri tabakalarının içinde stratum
corneum ve gözde kornea öncesi, dinamik ve statik oküler bariyerler vardır. Tüm ilaç
taşıyıcıları bu engelleri geçemez. Bu nedenle, bu engellerin ve taşıyıcının boyutu, toksisite ve
ilaç veya doku ile uyumsuzluk gibi diğer konuların üstesinden gelmek için nanoteknoloji ve
ilaç dağıtımı bir arada tutulur. Bu yüzden, ilacı mümkün olduğunca vücudun derinliklerine
iletmek için nano-taşıyıcılar kullanılır. Nano taşıyıcılar, boyutları 1 ile 100 nm arasında
değişen parçacıklardır. Bu nedenle, daha büyük malzemelere kıyasla insan vücudunda
serbestçe hareket edebilirler. Bazı taşıyıcılar her iki şekilde de kullanılır; normal ve nano
boyutlu. Lipozomlar ve dendrimerler bu kategoriye örnektir. Nano boyutlu ilaç dağıtım
sistemleri, normal boyutlu ilaç dağıtım sistemlerine kıyasla avantajlara ve daha geniş
uygulamalara sahiptir. Ayrıca, dikkatli tasarım ve mühendislik gerektiren çok bileşenli üç
boyutlu yapılar olarak daha yüksek maliyetler ve karmaşık nanoparçacık formu gibi
dezavantajlara sahiptirler. Buna ek olarak, ilaç dağıtımını gerçekleştirmek için çeşitli bilim
dallarının bir araya gelmesi gerekir. Biyoloji, kimya ve tıp başlıcalarıdır. Mühendislik
açısından ilaç dağıtımı bu alanlara uygun olarak yapılmalı, ilaç dağıtımının maliyeti ve hasta
uyumu da dikkate alınmalıdır.
 vi

TABLE OF CONTENT

ACKNOWLEDGEMENTS.......................................................................................................iii

ABSTRACT...............................................................................................................................iv

ÖZET..........................................................................................................................................v

TABLE OF CONTENT.............................................................................................................vi

LIST OF FIGURES.................................................................................................................viii

LIST OF TABLES......................................................................................................................x

LIST OF SYMBOLS/ABBREVIATIONS................................................................................xi

1. INTRODUCTION...............................................................................................................1

2. THEORETICAL BACKGROUND....................................................................................3

2.1. DRUG DELIVERY SYSTEMS......................................................................................3

2.1.1. Routes of Delivery....................................................................................................4

2.1.1.1. Oral Drug Delivery.................................................................................................5

2.1.1.2. Pulmonary Drug Delivery......................................................................................6

2.1.1.3. Transdermal Drug Delivery....................................................................................8

2.1.1.4. Injectable Drug Delivery.....................................................................................10

2.1.1.5. Ocular Drug Delivery...........................................................................................12

2.1.2. Delivery Vehicles...................................................................................................13

2.1.2.1. Vesicles.................................................................................................................14

2.1.2.2. Erythrocytes..........................................................................................................18

2.1.2.3. Dendrimers...........................................................................................................20

2.1.2.4. Hydrogels&Aerogels............................................................................................22

2.1.3. Cargo...........................................................................................................................22

2.1.4. Targeting Strategies.....................................................................................................24

 vii

2.1.4.1. Passive Targeting..................................................................................................25

2.1.4.2. Active Targeting...................................................................................................25

2.2.NANO-SIZED DRUG DELIVERY SYSTEMS................................................................27

2.2.1. Organic Nano-sized Carriers.......................................................................................28

2.2.1.1. Solid Lipid Nanocarrier........................................................................................28

2.2.1.2. Nanoliposome.......................................................................................................30

2.2.1.3. Polymeric Micelles...............................................................................................33

2.2.1.4. Nano-Dendrimers.................................................................................................35

2.2.2. Inorganic Nano-sized Carriers....................................................................................37

2.2.2.1. Carbon Nanotube..................................................................................................37

2.2.2.2. Gold Nanoparticles...............................................................................................38

2.2.2.3. Mesoporous Silica Nanoparticles.........................................................................40

2.2.2.4. Magnetic Nano-carrier..........................................................................................42

2.2.2.5. Quantum Dots.......................................................................................................44

2.3.APPLICATIONS OF NANOPARTICLE TECHNOLOGY..............................................46

2.3.1. Cancer Therapy..........................................................................................................46

2.3.2. Drug Targeting to the Brain.......................................................................................48

2.3.3. Diagnostic Testing.......................................................................................................48

2.3.4. HIV and AIDS Treatment...........................................................................................49

2.3.5. Nutraceutical Delivery................................................................................................50

2.4. NOVEL DRUG DELIVERY.............................................................................................51

2.5. NANO-DRUG DELIVERY FROM THE ENGINEERING PERSPECTIVE..................52

2.6. ADVANTAGES AND DISADVANTAGES OF NANO-SIZED DRUG DELIVERY /

OBSTACLES............................................................................................................................54

2.7. FUTURE PERSPECTIVES...............................................................................................56

3. CONCLUSION.....................................................................................................................58

REFERENCES.........................................................................................................................60
viii
 viii

LIST OF FIGURES

Figure 2.1. Summary of Typical Drug Delivery Routes .......................................................4

Figure 2.2. Upper and Lower Respiratory Tract ...................................................................6

Figure 2.3. Vials of the HIV Treatment Cabenuva .............................................................11

Figure 2.4. Structure of the Eye ..........................................................................................12

Figure 2.5. Self-assembled PL Bilayer Structure of Liposome ..........................................15

Figure 2.6.Liposome Structures ..........................................................................................16

Figure 2.7. Structure of Niosome ........................................................................................17

Figure 2.8. The Parts Where the Drugs are Kept in the Niosomes .....................................18

Figure 2.9. Structure of Erythrocytes ..................................................................................20

Figure 2.10. Structure of Dendrimer ...................................................................................21

Figure 2.11. Usage of Targeting Ligands as Active Targeting in Cancer Treatment .........26

Figure 2.12. Structure of Solid Lipid Nanoparticle .............................................................30

Figure 2.13. Nano-Liposome Included Moisturizing Day Cream ......................................31

Figure 2.14. Micelle Structures ...........................................................................................33

 ix

Figure 2.15. Mechanism of Micelle Formation from Different Types of Amphiphilic Co-
polymers ..............................................................................................................................34

Figure 2.16. Structure of Dendrimers .................................................................................35

Figure 2.17. Structure of Single-Walled and Multi-Walled Carbon Nanotube ..................37

Figure 2.18. Synthesis of Gold Nanoparticles According to the Method of Burst and
Schiffrin ...............................................................................................................................39

Figure 2.19. Several Pore Geometrics of Mesoporous Structure ........................................40

Figure 2.20. Iron Oxide Formation with Using Chemical Co-Precipitation Method .........42

Figure 2.21. The Entering of Magnetic Nano-carrier to the Diseased Cell ........................44

Figure 2.22. Structure of a Quantum Dot ............................................................................45

 x

LIST OF TABLES

Table 2.1. Transdermal Drugs Approved by the U.S FDA ...................................................9

Table 2.1. Transdermal Drugs Approved by the U.S FDA .................................................10

Table 2.2. SLNs formulations Reported by Different Researchers ....................................29

Table 2.3. Advantages and Disadvantages of Liposomes & Nano-liposomes ...................32

Table 2.4. Usage of Dendrimers for Cancer diagnosis .......................................................36

Table 2.5. Various Type of MSNs with Internal Structure and Pore Diameter ..................41

Table 2.6. Some of the Marketed Novel Drug Delivery Systems .......................................52

Table 2.7. Nano-pharmaceutical Design .............................................................................55

Table 2.8. Preclinical Evaluation ........................................................................................55

Table 2.9. Clinical Evaluation for Commercialization .......................................................56

 xi

LIST OF SYMBOLS/ABBREVIATIONS

COPD Chronic Obstructive Pulmonary Disease

MDI Metered Dose Inhalers

DPI Dry Powder Inhalers

IM Intramuscular

SC Subcutaneous
GI Gastrointestinal
SLNs Solid-Lipid Nanoparticles
FDA Food and Drug Administration
HIV Human Immunodeficiency Virus

AMD Age-related Macular Degeneration

PL Phospholipids
PEG Polyethylene Glycol
AIDS Acquired Immune Deficiency Syndrome
RES Reticuloendothelial System
PAMAM Polyamidoamine
ATC Anatomical Therapeutic Chemical
Classification
WHO World Health Organization
NIBIB National Institute of Biomedical Imaging
and Bioengineering
PEGylation Coating the Particle with Polyethylene
Glycol
BBB Blood Brain Barrier
PPI Poly Propylene Imine
CNTs Carbon Nanotubes
 xii

SWNT Single-Walled Nanotube

MWNT Multi-Walled Carbon Nanotube
GNPs Gold Nanoparticles
PSA Prostate-specific Antigen
MSNs Mesoporous Silica Nanoparticles
MCM Mobile Crystalline Material
SBA Santa Barbara Amorphous
MNPs Magnetic nanoparticles
(Fe3O4) Iron Oxide
MRI Magnetic Resonance Imaging
DOX Doxorubicin
TGA Thermogravimetric Analysis
SEM Scanning Electron Microscope
QDots Quantum Dots
ADME Absorption, Distribution, Metabolism
and Elimination
LDL Low Density Lipoprotein
PLGA Poly Lactic-Co-Glycolic Acid
hGH Human Growth Hormone
P.L.E.A.S.E Precise Laser Epidermal System
 1

1. INTRODUCTION

Over the years, drug delivery systems have been used and developed for the
treatment applications of various diseases. One of the main problems in pharmaceutical
and biotechnological fields is to deliver the drug to the structure where it will act.
Therefore, drug delivery systems have always been the focus of attention of researchers. In
addition, drug delivery systems have been divided into four main topics to overcome the
problems such as drug dosage form and release, low biocompatibility, toxicity and
solubility, and have provided great advantages in various ways. These four main topics
consist of routes of delivery, delivery vehicles, cargo and the strategies of targeting.

Drugs are taken into the body in different routes. The first of these is oral drug
delivery. Drugs which are made into tablets and capsules are taken orally into the body by
controlled release and sustained release systems. Both have various disadvantages and
advantages, but controlled release is mostly preferred because the release time and rate of
the drug can be adjusted. The second route is the pulmonary drug system. In respiratory
diseases such as COPD and asthma, drug delivery is provided by using devices such as
nebulizers, metered dose inhalers (MDI) and dry powder inhalers (DPI).The pulmonary
drug delivery system provides rapid absorption and retention of highly concentrated drugs
in the target area, but this system has disadvantages such as toxicity and addiction. The
third route is the introduction of drugs into the systemic tissue through the skin, that is,
transdermal delivery. Since the skin is a multi-layered layer, very little drug enters the
blood. Therefore, methods such as micro-needles and electroporation have been developed,
but they also have the potential to cause skin irritation. The fourth route is injectable drug
delivery. Intramuscular (IM) and subcutaneous (SC) injections ensure ease of
administration and patient compliance, while irritation or shell binding problems may
occur in the applied area. The last route is ocular drug delivery. They can be applied to the
eye with topical liquid or solution eye drops or ointments. In addition, nanotechnology-
based ocular drug delivery systems can be designed.

The drugs are of low bioavailability and can be chemically degraded. For this reason,
carriers that provide safe delivery by protecting medicines have been developed. These
 2

carriers are vesicles, nano drug delivery systems, dendrimers, hydrogels and aerogels.
Liposome, niosome and erythrocytes are the carriers in the vesicles title. Nano-carriers are
divided into organic and inorganic. Organic carriers are solid lipid nano-carriers, nano-
liposomes, dendrimer and polymeric micelles. Carbon nanotubes, gold nanoparticles,
mesoporous silica nanoparticles, quantum dots and magnetic nano-carriers are inorganic
nano-carriers.

On the other hand, targeted delivery of drugs is a very important factor for increasing
the effectiveness of the active substance and reducing its side effects. In various diseases,
such as cancer, the drug must reach the diseased area. This is very difficult without drug
targeting. On the contrary, it makes this reach possible with active and passive targeting
realized by Nanoparticles.

Nano-sized drug delivery systems have been investigated in this project. The aim of
this study is to investigate how nano-sized drug delivery occurs, advantages and
disadvantages, applications in various fields, engineering perspective on the subject and
future perspectives.

This thesis begins with a theoretical background that which includes drug delivery
systems, delivery vehicles, cargo, targeting strategies, nano-sized drug delivery systems,
applications of nanoparticle technology, novel drug delivery, engineering perspective,
advantage and disadvantage of nano-sized drug delivery and future perspective. In the drug
delivery systems part, routes of delivery, oral, pulmonary, transdermal, injectable and oral
drug delivery were described. In the delivery vehicles part, vesicles, dendrimers, hydrogels
& aerogels were described. In the targeting strategies part, active and passive targeting
were mentioned. In the nano sized drug delivery part, organic and inorganic carriers were
described.
 3

2. THEORETICAL BACKGROUND

2.1. DRUG DELIVERY SYSTEMS

Healthy cells in living organisms have the ability to divide in a controlled way.
Along with the ability to divide, it is possible to repair injured tissues. These properly
functioning systems can be disrupted, meaning that the structure can be degrade under the
influence of any disease. Drugs are used to eliminate this degradation. They are distributed
through the blood to the organism and interact with various tissue cells. They cause a
certain change in function. This is called "pharmacological effect". [1]

Functions in cells occur as a result of various biochemical reactions. The factors that
carry out these biochemical reactions are enzymes. Interacting with tissue cells, the drug
shows its effect either on the cell membrane or by entering into the cell. There are parts in
the cell membrane or inside the cell called "receptors". Receptors are proteins that
recognize drug molecules and bind to drug molecules. [2] Drugs that bind to receptors in
the cell membrane show their effects faster because they reach here faster, and those that
bind to receptors in the cell act later. [3]

In order for all these steps to take place, firstly the drug must be delivered. Drug
delivery systems are used to create pharmacological effects as mentioned earlier. In other
words, drug delivery is the pharmaceutical technique and processes which are applied to
achieve the therapeutic effect in living organisms [4]. Additionally, drug delivery is
performed to overcome problems such as drug collection, low bioavailability and
solubility. [5]

Drug delivery takes place through many routes of administration. Frequent and
repeated dosing is generally available in these ways. Also, undesirable situations may be
encountered when the dose used to concentrate the active substance released into the cell
falls below the required amount or exceeds the toxic level. In order to prevent such
situations, it is possible with drug delivery systems that reduce the dosage form of the
 4

active substance, extend the dose interval, eliminate side and toxic effects and deliver the
active substance to the target area.

Drug Delivery Systems are trying to control drug’s rate, releasing time and the
location in the body. Some drug delivery systems can control all of them. Thus, it can be
said that drug delivery mainly got affected by dosage form and routes of administration.
Drug delivery can be categorized into four topics; routes of delivery, delivery vehicles,
cargo and the strategies of targeting [6]

2.1.1. Routes of Delivery

Medications can be taken in body in several ways as shown in figure 2.1. Some of
them are oral, pulmonary, transdermal, injectable and ocular. [7]

Figure 2.1. Summary of Typical Drug Delivery Routes [7]

2.1.1.1. Oral Drug Delivery

 5

Oral medications are produced to be absorbed in the stomach and small intestine.
Therefore, therapeutic agents (drugs) are given at higher doses than drugs given by all
routes outside the digestive system. Because oral medications are broken down by the liver
before reaching the effective dose in the circulation. [8] Drugs are transported orally by
being formed into tablets or placed in capsules and oral medications are delivered to the
diseased area through various oral delivery systems. These systems are Sustained and
Controllable drug delivery.[9]

The sustained drug delivery system is designed to continuously release into the
diseased area without changing the drug level over a period of time. It is also designed to
minimize the side effects of the drug and to reduce the amount of dosing. Mechanisms
such as dissolution and diffusion are used to ensure slow release into the gastrointestinal
(GI) system. In this way, a desired drug release is achieved [10]. On the other hand, the
taste of the medications can be irritating. They may cause stomach irritation and may
undergo drug elimination processes in the first pass both in the intestine and the liver. In
addition, the physiological environment in the gastrointestinal system may affect the
stability and solubility of drugs [11]. Another disadvantage is that it is usually dosed at
least once or twice a day, although the aim is to reduce dosing. Consequently, the
possibility of missed dose should also be taken into account. [12].

Another oral drug release system is the controllable drug delivery system. The main
purpose of the Controlled Release System is to release the drug at predetermined rates and
at specific time intervals. The biggest advantages of controlled release systems are the
ability to adjust the released time and speed [13]. The drug is placed in a carrier and this
releases it. Since the plasma level of the drug is precise, it remains constant within the
specified time. Since it does not require continuous application, the drug level in the blood
does not increase. It is the biggest feature that distinguishes it from the sustained drug
delivery system [14]. Another feature that separates the control system from continuous
oscillationis that it reduces the side effects of the gastrointestinal system. In this way, it
provides great convenience to patients.

2.1.1.2. Pulmonary Drug Delivery

 6

In order to perform pulmonary drug administration, it is necessary to look at the

complex structure of the human respiratory system. As shown in Figure 2.2, the respiratory
system is divided into upper and lower airways. In the upper respiratory tract, some
particles of the drug are filtered in this area. It also has a low surface area with little blood
flow. Other inhaled substances that pass through the filter begin to accumulate as a layer of
mucus around the conductive airways. In subsequent steps, unwanted substances are
removed from the body by cells. The lower respiratory region consists of small airways
and alveoli. In addition to this, the lower respiratory region is connected to the pulmonary
circulation path, although it constitutes a large part of the lung surface area [15].

Figure 2.2. Upper and Lower Respiratory Tract [16]

The purpose of pulmonary drug delivery is to accumulate the active substance in the
lower respiratory tract. With the pulmonary system, the drug can be given by oral and
intranasal method. Intranasal has a smaller airways. In addition, they have a small surface
area and less blood flow in that area. It has been determined that orally administered drugs
cause less concentration loss when compared to the intranasal route. Oral inhalation takes
place in two ways. The first one is intratracheal instillation. In this method, medicine is
administered into the lungs with the help of a syringe. This method is a localized method
and is fast, measurable and cost-effective. However, it is not a physiological method. The
other method is the intratracheal inhalation method. With this method, the uniform
 7

distribution of the drug is observed and the aerosol technique is used. However, it cannot
measure the exact dose in the lung and it is a costly method. [15]

In the pulmonary drug transport system, the drug is given to the patient with devices
such as nebulizers, MDI and DPI. MDI involves curing as a solution or a suspension held
under high pressure. Nebulizers can produce a large number of droplets that can penetrate
the lungs without requiring propulsion [15]. DPI is the most popular and widely used
method. It transfers the drug to the lungs as in dry powder form. The patient takes the
medicine manually in a capsule or from the inhaler itself. When taking a deep breath, the
drug is delivered to the targeted area. COPD and asthma are examples of lung diseases.
[15]

One of the advantages of pulmonary drug delivery is rapid absorption and retention
of high concentration drugs at the target site. This absorption and retention is made with
the help of the large inner surface area of the lung and the thin epithelial layer covering the
airways. Also, protein-containing solutions can be nebulized and there is greater protection
against oxygen and moisture and drug degradation, so stability is increased for unstable
substances. In addition, the bioavailability of the drugs is much higher in this way. [17]

The disadvantage of the pulmonary drug delivery system is that the patient may have
difficulty in regulating the dose. For this reason, treatment may fail if regular doses are not
taken. Other disadvantages of this system are: drug irritation and toxicity, the drug can
quickly enter the brain and cause drug addiction, and some patients may have difficulty
using an inhaler. [17]

Asthma is a long-term lung disease caused by inflammation and narrowing of the

respiratory tract. Symptoms of asthma include recurrent wheezing, chest tightness,
shortness of breath and coughing. Asthma affects people of all ages, but most often begins
in childhood. In the United States, more than 22 million people are known to have asthma.
About 6 million of these people are children. Children born prematurely are likely to have
asthma. In recent studies, it has been observed that a nebulizer device is mostly used to
improve the patient's inhalation coordination. Using the nebulizer device, a child under 2
years of age can easily be given medication. On the other hand, pulmonary drug systems
 8

can be used for migraines. Ergotamine is a drug that is effective for migraines. Ergotamine
with a metered dose inhaler has been successfully used to treat migraine headaches. [18]

2.1.1.3. Transdermal Drug Delivery

Transdermal Drug delivery is another route for delivering the drug. In this route, the
main objective is to deliver drugs into systemic circulation through the skin at
predetermined rate. The medication initially penetrates through the special layer ‘stratum
corneum’, when applied on the skin and then passes through the deeper epidermis and
dermis. After the drug reaches the dermal layer, it becomes available for systemic
absorption via the dermal microcirculation. [19]

Delivering the drug through the skin offers controlled release of medication. Hence,
it minimizes harmful side effects of a drug caused from temporary overdose and improves
dosage efficacy by enabling steadier blood drug profiles. However, the extensive
applications of transdermal drug delivery are limited by the excellent barrier function of
the skin, the stratum corneum, which is a multilayer organ to prevent the invasion of
external molecules. Only a few drugs can passively penetrate through the skin to reach an
effective concentration in the blood. Usually these drugs are expected to be highly efficient
and have a low molecular mass. During the past two decades, wide range of physical and
chemical techniques have been used to penetrate the drugs, such as; micro needles,
electron beam irradiation and electroporation. Unfortunately, most of the methods may
suffer from a risk of skin irritation, which would decrease patient compliance. Recently,
due to the unique physicochemical properties, nanoparticles have been introduced into a
wide array of biomedical devices as the nanocarriers of drugs. A nanoparticle is a small
particle that ranges between 1 to 1000 nanometers in size. In the case of transdermal drug
delivery, nanoparticles could significantly improve the penetration of drugs across the
stratum corneum, with the potential to reduce immunogenicity and advance bioavailability.
The most common nanoparticles used for transdermal drug delivery are liposomes, solid-
lipid nanoparticles (SLNs), polymeric micelles and inorganic nanoparticles. [20]

Transdermal delivery products are present in people’s lives for thousands of years.
People have placed substances on the skin to obtain therapeutic effects, and in the modern
 9

era, a variety of topical formulations have been developed to treat local indications. The
first transdermal system for systemic delivery was a three-day patch that delivers
scopolamine to treat motion sickness. It was approved for use in the United States by the
US Food and Drug Administration (FDA). A decade later, nicotine patches became the
first transdermal blockbuster, raising the profile of transdermal delivery in medicine and
also in public. Today, there are versatile transdermal delivery systems approved by FDA.
Some of them are shown on the Table 2.1 [21]

Table 2.1. Transdermal Drugs Approved by the U.S FDA [21]

Approval Drug Indication Product Marketing

Year Name Company
1979 Scopolamine Motion Transderm- Novartis,
Sickness Scop Consumer
Health
1984 Clonidine Hypertension Catapres- Boehringer
TTS Ingelheim
1986 Estradiol Menopausal Estraderm Novartis
Symptoms
1990 Fentanyl Chronic pain Duragesic Jannsen
Pharmaceutica
1991 Nicotine Smoking Nicoderm, GlaxoSmithKlin
Cessation Habitrol, e , Novartis
ProStep Consumer
Health
1993 Testosterone Testosterone Testoderm Alza, Mountain
Deficiency View
1995 Lidocaine/ Local Dermal Iontocaine Iomed
Epinephrine Analgesia
1998 Estradiol/ Menopausal Combipatch Novartis
Norethidrone Symptoms
1999 Lidocaine Post-Herpetic Lidoderm Endo
Neuralgia Pharmaceuticals
 10

Pain
Table 2.2. Transdermal Drugs Approved by the U.S FDA [21]
(Continued)

Approval Drug Indication Product Marketing

Year Name Company
2003 Oxybutynin Overactive Oxytrol Watson Pharma
Bladder
2004 Lidocaine Local Dermal SonoPrep Echo
(Ultrasound) Anesthesia Therapeutics
2005 Lidocaine/ tetracaine Local Dermal Synera Endo
Analgesia Pharmaceuticals
2006 Fentanyl HCL Acute Ionsys Alza, Mountain
Postoperative View
Pain
2006 Methylhenidate Attention Daytrana Shire
Deficit
Hyperactivity
Disorder
2006 Selegine Major Emsam Bristol-Myers
Depressive Squibb
Disorder
2007 Rotiogotine Parkinson’s Neupro Schwarz Pharma
Disease
2007 Rivastigmine Dementia Exelon Novartis

2.1.1.4. Injectable Drug Delivery

Injections are the most common drug delivery systems due to their ability at
releasing drugs longer than one week. In other words, they offer a controlled drug-delivery.
Generally, injections are administrated by two routes; intramuscular (IM) and
subcutaneous (SC). In IM, drug moves through the muscles and in subcutaneous, drug goes
to the sub layers of the skin. In order to determine the route of administration for long-term
 11

delivery, several factors should be considered, such as; safety profile, patient’s limited
mobility, area for target injection sites, quality of life and cost of the therapy. SC delivery
is the preferred route in many cases because it offers better safety profile, greater area for
target injection sites and use of shorter needles. Versatile insulin products are given
subcutaneously. However, the volume of SC injection is usually changes between 1 and 2
mL, thus, only nonirritant substances can be injected by this route. Irritant substances can
cause pain, necrosis and sloughing at the site of injection. On the other hand, intramuscular
delivery provides greater injection volumes (2-5 mL). By IM route; mild irritants, oils and
suspensions can be injected in the large skeletal muscles such as deltoid, triceps and rectus
femoris. These muscles are considered as poor at sensory nerves and are more vascular.
[22]

Long-acting injectable formulations offer many advantages. They are; a predictable

drug-release profile during a defined period of time following each injection, better patient
compliance, ease of application, reduced dosing frequency and overall cost reduction of
medical care. [23]

Recent approved injectable by FDA is Cabenuva (cabotegravir and rilpivirine) for

the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults which
is shown in Figure 2.3. Cabenuva approved in January 21, 2021. This is the first FDA-
approved injectable for HIV-infected adults that is administered once a month. Other
medications in this disease are taken in every day basis by patients. This drug is considered
as milestone in HIV treatment. [24]
 12

Figure 2.3. Vials of the HIV Treatment Cabenuva [25]

2.1.1.5. Ocular Drug Delivery

The eye is a complex organ with a unique anatomy and physiology. The structure of
the eye can be separated into two parts; anterior segment and posterior segment, which are
shown in Figure 2.4. Eye is occupied by anterior and posterior segments with 1:2 ratio
respectively. Cornea, conjunctiva, aqueous humor, iris, ciliary body and lens are the tissues
which composed the anterior portion. Posterior segment or back of the eye includes sclera,
choroid, retinal pigment epithelium, neural retina, optic nerve and vitreous humor. Anterior
and posterior segments are affected by various vision threating diseases. For instance;
glaucoma and cataract occurs in the anterior part. Whereas, age-related macular
degeneration (AMD) and diabetic retinopathy are the most prevalent diseases affecting the
posterior segment. [26]
 13

Figure 2.4. Structure of the Eye [26]

Especially for the treatment of anterior segment diseases, eye drops are the most
convenient and patient compliant route of drug administration. 90% of the marketed
ophthalmic formulations are accounted by conventional solutions such as eye drops.
Topical liquid or solution eye drops, emulsions, suspensions and ointments are the contents
of conventional ocular drug delivery. Besides, nanotechnology based ocular drug delivery
systems are currently being pursued for both anterior and posterior segment. Their particle
size can be designed to ensure low irritation, adequate bioavailability and ocular tissue
compatibility. Several nano-carriers have been developed for ocular drug delivery such as
liposomes, nanomicelles, and nanospheres.

One of the challenges in the ocular drug delivery is; pre-corneal, dynamic and static
ocular barriers restrict the delivery of the drug to the targeted ocular tissues. Also,
therapeutic drug levels are not maintained for longer duration in these tissues. Thus, the
ocular bioavailability is very low with topical drug administration. Because of the barriers
and numerous anatomical and physiological constraints such as reflex blinking, less than
5% of topically applied dose reaches to deeper ocular tissues. [26]

In the past two decades, ocular drug delivery research accelerated in order to develop
a novel, safe and patient compliant formulation which may surpass the barriers and
 14

maintain drug levels. For anterior segment, conventional solutions have been modulated
with permeation and viscosity enhancers. Versatile nano-formulations have also been
introduced for anterior segment drug delivery which were mentioned above. On the other
hand, for posterior ocular drug delivery, research has been focused towards development of
drug releasing devices and nano-formulations for treating chronic vitreoretinal disease.
These novel devices and formulations may help to surpass ocular barriers and associated
side effects with conventional techniques. Also, they are easy to formulate, negligibly
irritating, possess high pre-corneal residence time, and can enhance ocular bioavailability
of therapeutics. [26]

2.1.2. Delivery Vehicles

Drug molecules with low bioavailability require protection against enzymatic and
acid catalyzed degradation and safe transport to the target site. Thus, drug carriers were
developed to increase bioavailability and to defend against degradation. Especially drug
carriers are produced to control the circulatory system in the body. An ideal drug carrier
should deliver the active substance to the target site and release the drug at an appropriate
rate. At the same time, the carrier should not be toxic and have the ability to degrade and
accumulate in tissues. Drug carriers are colloidal delivery vehicles in micron or nano size.
This system improves therapeutic efficacy and reduces the amount of drug administered. In
this way, it minimizes the toxic effect.

There are lots of drug carriers. Some of them are; Nano Drug Delivery Systems,
Vesicles, Erytrosyte, Dendrimers, Hydrogels and Aerogels. Nano Drug Delivery Systems
will be handled in further parts. In addition, some of the drug carriers which were
discussed in this part, will be discussed again in nano-sized carriers. [27]

2.1.2.1. Vesicles

The vesicular drug delivery system is a concentric double-layer structure that occurs
as a result of the combination of amphiphilic molecules in the presence of water. Vesicular
drug delivery systems have the ability to localize the activity of the drug in its domain of
 15

action. In this way, it reduces the concentration of the remaining areas of the body. Some
of the vesicular systems are Liposome and Niosome [28]

Liposomes are microscopically sized semi-solid vesicles made up of a double lipid

layer, similar to a biological membrane, as shown in Figure (2.5). The basic structure of
liposomes is phospholipids (PL). PL are amphiphilic in structure and the molecule has a
hydrophilic head and a hydrophobic hydrocarbon chain. When PL are added to water, they
form PL bilayers so that their hydrophilic parts rotate to water and the hydrophobic parts to
each other. When the amount of water is increased, these double layers form spherical
structures to reduce their surface as a result of the tendency to escape from the water. Fat-
soluble drugs are carried in the PL layers of liposomes, while water-soluble drugs are
carried in the aqueous compartments of liposomes. [29]

Figure 2.5. Self-assembled PL Bilayer Structure of Liposome [30]

The most important factors determining effectiveness in liposome use are its content,
size, drug loading efficiency and biological interaction with cells. The most common of
these forms of interaction is either adsorption or endocytosis. Also, liposomes are
biodegradable, have limited toxicity and prolonged drug release. As a disadvantage, the
permeability of the liposome membrane may cause leakage of the encapsulated drug. In
addition, having a phospholipid structure leads to chemical degradation. Ester bonds that
bind fatty acids to glycerol can be hydrolyzed in the structure of liposomes. These two
disadvantages, on the other hand, bring up the problem of stability. [31]
 16

Liposomal surfaces have the ability to carry molecules with different properties. The
biggest problem with liposome use is the rapid release of the drug into the medium, which
is encapsulated in the carrier as a result of their lack of stability in biological fluids. After
liposomes were given to the body, they were perceived by the body as foreign substances,
and as a result, they were tried to clear the phagocytic system from the bloodstream. This
problem has been resolved as a result of various studies. Liposomes containing
polyethylene glycol (PEG) and variants were the solution. In other words, PEG coated
liposomes and their types have been used. It has been observed that the development of
small, hard and cholesterol-rich liposome vesicles that can resist the phagocytic system
increases the durability of liposomes in plasma. [32]

As shown in Figure 2.6., in order to direct liposomes to a specific target, ligands that
can recognize specific molecules can bind to appropriate sites of these vesicular structures.

Figure 2.6.Liposome Structures [33]

Liposomes, nanoparticles or micro-emulsions can be used as drug carriers according

to the systems of drug delivery vehicles. Additionally, depending on the use and purpose of
liposomes; in the form of suspension, aerosol, gel, cream or dry powder can be prepared.

As an example of liposome in drug delivery field, Liposomal doxorubicin, traditional

name Doxil, is a type of drug used in Kaposi's sarcoma disease. Kaposi's sarcoma is a type
of virus associated with Acquired Immune Deficiency Syndrome(AIDS). Doxil is one of
 17

the most commonly used drugs in the treatment of solid tumors. This drug has also shown
a positive result in breast cancer and ovarian cancer. The drug is encapsulated in PEG-
coated liposomes and delivered into the body via chemotherapy. The principle of the drug
works by blocking an enzyme called topo isomerase 2, which cancer cells need to divide
and grow. It provides better delivery to the disease site and results in a decrease in the
systemic toxicity of the free drug. It also affects more cancer cells as it stays in the
bloodstream for a long time. [34]

Another vesicle is niosome, also known as Non-Ionic Surfactant Vesicles, have been
developed as an alternative carrier to liposomes. Niosomes are structures formed by non-
ionic surfactants and cholesterol in an aqueous environment. The spontaneous combination
of non-ionic surfactants in an aqueous environment causes two-layered structures as shown
in the Figure (2.7). Niosomes are divided into small single-layer vesicles (10-100 nm),
large single-layer vesicles (100-3000 nm), and multi-layer vesicles according to their
double layer and size. [35]

Figure 2.7. Structure of Niosome [35]

Non-ionic surfactants are generally saturated surfactants. In addition, they have

amphiphilic properties like liposomes. Therefore, they provide a wide solubility spectrum
for drug active ingredients and it provides the opportunity to contain hydrophilic and
lipophilic, in other words, fat-soluble drugs. These drugs are held in the aqueous core and
membrane bilayer of the niosome. In Figure 2.8, the parts where the drugs are kept in the
 18

niosome are shown. [35] Niosomes are much more stable because their forming materials,
non-ionic surfactants, are more stable than those of lipids both in terms of physical and
chemical stability [35]

Figure 2.8. The Parts Where the Drugs are Kept in the Niosomes [35]
(The targeted delivery indicates that niosome surfaces can be combined with
molecular or macromolecular targeting ligands. Proteins and peptides, carbohydrates,
which are the most common, can bind specifically to a target on the cell surface.) [36]

The most important advantages of niosomes are that, they are biodegradable and not
immunogenic. In addition, they exhibit high stability and allow controlled or continuous
delivery of the drug to the target area. The aqueous suspension of the niosome may show
fusion, aggregation, leaching, or hydrolysis of the drug contained in the carrier. In other
words, it shortens the shelf life of the drug. [35]

2.1.2.2. Erythrocytes
 19

Erythrocytes are seen as suitable carriers for loading drugs, enzymes, and some
molecules with therapeutic activity. Erythrocytes are 7.8 µm in diameter, disc-shaped and
have a concave structure on both surfacesas shown in the Figure (2.9). Due to this special
structure, the membrane of erythrocytes can swell without much tension and can carry
plenty of oxygen and carbon dioxide. Also, they have a suitable flexibility to pass through
capillaries. [37]

Under low oxygen pressure, kidneys and liver release erythropoietin in glycoprotein
structure. Erythropoietin first passes into the blood and then into the bone marrow, where
erythrocyte production occurs. Erythropoietin is a glycoprotein hormone consisting of
sugar and amino acids and allows cells to communicate with each other. Since this cell
does not have a nucleus, they cannot synthesize protein.

The aim of the erythrocyte is to deliver the carbon dioxide produced in the tissues to
the lungs while delivering oxygen through the lungs to the tissues. In addition, the active
substance is loaded into erythrocytes. They live about 100-200 days after entering the
bloodstream of erythrocytes. [38]

The erythrocyte membrane is a special membrane containing lipids, proteins and

carbohydrates. Important in loading drugs into erythrocytes is the preservation of
erythrocyte content and membrane structure. The ability of erythrocytes to deform allows
them to easily pass through capillary vessels. When the membrane structure is disrupted
and this property is lost, the cells are removed from circulation by the reticuloendothelial
system (RES) [39]. Drug loading of erythrocytes occurs by various ways such as
Hypoosmotic lysis, isotonic osmotic lysis, osmosis-based methods. When erythrocytes are
diluted in a hypotonic environment containing an active substance or in water, the holes
formed in their membranes cause some cell elements in the erythrocyte to leave the cell,
the active substance to enter the erythrocyte, and a balance to be established within a few
minutes. The biggest disadvantage of this method is that hemoglobin output can be
observed from pores with a diameter of 20-50 nm or from many parts of the membrane.
[40]
 20

Figure 2.9. Structure of Erythrocytes [41]

The disadvantages of erythrocytes are that some encapsulated active ingredients may
leak from loaded erythrocytes and drug storage problems may occur. [40]Erythrocytes
have been developed to carry a variety of therapeutic agents, including proteins, nucleic
acids, and small molecule drugs, and some of these have entered the clinical trial stage and
are used to treat a variety of diseases such as cancer-targeted or intestinal problems.

Dexamethasone is a drug used in ulcerative colitis. Ulcerative colitis is a disease that

causes long-lasting sores (ulcers) in the innermost lining of your large intestine (colon) and
rectum. A study conducted in June 2005 attempted to treat 10 people with ulcerative colitis
by loading the drug dexamethasone on erythrocytes. As a result, after an average of 1year
follow-up, loading of dexamethasone drug in erythrocytes is feasible and safe. The very
low dose of medication released in the bloodstream provided the treatment of the disease.
[42]

2.1.2.3. Dendrimers

Dendrimers can be defined as branched and globular macromolecules which

encapsulates individual and small drug molecules. These macromolecules can be used as
centers for the transportation and the protection of loaded drugs which are linked to the
branches by the covalent bonds. In these system, the drug is encapsulated in the inner
branches of the dendrimer or attached at the external ends of the branches. Also, more than
one single drug can be transported via dendrimers and hindered by different empty sections
which are created by branches. Another significant feature of dendrimers is that they can
 21

provide a modification of the environment for guest molecules. In other words, they can
change properties such as solubility. Their shapes can be hexagonal or cubic as shown in
Figure 2.10. [43]

Figure 2.10. Structure of Dendrimer [44]

Dendrimer offer numerous benefits. The flexibility in the structure, makes them
perfect drug transporters. By adding of stimuli response properties to the dendrimers, make
them release the drug in response of some specific triggers. Triggers can be internal from
the tumor environment like acid, enzyme and redox potentials; or they can be induced from
the external such as light and temperature. Wide variety of dendrimers used is the
polyamidoamine (PAMAM) dendrimers which are proper for numerous biological,
biotechnological, regenerative medicine and applications of tissue engineering. Also,
dendrimers hold a high density of functional surface molecules, thus, they are able to
conjugate with quite lot of targeting agents. These agents surround voids which are present
in the core for encapsulation of lipophilic macromolecule, and allow them to transport
highly hydrophobic drugs. [43]

According to another study, dendrimers are incorporate with gold nanoparticles. The
molecule is named as curcumin-loaded dendrimer-gold hybrid structures. This developed
structure used as effective antitumor therapy. [43]
 22

2.1.2.4. Hydrogels&Aerogels

Hydrogels are systems made of distilled water and smart polymers and act as
gelification agents. They are characterized by a network of hydrophilic polymers that can
hold large amounts of water, so they save the backbone of the structure. The essential point
about hydrogels is choosing a polymer that can form a three-dimensional network by
cross-linking its chains and can take advantage of weak forces, such as hydrogen bonds
and van der Waals forces. Hydrogels can protect loaded drugs from external environment,
such as the acidic pH of the stomach during oral administration. In addition, they can
modulate drug release by changing the kinetics. Similar to hydrogels, lipogels are
preparations based on vegetable or animal oils and they are used for gelification agents.
[45]

Aerogels are low-density solids with high porosity with the ability to protect their
structure after exchanging their liquid pores with gas. They are employed in several
biomedical applications, such as diagnostic agents and for the artificial reconstruction of
human tissues especially with the use of supercritical carbon dioxide for biocompatibility
in drug delivery applications. [45]

2.1.3. Cargo

The most obvious route to improve disease treatment would be to focus on the
medications themselves. The meaning of cargo is the substance that delivered, in other
words, drugs. In pharmacology, a drug is a chemical substance which produces a biological
effect when administered to a living organism. Drugs can be obtained from different
sources; plants (cannabis, mushrooms or tobacco), processed plant products (alcohol or
heroin) or synthetic chemicals (ecstasy or amphetamines). The content of drug products
can be divided into two; active ingredients or inactive ingredients. Active ingredients affect
the body biologically, whereas inactive ingredients generally have no biological effect.
They contain binding agents, capsules, dyes, flavorings and other ingredients. People take
drugs in different ways; swallowing, breathing, snorting, injecting, and through the skin.
[46]
 23

A pharmaceutical drug, also called a medication or medicine, is a chemical

compound used to treat, cure, prevent or diagnose a disease. For instance, aspirin is a very
common pharmaceutical drug which is generally used to treat pain, fever and
inflammation.90% of aspirin consists of acetylsalicylic acid, 10% is inert fillers and
binders. There are thousands of different drug classes and subclasses. In order to categorize
the pharmaceutical drugs, the most widely used system is The Anatomical Therapeutic
Chemical Classification System (ATC) which created by World Health Organization
(WHO). This system assigns drugs a unique ATC code, which is an alphanumeric code
that assigns it to specific drug within the ATC system. ATC focuses on active ingredients
and classifies them according to the organ or system on which they act and their
therapeutic, pharmacological and chemical properties. According to the system there are
five levels.

Level one: Describes the system that drug will be treated

Level two: Describes the drug’s therapeutic effect.
Level three: Describes the mechanism/ mode of action.
Level four: Describes the general chemical properties of the drug.
Level five: Describes the chemical components that make up the drug (essentially the
chemical name of the drug, such as ibuprofen) [47]

Other than pharmaceutical drugs, psychoactive drugs are chemical substances that
affect the function of the central nervous system. They can alter perception, mood or
consciousness. These drugs can be divided into several categories such as; stimulants,
depressants, antidepressants and hallucinogens. Psychoactive drugs have been proven
useful in wide range of medical conditions including mental disorders around the world.
The most commonly used drugs in the world include caffeine, nicotine and alcohol, which
are also considered as recreational drugs since they are used for pleasure rather than
medical purposes. Meaning of recreational drugs is the use of a drug with the primary
intention of altering the state of consciousness. All drugs can have several potential side
effects, abuse of several psychoactive drugs can cause psychological or physical addiction.
[48]
 24

Medications have been a solution to many life-threatening diseases. Choosing a drug

depending on the type of disease is the primary factor. Otherwise, worse results may occur
with the wrong medication.

2.1.4. Targeting Strategies

Targeted Drug Delivery is a method for delivering the drug to the patient in a
manner that increases the concentration of the medication in some parts of the body
compared to others. The aim of targeted drug delivery is to prolong, localize, target and
have a protected drug interaction solely with diseased tissue. In other words, targeted drug
delivery is believed to improve efficacy while reducing side-effects.

The traditional drug delivery systems such as oral intake, include the distribution of
the drug throughout the body by the systemic blood circulation. They are capable of
distribute the drug evenly within the body. In addition, they have to cross many biological
barriers to reach the site of the disease. Also drugs can be inactivated in organs and tissues
not even involved in the pathological process. For most therapeutic agents, only a small
portion of the drug reaches the organ or tissue to be affected. Thus, the goal of targeting
drug delivery has been largely accomplished by nano-medicine. Nano-medicine plans to
employ nanoparticles as drug delivery devices in order to fight with downfalls of
conventional drug delivery. [49] The concept of targeted pharmaceuticals includes a
coordinated behavior of some key components; the pharmaceutical agent itself
(immunoglobulins, monoclonal antibodies), the pharmaceutical carrier (soluble polymers,
microcapsules, micro-particles, cells ,micelles) and a potential target. The recognition of
the target can occur on different levels; target can be whole organ, or certain cells specific
for a given organ, or individual components of these cells, such as cell surface antigens.
The recognition on the molecular level is probably the most universal form of the targeting
idea because each organ or tissue is characterized by a unique set of chemical compounds.
[50]

The ability to concentration on diseased tissue by nanoparticles, is accomplished

through two ways; passive or active targeting.
 25

2.1.4.1. Passive Targeting

The drug’s success is directly related to circulation time in passive targeting. Process
includes cloaking the nanoparticle with some sort of coating. In other words, nanoparticle
is being disguised. Several substances can be used for coating, one of them is PEG. By
adding PEG to the surface of the nanoparticle, it becomes hydrophilic. Thus, water
molecules can bind to the oxygen molecules on PEG via hydrogen bonding. When this
bonding occurs, a film of hydration is produced around the nanoparticle which makes the
substance anti-phagocytic. Therefore, the drug-loaded nanoparticle is able to stay in
circulation for a longer period of time. [51]

2.1.4.2. Active Targeting

Active targeting of nanoparticles improves the effects of passive targeting to make

the particle more specific to the target site. There are several ways that active targeting can
be accomplished. One of them is,the nature of the receptor on the cell for which the drug
will be targeted to, must be known. Then, cells-specific ligands can be utilized, they will
allow the nanoparticle to bind specifically to the cell that has the complementary receptor
that is shown in Figure 2.12 .By this way, the drug conjugates to the nanoparticle to target
tumor cells, which possesses drug-receptor mediated endocytosis mechanisms on their
membrane. [51]

Furthermore, a nanoparticle has the capability to be activated by a trigger that is

specific to the target area, such as pH sensitivity. Most of the body has a stable, neutral pH.
Although, some areas of the body are more acidic than others, so, nanoparticles can take
advantage of this situation by releasing the drug when it meets a specific pH. Also redox
potential can be one of the triggers. Hypoxia is one of the side effects of tumors, it is a
condition that the body or a region starves for oxygen. It changes the redox potential
around the tumor. By modifying the redox potential that stimulates the payload release, the
medication can be selective to different types of tumors.

National Institute of Biomedical Imaging and Bioengineering (NIBIB) researchers

are studying a new system of drug delivery using the specific bacteria that has a two parted
 26

navigation system; magnetic and oxygen sensing. Scientists tested this bacteria method on
mice, and achieved important success about delivering the medicine to the tumors. The
bacteria look for low-oxygenated fields; which is specific feature of tumors. By using a
computer program, a magnetic field is created and directed the bacteria to the tumors. At
the end of the experiments, seen that the bacteria go into the oxygen starved tumors, far
away from healthy cells. Hence, it can be said that targeting is successful, healthy parts are
not touched by drugs. By developing this process, the bacteria filled by drug, can deliver
the drug to the tumors deep in the body of patient. [52]

By managing both passive and active targeting, a drug-loaded nanoparticle can gain
advantage over a conventional drug. The nanoparticle can circulate throughout the body
for an extended period of time, until it is attracted to its target through the ways that are
mentioned above. Only the disease tissue will be affected, hence, the side effects from
conventional drugs will be largely reduced.

Figure 2.11. Usage of Targeting Ligands as Active Targeting in Cancer Treatment [53]

2.2.NANO-SIZED DRUG DELIVERY SYSTEMS

Humans have commonly used plant-based natural products as medicines to fight the
diseases since the ancient times. Modern medicines are mainly derived from herbs with
 27

traditional knowledge and practices. Around 25% of the major pharmaceutical compounds
and their derivatives that available today, are obtained from natural resources. Natural
products exhibit significant characteristics such as extraordinary chemical diversity, good
therapeutic potential, chemical and biological properties with macromolecular specificity
and less toxicity. Also they have low price. [54]

Despite with these advantages, many natural compounds are not clearing the clinical
trial phases. The use or large sized materials in drug delivery causes major challenges,
including poor bioavailability, poor solubility, poor absorption in the body and issues with
target-specific delivery. Therefore, using new drug delivery systems for targeting drugs to
diseased areas could be an option in order to solve these critical issues. Thus,
nanotechnology plays a crucial role in advanced medicine, targeting area and controlled
release of drugs with remarkable success. [54]

Nanotechnology crosses the barrier of biological and physical sciences by applying

nanostructures and nano-phases at various fields of science, especially in nano-medicine
and nano based drug delivery systems. Nanomaterials can be defined as a material with
size ranges between 1 and 100 nm. Hence, they can move freely in the human body
compared to bigger materials. Nanoscale sized particles have unique structural, chemical,
mechanical, magnetic, electrical and biological properties. Nano-medicine implicates the
utilization of nano-dimensional materials including nano-robots, nano-sensors for
diagnosis, delivery and actuate materials in live cells. For instance, a nanoparticle-based
therapy has been developed which can combine both the treatment and imaging modalities
of cancer diagnosis. [55]

Nano-sized drug delivery systems generally focus on formulating bioactive

molecules in biocompatible nano-systems such as; nanocrystals, solid lipid nanoparticles,
nanostructure lipid carriers, nano-liposomes, dendrimers, quantum dots etc. These systems
are addressing the challenges to overcome the delivery problems of wide ranges of drugs
via their narrow submicron particle size range, easily manipulatable surface characteristics
in tissue targeting, controlled and sustained drug release property and having reduced side
effects. Versatile fabrications such as PEGylation (coating the particle with polyethylene
glycol), specific antibody conjugation, specific ligand binding on the nano-sized delivery
 28

devices make them in the streamline of research to target the diseases cells thus avoiding
the healthy ones. Capability of nanoparticles about crossing the BBB encourages the
medicine world to build up a new strategy for delivery of medications to the brain. [55]
Also, nano-systems are showing an emerging effect in chronic diseases such as diabetes,
cancer and neurodegenerative diseases. Studies on nano-structural drug delivery show that
it is a highly growing field today as an extensive amount of research is on with an
expectation to open up new avenues to drug delivery. There is no doubt that the next era of
drug therapy will be greater influenced by nanoscale drug delivery systems with condition
that must being reliable, efficient and safe. [55]

Nano-sized drug carriers can be divided into two main categories; organic and
inorganic. Organic nano-drug vehicles are; solid lipid nanocarriers, nanoliposomes,
dendrimer and polymeric micelles. Whereas inorganic ones are; carbon nanotubes, gold
nanoparticles, mesoporous silica nanoparticles, quantum dots and magnetic nanocarriers.

2.2.1. Organic Nano-sized Carriers

Organic nano-carriers are very common in nature with less toxicity and have the
ability to conjugate a variety of drugs as well as ligands for drug delivery. Polymeric
nanocarriers and liposome mediated drug delivery are the first generation nano-carriers.
Organic nanocarriers include nanoparticles such as solid lipid nanocarriers, liposomes,
dendrimer, and polymeric micelles. [56]

2.2.1.1. Solid Lipid Nanocarrier

SLNs prepared with solid lipids at room and body temperature and stabilized with
surfactants. As shown in Figure2.13., SLNs generally consist of solid lipids, surfactants
and water. The term lipid is widely used and includes triglycerides, fatty acids, and
steroids. The type and amount of surfactant affects particle size and stability. The choice of
surfactant depends on the route of administration. Also, the amount of it should be such
that it covers the surface of the nanoparticle. Straight chain alcohols, alkyphenol,
propylene, glycols and fatty acids can be used as surfactants. On the other hand, lipids are
 29

amphiphilic due to their bi-molecular structure and are generally insoluble in water [56].
SLNs formulations reported by different researchers are shown in the Table 2.2.

Table 2.3. SLNs formulations Reported by Different Researchers [57]

Drug Lipid Surfactant Method for

Preparation
of SLNs
Ibuprofen Trilaurin, Pluronic®F127, Solvent-free
tripalmitin, sodium high-pressure
stearic acid taurocholate homogenizatio
n (HPH)
Amphotericin B Compritol® Pluronic® F-68, Solvent
ATO 888, Pluronic® F-127, diffusion
Precirol ATO method
5 and stearic
acid,
Methotrexate Stearic acid, L-α-Soya lecithin, Solvent
monostearin, and Sephadex G- diffusion
tristearin, and 50 method
Compritol
888 ATO
Ketoprofen Beeswax and Tween 80, egg Microemulsion
carnauba wax lecithin technique

SLNs not only increases the bioavailability of hydrophobic molecules, but also
enables the use of allows the use of fat-soluble drugs and hydrophilic drugs together. On
the other hand, low drug loading capacity and drug storage and unpredictable gelation
tendency problems are disadvantages of solid lipid nanocarrier. In addition, SLN's provide
better control and controlled release of the drug.[58]
 30

Figure 2.12. Structure of Solid Lipid Nanoparticle [59]

Drug loading on SLNs depends on the solubility of the drug in the molten lipid and
the chemical structure of the lipid. In the process of drug loading into SLNs, the
prerequisite for obtaining a suitable loading capacity is a sufficiently high solubility of the
active substance in the molten lipid. The solubility of the active substance should be as
high as possible, because the solubility decreases when the molten lipid is cooled.
Depending on the active substance-lipid ratio and solubility, the active substance can be
localized in the nucleus or shell, or molecularly dispersed within the matrix structure. This
directly affects drug release. [60]

SLNs are used in oral, pulmonary and ocular applications. They can be administered
orally, directly in the form of aqueous dispersions or in the form of tablets or capsules. In
pulmonary application, SLNs are of small size and are immediately ejected by exhalation.
Therefore, they are not administered via the pulmonary route in powder form. They are
supplied in the form of an aqueous dispersion with a nebulizer. In ocular application, SLNs
provide a high drug concentration by staying in the eye longer as a result of adhesion,
without distorting the image.

2.2.1.2. Nanoliposome

Liposomal carrier systems are the most promising encapsulation technologies

employed in the rapidly developing field of nano-biotechnology. Nanoliposomes are
defined as bilayer lipid vesicles which possess and maintain nanometric size range during
storage and applications. They present a greater surface. These drug carriers are mainly
 31

composed of lipids and PL. Whereas, some of them may contain other molecules such as
carbon hydrates, proteins and antioxidants. Due to their amphiphilic nature, they can entrap
and release a massive range of hydrophilic and hydrophobic compounds simultaneously,
which offers a combined benefit. Compared with other nano-sized drug delivery systems,
nanoliposomes have the advantage of being produced using natural and inexpensive
ingredients; such as soy, egg yolk, sunflower and milk. This advantage with
biocompatibility and biodegradability, make nanoliposomes ‘’smart’’ drug delivery
vehicles. Hence, numerous clinical trials have revealed that nanoliposomes are great
candidates for varied delivery systems; such as anti-cancer and anti-biotic drugs. [61]

One of the common used area of nanoliposomes is cosmetic, specially skin care
products as shown in Figure 2.14. Skin is the largest and the most important organ for
topical and systemic drug administration. Stratum Corneum is the main barrier of the skin,
composed of 15-20 layers of dead epidermal cells. Nanoliposomes are usually
implemented as penetration enhancers of active ingredients into the skin layers. The
composition of this drug carrier allows them to create a drug reservoir when mixing with
the lipids of Stratum Corneum.[61]

Figure 2.13. Nano-Liposome Included Moisturizing Day Cream [62]

The commercial content of the above product is ‘’ With its everyday use, you can
reduce the tension caused by dry skin. Vitamin A, E and C encapsulated in liposomes
 32

assure the skin’s long lasting vitamin supply as they are absorbed in the deeper layer of the
skin.’’ [62]

When nanoliposomes compared with regular liposome, several differences can be

seen. Due to having penetration enhancers, nanoliposomes offer high penetration. Also,
liposomes have long manufacture process, and poor bio-distribution compared to
nanoliposomes. The differences between liposomes and nanoliposomes with advantages
and disadvantages are shown in Table 2.3

Table 2.4. Advantages and Disadvantages of Liposomes & Nano-liposomes [61]

Advantages
Liposomes
Entrapment of hydrophilic and hydrophobic
compounds separated or simultaneously.
Made of natural ingredients.
Simple fabrication process.
Cost-effectiveness
The increase in number of layers may be
beneficial to prevent or delay the release of
active molecules.
Nano-liposomes
Entrapment of hydrophilic and hydrophobic
compounds separated of simultaneously.
Reduced toxicity and side-effects
Better solubility and accurate targeting
Higher surface area-to-volume ratio
Disadvantages
Reduction in encapsulation efficiency due to
size enlargement.
Drug leakage.
Higher physical instability during storage.
Reduced bioavailability compared to
nanoliposomes
Susceptibility to fast clearance from the
blood stream.
Manufacturing process usually involves
mechanical energy that may degrade the
lipid structure.
Aggregation and coalescence can occur due
to stronger electrostatic interactions.
In some cases, the use of surfactants as
stabilizers is needed.
Reduced drug storage capacities.
 33

2.2.1.3. Polymeric Micelles

Polymeric micelles are amphiphilic block copolymers with hydrophilic and

hydrophobic monomers as shown in Figure 2.15. The hydrophobic part moves away from
the water, forming the structure of micelles in a vesicular manner. The formation of
micelles occurs with the reduction of free energy. In an aqueous environment, the micelles
form, while the hydrophobic part of them combines with the tendency to escape from
water, forming a semi-solid micelle nucleus, while the hydrophilic part interacts with the
aqueous medium to form a hydrogen bond and spontaneously regulates to form a shell
layer, causing a drop in the free energy of the system. The core-shell architecture formed
in micelle formation is suitable for the purpose of drug transport. Because the outer shell
acts as a reservoir that increases the solubility of drugs insoluble in hydrophobic core
water. Polar molecules, on the other hand, adsorb to the surface of the micelle, while
medium polar molecules are trapped in the hydrophilic sheath. Although block copolymers
with different properties are used for micelle formation, the most important criterion is the
biocompatibility and/or bio-particity of polymers. [63]

Figure 2.14. Micelle Structures [64]

Since micelles have the ability to dissolve and transport substances, they offer
activities to be used in many areas. One of them is drug delivery. Polymeric micelles are
used in drug transport and amphiphilic block copolymers forming polymeric micelles.
Various mechanisms of amphiphilic block copolymers are shown in the Figure 2.16. Some
of the reasons for use polymeric micelles are that low-solubility active substances make
them soluble and thus increase their bioavailability, they can remain in the body for a
 34

sufficiently long time and can be targeted by binding specific ligands. In addition to its
advantages, it also includes disadvantages such as limited active ingredient solubility, poor
stability in water after the active ingredient is loaded. [63]

Polymeric micelles are spherical, colloidal particles and structures formed by self-
regulation of amphiphilic block copolymers containing biocompatible hydrophilic and
hydrophobic blocks in aqueous media in the form of a core-shell [65].

Figure 2.15. Mechanism of Micelle Formation from Different Types of Amphiphilic Co-
polymers [66]

The drugs can be loaded into the nucleus of polymeric micelles or into the shell
region. This loading occurs by chemical conjugation or physical capture techniques.
Furthermore, minimizing hydrophobic interactions between drug carriers and components
of the biological system (such as proteins and cells) is an important key in targeting
[63].Polymeric micelles offer use for cancer, neurological diseases or gene diseases.
 35

2.2.1.4. Nano-Dendrimers

The structure of dendrimers are polymeric drug carrier systems consisting of a core
in the center, functional groups on the surface and generations located between the center
and the surface. As shown in Figure 2.17., these generations are called “G1, G2, G3...” in
order from the nucleus to the surface, with the nucleus being “G0”. "G” means
"generation", while the number next to the letter G indicates the level at which the
generation is relative to the center. Inside these tree-like structures, there are gaps. The
gaps in the dendrimers are used for many purposes, while the functional groups on their
surfaces also allow the dendrimers to come into contact with the desired surface [67]

In the branched structures of dendrimers, drug binding, controlled release and

targeting are possible both to the inner space and to many functional groups. Having too
many chain ends in dendrimers gives dendrimers high solubility and miscibility. The
higher the chain ends, the higher the activity. Also, the solubility of dendrimers is directly
related to groups on the surface. Dendrimers ending in hydrophilic groups are well soluble
in polar solvents, while dendrimers ending in hydrophobic groups are soluble in non-polar
solvents. [67]

Figure 2.16. Structure of Dendrimers [68]

The most important feature of drug carriers is to reduce toxicity. Biocompatible

dendrimers must be designed and synthesized to prevent the toxic effects of dendrimers. In
addition, applications such as neutralizing the environmental charges of dendrimers by
PEGcoating, acetylation, carbohydrate and peptide binding play an important role in
 36

reducing toxicity. Also, various dendrimers such as polyamidoamine (PAMAM), poly

(propylene imine) (PPI), poly (glycerol-co-succinic acid) have been developed as drug
carriers. [67]

On the other hand, dendrimer properties can be modified to be designed for a specific
application. It is possible to obtain by changing the chemical properties of the core, shells,
and especially surface layers. Branching of the dendrimer nucleus by successive reactions
occurs as a result of successive multi-step reactions. In this way, a dendrimer molecule
with the desired properties is designed. The co-surface groups of dendrimers are well
suited for specific drug delivered applications with their excellent encapsulation properties
and largely controllable chemistry. Depending on the surface groups, the drug can be
loaded into molecular dendrimer. In genetic therapies, the nano-robot that carries DNA
molecules into the cell acts and has been used to obtain anti-cancer drugs using Dendrimer
and dendrimer polymers. In Table 2.4. some dendrimers used for cancer disease are shown.
[69]

Table 2.5. Usage of Dendrimers for Cancer diagnosis [70]

Type of Dendrimer Type of Cancer Use

Gadolinium (III) (Gd(III))- Lung Cancer Mestastais MRI and CT Scan
complexed dendrimer-gold
nanoparticles
Ferrocene-cored Breast Cancer Electrochemical DNA
poly(amidoamine) Detection Strategy
dendrimers
Dendrimers complexed Different Cancer Types MR Imaging
with copper and Metastases
Dendrimer-gold nano Tumors Multimode Imaging
flowers
PAMAM coated magnetite Liver Cancer CT Imaging
nanoparticles
 37

2.2.2. Inorganic Nano-sized Carriers

The inorganic nano-carriers can be effectively used in bio-sensing, cell labeling,

targeting and imaging. They also have the advantage of tractable features. As
disadvantage, use of heavy metals as inorganic nano-carrier would result in long term
health issues. Inorganic nano-carriers are; carbon nanotubes, gold nanoparticles,
mesoporous silica nanoparticles, magnetic nano-carrier and quantum dots. [56]

2.2.2.1. Carbon Nanotube

Carbon nanotubes (CNTs) are cylindrical nanotubes formed from carbon atoms.
Diameters can be up to 1 nm and lengths can be millimeters in size. CNTs are sheets of
graphene wrapped in a seamless cylinder with two ends open or capped. If they are made
from a single sheet of graphene, a single-walled nanotube (SWNT) is formed. On the other
hand, if made from multiple sheets of graphene, multi-walled carbon nanotube is formed
(MWNT). A single-walled nanotube and multi-walled carbon nanotube are shown in figure
2.15 [71]

Figure 2.17. Structure of Single-Walled and Multi-Walled Carbon Nanotube [71]

CNTs have high durability, low weight, and have excellent transport conductivity
and thermal and chemical stability. CNTs with large surface area can be conjugated with
various biological molecules such as proteins, enzymes or drugs. But the ability of CNTs
to enter cells can lead to the formation of toxicity. [71]
 38

CNTs penetrate the cell membrane and by passive diffusion, pierce the cell
membrane with the help of a needle-like structure and pass into the cell. These drug
carriers, which can easily pass through barriers even if there are cellular barriers, can even
enter the nucleus. These nanotubes that enter the cell are found in the endosome organelle.
Endocytosis causes an extracellular particle to be swallowed. [71]

When the applications of carbon nanotubes were investigated, it was obtained that
these nanocarriers are used in lung cancer. Many people die each year from lung cancer. It
is known to be among the most common cancers in the world. Gemcitabine, a
chemotherapy drug, is among the anti-cancer drugs for non-small cell lung cancer. In a
clinical study on mice, the drug was tested with a SWCNT carrier. As a result, these
research SWCNTs have been shown to be incentive carriers for drug delivery due to the
high loading tendency of the drug, long delivery time and remarkable cell membrane
permeability. [72]

Methotrexate, a chemotherapy drug, can be delivered with MWCNTs for lung cancer
treatment. Animal tests have shown that this complex has no toxic effects on the heart,
liver and nephrotic systems. [72]

2.2.2.2. Gold Nanoparticles

Gold has been used for medical purposes since ancient times especially in India and
China, which are the countries that gold is linked to long living and fertility. Gold (Au) is
unique compared to other metals because of its resistance to tarnishing, which means
losing the brightness. During the middle and modern ages, gold has been used in
neurological affections. Therapeutic properties of gold as nanoparticles have been reported
in the 17th century by the philosopher and medical doctor Francisci Antonii. In the 20 th
century, its area has extended to tuberculosis and rheumatic diseases. [73]

Gold Nanoparticles (GNPs) are composed of a core which has size from 1.5 to 10
nm, containing gold which is encircled by a protecting outer layer or organic ligands. The
features such as being easily modified and possibility of loading them with drug therapies,
make them ideal vehicle for drug delivery. Large surface to volume ratio of GNPs offer a
 39

large number of drug molecules being carried by them. In addition, use of ligand place-
exchange reactions allows to contain multiple targeting agents and drugs such as small
molecules, peptides, proteins and antibodies. [73]

These nanoparticles can be synthesized using a variety of methods. In these methods,

chemical ones are based on the reduction of HAuCl4. In 1994, Brust and Schiffrin
introduced a novel method for the synthesis of thiol-capped gold nanoparticles using
sodium borohydride as a reducing agents in the presence of the desired ligand, as shown in
Figure 2.19. [73]

Figure 2.18. Synthesis of Gold Nanoparticles According to the Method of Burst and
Schiffrin [73]

GNPs are currently playing a significant role in the fields of clinical diagnosis as
well as several biomedical applications. One of the studies includes using GNPs to detect
cancers. The functionalized GNPs with the pattern recognition methods were introduced to
diagnose the lung cancer from breath testing. Biomarkers were detected in exhaled breath
of lung cancer patients. Another study presents the combination system based on gold
nanoparticles with the prostate-specific antigen (PSA) to diagnose prostate cancers. In this
system, the GNPs conjugated with the PSA specific antibodies were used to extract the
traceable amounts of PSA in the serum samples from patients.[74]
 40

2.2.2.3. Mesoporous Silica Nanoparticles

Mesoporous Silica Nanoparticles (MSNs) were discovered in 1992 by the Mobile Oil
Corporation, and have received considerable attention due to their superior textual
properties such as high surface area, large pore volume, tunable pore diameter and narrow
pore size distribution. They have a solid framework with porous structure. Having large
surface area allows the attachment of different functional group for targeted drug moiety to
a particular site. Chemically, MSNs have honeycomb-like structure and active surface.
This surface enables functionalization to modify surface properties and link therapeutic
molecules. Various pore geometric structures are shown in Figure 2.20 [75]

Figure 2.19. Several Pore Geometrics of Mesoporous Structure [75]

In the above figure, a represents 2D hexagonal p6 MM, b represents biocontionus

cubic Ia3d, c represents biocontionus cubic pn3 m and d represents cage type pm3n.

MSNs are considered as a good choice in controlled and targeted drug delivery
system due to their low toxicity and high drug loading capacity. The mesoporous form of
 41

silica has unique properties, especially in loading of medication at high quantities. Because
of strong Si-O bond, silica based nanoparticles are more stable to external response such as
degradation and mechanical stress, when compared to niosomes, liposomes and
dendrimers. The pore size and porosity can be altered according to the size and type of
drugs. Various type of MSNs with internal structure and pore size are shown in Table
2.5Another significant challenge is to avoid the premature cargo release before reacting the
target. The pore of MSNs can act as stimuli-responsive gatekeepers. Thus, the exposure to
internal or external stimuli, such as pH and temperature, would trigger pore opening and
allow cargo departure. In addition, having surface functionalization offers loading proper
type of drug molecules such as hydrophobic or hydrophilic, positive or negative charged.
[75] MCM represents Mobile Crystalline Material, SBA represents Santa Barbara
Amorphous- type mesoporous.

Table 2.6. Various Type of MSNs with Internal Structure and Pore Diameter [75]

Type Internal Structure Pore Diameter (nm)

MCM-41 2D hexagonal 1.5-3.5
MCM-41 Hexagonal structure with 3.7
uni-directional pore
structure
SBA-15 2D hexagonal 6.0-10.0
SBA-15 2D hexagonal 7.8
SBA-15 3D cubic cage like 4.0-9.0
MCM-48 3D cubic 2.5-3.0

The application of MSNs for cancer therapy has been emerging as a new interesting
field of interdisciplinary research with chemistry, medicine, material science, biology and
pharmacology. Employing ligands that specifically bind to receptors on the cell surface of
interest, provides binding and internalization of the nanocarrier. This strategy requires that
receptors are highly overexpressed by cancer cells compared to normal cells. [75]

Besides these advantages mentioned above, the major disadvantage of porous silica
nanoparticles is that, hemolysis may occur when the cylanol groups interacted with the
 42

surface of phospholipids of the red blood cell membranes. Also, when the metabolic
changes induced by porous silica nanoparticles, it may lead to melanoma which is some
kind of tumor.

2.2.2.4. Magnetic Nano-carrier

Magnetic nanoparticles (MNPs) with sizes ranging from 1 to 100 nm consist of

magnetic components such as iron, nickel, cobalt and chromium, but in biomedical
applications, the most commonly used is iron oxide (Fe 3O4). The reason for this is that iron
oxide has excellent magnetic properties. These MNPs can make solutions called
homogeneous ferrofluidics. (Ferrofluid is a liquid containing very small iron particles) In
addition, these nanoparticles are of great importance due to their unique biocompatibility,
magnetic, physical, chemical, thermal and mechanical properties. [76]

MNPs can be synthesized in a variety of ways. Among these syntheses, chemical co-
precipitation is mostly preferred because of its simpler and easier reaction kinetics. The
purpose of using this method is to synthesize MNPs with superparamagnetic properties
with dimensions of approximately 5-20 nm. As shown in Figure 2.21, A schematic of the
synthesis of iron oxide MNPs using the co-precipitation method. In this figure, the
precursors (Fe 2+
/Fe 3+
chlorides, sulfates, or nitrates) are dissolved in an acidic solution.
Then, a strong base is added to increase the pH > 8 in a non-oxidizing environment. [76]

Figure 2.20. Iron Oxide Formation with Using Chemical Co-Precipitation Method [76]

The concept of MNPs as drug delivery agents has been widely investigated over the
past few decades, and the researches are continuing. The ability to use magnets within the
 43

body to focus therapy to the deep tissue targets has remained an exclusive goal in magnetic
drug targeting. So far, several studies have been conducted such as; magneto-responsive
smart capsuled have produced with polyelectrolytes, lipid bilayers and MNPs.
Superparamagnetic iron oxide nanoparticles with PEG-modified phospholipid micelle and
their delivery into living cells by using MRI (magnetic resonance imaging) technology
have been reported. The MRI system also has been used in targeted drug delivery systems
to different sites, such as gliomas, the cardiovascular system and the tumor tissues. [77]

MNPs are used in cancer treatment in order to deliver the most common and
effective anticancer drug, doxorubicin (DOX) as shown in the Figure 2.22. This
medication is used various forms of cancer such as sarcomas, breast cancer and
lymphomas. Unfortunately, DOX has several disadvantages. 40% of the drug is excreted
on the way and only a small amount of it reached the tumor target area. Also DOX causes
a significant cardiac toxicity. On the other hand, tumors have drug resistance [78]. Tumors
develop a drug resistance mechanisms and this issue contributes to a 90% failure rate of
chemotherapy treatments. In order to overcome this chemotherapy problems, hybrid
magnetic nanomaterials have step upped as pH dependent doxorubicin carrier. The shells
have high drug loading capacity and favorable drug release profile, while the iron oxide
core allows manipulation by an external magnetic field. They carry the drugs to the tumors
cells, cross biological barriers and protect the drug from biological clearance. Finally, they
release the drug specifically on tumor, after get triggered by specific stimulus. The pH
responsiveness was defined as pH levels equivalent to those of blood pH (7.4) and tumor
microenvironment pH (4.2-5). MNPs can be guided towards target tissues under magnetic
gradients. They used as contrast agents for MRI. Via the MRI, simultaneous cancer
treatment and monitoring can be accomplished. [78]
 44

Figure 2.21. The Entering of Magnetic Nano-carrier to the Diseased Cell [78]

In another study with DOX, biocompatible nano-carriers conjugated with magnetic

nanoparticle with using PEG to create a magnetic vector under magnetic field and
doxorubicin is carried as cargo. Acylhydrazine linker is used to release the drug exactly at
mild acidic conditions. Monomers and polymers are characterized carefully by the proper
techniques. Thermogravimetric analysis (TGA), FT-IR spectroscopy and scanning electron
microscope (SEM) methods are used to confirm the attachment of iron particle to the
PEGylated doxorubicin included carrier. Drug release profile from the magnetic
nanoparticle is monitored by fluorimeter. [79]

Unfortunately, magnetic drug delivery and using MNPs are highly expensive and are
based on trial and error. Therefore, approaches may not be practical and affordable in all
situations. Using computational methods to predict the efficiency of this technology may
reduce the need for costly and expensive experiments. [79]

2.2.2.5. Quantum Dots

Quantum Dots (QDots) are composed of a core and a shell. The core includes various
metal complexes such as, noble metal, semiconductors and magnetic transition metals. In
Figure 2.23 structure of quantum dot is shown. Also it can easily be replaced with other
drug carriers (such as gold and magnetic nanoparticles) or biomolecules by their similar
size and surface properties. [80]
 45

Figure 2.22. Structure of a Quantum Dot [81]

These nano-carriers present exceptional features, thus, they are considered an

efficient drug delivery system. QDots have advantage of high surface area because
multiple attachment sites are available for drug targeting. Also, they can easily cross the
cell membrane. They show strength to chemical degradation, pH changes and have high
thermal stability. In addition, they are water soluble and biocompatible. These features are
improved by surface modification which also helps the QDots to be used as fluorescent
probes when targeting the molecules.Another feature of them is having a broad a robust,
absorption spectra. QDots can be used as photosensitizers. Also QDots can acts as a radio-
sensitizer due to being an absorber of high- energy photons. [80]

Quantum based nanoparticles are tiny in size but have wide-ranging application
potentials. They have become a promising topic for research in the oncology subject. In
order to obtain effective cancer treatment, high accuracy is required because of treatments
is conducted through ionizing radiations to reduce exposure and toxicity to healthy cells.
QDots show a very narrow array of emission spectra, so they are highly used in
multiplexed imaging. This means several magnetic fields and colors are united for small
molecules. As an alternative treatment to radionuclide imaging, optimal imaging is now
evolving as a new method. Another studies which conducted in vivo, QDots are mostly
used to localizing and targeting tumors. Using PEGylated QDots helps localize them in
specific tumor cells. QDots are also used in the detection of cancer cells. QDots based
multifunctional probes give excellent sensitivity for cancer molecular imaging and targeted
 46

therapy by their brightness. QDots imaging technique has become to the most favorable
tool for detecting cancer early due to its perfect imaging performance. [80]

Furthermore, some studies have been dedicated to fabricating photosensitizer- based

QDots which yield free radicals upon visible light immersion. According to other
researches, QDots-conjugated oligonucleotide sequences are targeted to connect with DNA
or m RNA. Bio conjugated quantum dots are also under consideration for the site specific
gene as well as drug delivery in cancer. Targeting moieties such as antibodies, high
molecular-weight dextran, peptides or folate can be combined with QDots. [80]

2.3.APPLICATIONS OF NANOPARTICLE TECHNOLOGY

2.3.1. Cancer Therapy

Cancer is a very complicated biological phenomenon, and can be said that it is a

disease of many diseases. Cancer Therapy has saved lives of many individuals; however,
the side effects of treatment are harsh and affect the entire body due to non-specificity of
the chemotherapeutic agents. One of the characteristic feature of cancerous cells it that,
they divide and multiply rapidly out of control. In current treatment, mainly aimed idea is
to destroy all rapidly dividing cells. The disadvantage of this method is that the body’s
other rapidly growing cells, such as hair follicles and intestinal epithelium are also killed
off. In the end, patients are struggling with life altering side effects. [82]

The development of nanoparticles has provided hope and a new avenue for
chemotherapy. Using smartly designed nanoparticles, targeted drug delivery at the tumor
site has accomplished and toxic effects to other normal tissues and organs has avoided.
Liposomes are examples of nanoparticles which being used in cancer treatment.
Doxorubicin, a very significant drug used in chemotherapy, can encapsulated by liposome
and go to the tumor sites. Additionally, micelles are alsmico a great way to make insoluble
drugs soluble due to their hydrophobic core and hydrophilic shell. If the surface of micelle
is PEGylated, it increases the ability of the nanocarriers to get through the vasculature of
tumors and inflamed tissue through passive targeting. It results in higher drug
concentration in tumors. Now, several polymeric micelles containing anticancer drugs are
 47

under clinical trials; NK102, NK105, NK911, NC-6004. Also Genexol-PM (paclitaxel) is
approved for breast cancer patients. [82]

Magnetic nanoparticles are also very common in cancer treatment. These

nanoparticles composed consists of two components, a magnetic material (generally iron,
nickel and cobalt) and a chemical component. MNPs can be guided towards target tissues
under magnetic gradients. MRI is another technology that uses the magnetic gradient in
order to monitor the treatment. The tumor sites have lower pH varies between 4 and 5.
MNPs triggered with pH of the environment and after release the medication. [82]

Furthermore, dendrimers are highly branched particles with many functional groups
available for the attachment of drug, targeting and imaging agents. These branches also
offer absorption, distribution, metabolism and elimination (ADME) profile of drugs and
targeting agents. Nanoparticle therapeutics based on dendrimers are able to improve the
therapeutic index of cytotoxic drugs by employing biocompatible components. Also
surface can be improved with PEGylation, acetylation and glycosylation. [82]

Another recently used system is CNTs. They are allotropic forms of carbon with
cylindrical framework and go deep with number of sheets in concentric cylinders. CNTs
have very hydrophobic hollow interior, thus, water insoluble drugs can easily be loaded in
them. Also the large surface area allows for outer surface functionalization. This
functionalization can be done specifically for a particular cancer receptor as well as
contrast agents. [82]

Finally, Buckministerfullerene C60 (spherical molecule) and its derivatives are

evaluated for cancer treatment. Fullerene C60 can bind up to six electrons. Thus it acts as
an excellent holder for reactive oxygen species. In addition, Fullerene nanocrystals (Nano-
C60) are able to enhance the cytotoxicity of chemotherapeutic agents. Thus, chemotherapy
with Nano-C60 can be evaluated. Another study has conducted with using the complex of
Fullerene C60 with Doxorubicin and obtained that the tumor volumes of the treated rats to
be 1.4 times lower than the control groups which are untreated rats. [82]
 48

2.3.2. Drug Targeting to the Brain

Brain is a challenging organ for drug delivery. Because, the possibility of

degenerative diseases in the brain will increase with aging and the BBB is known as best
gatekeeper in the body against exogenous substances. Meaning of endothelium is; it is a
thin membrane that present in the inside of the heart and blood vessels. [83]

By coating of nanoparticles with the polysorbate (Tween), it was seen that drug is
transported across the BBB. The mechanism of transport was proposed to be endocytosis
by the Low Density Lipoprotein (LDL) receptor of the endothelial cells, after adsorption of
lipoproteins from blood plasma to the nanoparticles. In another research, role of
apolipoprotein-E for transport the drugs across the BBB was revealed. Apolipoprotein-E
variants which is not recognize the lipoprotein receptors failed in transporting the drug. At
the end, it was understood that the recognition and interaction with lipoprotein receptors on
endothelial cells was responsible for the drug uptake by the brain. [83]

Another way to transport the drugs to the brain is, masking certain drug features that
prevents binding to cellular efflux systems such as p-glycoprotein. It is a cellular
transporter associated with drug removal from cells. It is one of the ATP dependent efflux
transporters that has a significant role in limiting the drug entry to the brain. [83]

However, there is an issue that brain may be in danger intentionally or

unintentionally by drug treatment allowing passage of nanoparticles. When nanoparticles
with different surface characteristics were developed, it was understood that neutral
nanoparticles and low concentrations of anionic nanoparticles have no effect on BBB.
Whereas, high concentrations of anionic nanoparticles and cationic nanoparticles were
toxic for the BBB. Thus, surface charges of nanoparticle must be investigated for toxicity
and brain distribution profiles. [83]

2.3.3. Diagnostic Testing

Current technology for diagnostic testing includes issues such as fading of

fluorescence after single use, color matching and restricted use of dyes due to a bleeding
 49

effect. Fluorescent nanoparticles, provide researches with the answer to overcome these
breakdowns. Unfortunately, the usage of nanoparticle for diagnostic purposes is
unavailable for clinical applications currently.

One of the important nanoparticle for diagnosing is quantum dots. Their absorption
spectrum ranges from UV to a wavelength within visible spectrum, which provides high
quantum yield, tunable emission spectrum and photo-stability. Quantum yield is the factor
that determined a material’s photo-emissive efficiency up to a maximum value. It is also
called as unity [84]. The place that individual particle falls is determined by the size of the
nano-dot. Furthermore, tagging of the quantum dots has advantages such as; quantum dots
are excitable using white light and they can be linked to biomolecules that can spend
considerable amount of time in the living system to probe various bio-mechanisms. Thus,
biological events can be monitored simultaneously by tagging various biological molecules
with nano-dots of a specific color.

Usage of nanoparticles in diagnostic testing has gain much attention. This method
can be evaluated by many classes of nanoparticles including dendrimers, micelles, vesicles,
core-shell particles and carbon nanotubes. By combining drug and imaging agent in one
smart formulation offers to monitor the pathway and localization of these nanoparticles at
the target site. Hence, drug action as therapeutic response will be accomplished. [82]

2.3.4. HIV and AIDS Treatment

Infection with HIV can lead to AIDS if not being handled. HIV is a devastating
disease where an individual’s immune system is almost completely destroyed. When
treatment of HIV was first developed, it was difficult, most patients used to take 30-40
pills in a day. In the past decade, here have been studies in therapeutics to decrease the pill
uptake to a few amount for each day. Research has shown a way to make this treatment
even more effective by creating polymeric nanoparticles that deliver the antiretroviral
drugs intracellularly as well as to the brain. This technology can also be used with
vaccinations to prevent HIV infection.[82]
 50

Antiretroviral drugs to treat HIV, can be categorized according to the stages of HIV
life cycle. In order to prevent the development of resistance and aggressively counter the
HIV progression, a combination of multiple drugs can be used. This known as highly
effective antiretroviral therapy. Nanotechnology has played a significant role in delivering
the antiretroviral drugs and improving compliance. These drugs must be able to cross the
mucosal epithelial barrier when taken orally or other non-parenteral routes. Several reports
have shown that the nanoparticle loaded with antiretroviral drugs are able to target the
macrophages. [82]

An important example of superiority and success of nanoparticle system for

sustained and targeted drug delivery was reported by Destache C.J. The researchers used
poly(lactic-co-glycolic acid) (PLGA) to prepare nanoparticles entrapping three
antiretroviral drugs; ritonavir, lopinavir and efavirenz. The nanoparticle system yielded
sustained drug release for over 4 weeks while free drugs were eliminated within 2 days.
The Central Nervous System is another site for HIV to place and resulting in serious HIV-
associated neurocognitive disorder. Nanoparticles are known by crossing BBB by
endocytosis and phagocytosis, many reports exist that show successful delivery of anti-
HIV medications. [85]

2.3.5. Nutraceutical Delivery

Nutraceuticals are food derived, standardized components with significant health

benefits. They are commonly used at various treatments to provide extra health benefits
and decrease risks of several chronic illnesses. Most nutraceuticals are lipophilic molecules
such as fat-soluble vitamins (A, D E and K), polyunsaturated lipids and other
phytochemicals. Nanotechnology provides a comprehensive assistance and most of the
researches have been targeted at improving the dissolution mechanisms of nutraceuticals
by nano-carriers. [82]

Most prominent and investigated nutraceutical is curcumin, which is

diferuloylmethane. It is soluble in water and has very poor bioavailability. So, several
researches have been directed to solve this issue; such as liposomes, phospholipid vesicles,
and polymer-based nano formulations. [82]
 51

Resveratrol is an important polyphenol and it occurs in several plants, mostly in

grapes. Resveratrol is known as antioxidant, cardio-protective and protects from cancer. It
has low solubility with sufficient bioavailability, however, it can rapidly be metabolized
and eliminated from the body. There are two geometric isomers; cis and trans. Trans-
resveratrol is more abundant, bioactive and photosensitive, can become cis-resveratrol in
the presence of light. In order to improve this nutraceuticals’ pharmacokinetic profile and
bioavailability, many nano-formulations have been reported. They are polymeric
nanoparticles, nano-emulsions, liposomes and dual nanoencapsulation methods. Most
recently, effect of neuro-protectivity of resveratrol is investigated by preparing solid lipid
nanoparticles. These particles decorated with apolipoprotein E. [82]
.

2.4. NOVEL DRUG DELIVERY

The main objectives of the new drug systems are to provide the optimum dosage
form and auxiliaries and reduction in the cost of production. In addition, it provides better
treatment to patients, better comfort and a standard of living. Novel therapeutic approaches
such as nanotechnology and their fabrication methods provide a new direction in
biomedical field. Novel drug delivery’s difference from conventional drug systems is that
it minimizes toxicity and allows for higher cell permeability by providing smaller particles,
capability of encapsulating small molecules, protecting the drugs in biological
environments, improving the drug bio-distribution, providing controlled or stimuli
responsive drug release. Systems get affected by the patient, the disease level, route of
administration and target sites. This new technology can be queued as liposomes,
niosomes, nanocapsules, nanospheres, nanosuspensions, micelles, microspheres,
microcapsules, micropellets and microemulsion. [86]

When a new technology is developing in drug delivery subject, main consideration

must be given to the patient who will be using it. For instance, microneedles are examples
for novel transdermal drug delivery. In order to get successful translation, the optimal
therapeutic outcomes of microneedles by older people should be considered. A study about
the feasibility of transdermal delivery of human growth hormone (hGH), shows the
importance of nanosized drug delivery. On purpose of transporting the drug through skin, a
 52

special system is used as P.L.E.A.S.E. (Precise Laser Epidermal System). The epidermal
skin barrier protects the underlying structure and allows the passage of lipophilic
molecules with low molecular weights. Although, it restricts the passage of hydrophilic
and macromolecules. Alternative routes are promising but large peptides and proteins
including human growth hormone can’t be delivered across the skin because of their size
and hydrophilic nature. At the end, laser-assisted microporation studies creates
microchannels in the skin that result in the enhancement of drug delivery. The resulting
data shows the possibility of transdermal delivery of hGH using microporation with
P.L.E.A.S.E technology. [87]

Although, the main issue is translating these drug delivery systems into commercial
products.Table 2.6.lists the various formulations marketed based on some of the novel drug
delivery systems.

Table 2.7. Some of the Marketed Novel Drug Delivery Systems [88]

Drug Indication Company Name

Dexorubicin Kaposi’s Sarcoma SEQUUs
Daunorubicin Advanced Kaposi’s NeXstar
Sarcoma
Amphotericin B Systemic Fungal Infection NeXstar
Amphotericin B Systemic Fungal Infection SEQUUs
Leuprolide Acetate Prostate Cancer Takeda-Abott
Triptorelin LHRH Agonist Novartis

2.5. NANO-DRUG DELIVERY FROM THE ENGINEERING PERSPECTIVE

In order to design and manufacture new drug delivery systems, an engineer must
know the properties of the drug to be produced, the properties of the materials to be used,
and the various factors that affect the release of the drug from the systems. In drug delivery
systems, measuring drug concentrations is an important factor. Drug concentrations, acid-
base, redox titrations, such as, gas chromatography, high performance liquid
chromatography equipment, such as spectroscopic analysis, is determined by various
 53

analytical techniques such as electrochemical techniques. All of these techniques require

knowledge of chemical engineering concepts such as mass transfer, reaction kinetics,
thermodynamics, and transport phenomena. [89]

One of the important aspects of drug delivery is the region where the drug will be
released. Drug delivery agents are designed according to the chemical structure of the
region to be delivered. As an example, drugs designed for the stomach are encapsulated in
a pH-sensitive polymer. The protective polymer that encapsulates the drug dissolves at a
rate dependent on the pH of the stomach. Drug delivery can be adjusted by controlling the
dissolution rate of the polymer. Since it is a chemical reaction, the rate of dissolution of the
reaction can be controlled. Therefore, knowledge of chemical engineering is necessary in
such designs. [90]

Another factor affecting drug delivery is surface tension. Most carriers of drugs
consist of hydrophilic and hydrophobic substances. Because it may not work in a
hydrophobic aqueous environment, the necessary attention should be paid to surface
energy when designing a distribution agent. In such cases, the calculation of surface energy
and its use for replacing surfactants can be done with chemical engineering knowledge.
[89]

Furthermore, nano delivery systems should supply some certain technical and
economical requirements. First of them is the material used as drug carrier should not
trigger any adverse effect in the targeted organism. Secondly, the mechanical features of
the carrier must provide prolonged protection to its cargo, the drug, when allowing
chemical stability over time. Also, the scalability of the fabrication process should be
feasible with the technology and economically appropriate. In other words, the process
used for the preparation of nanocarriers should yield logical results in a batch to batch
basis, in terms of size, encapsulation efficiency and stability. The material to be acts as
nano-carrier should be selected carefully because they must supply the technical criteria to
being commercialized and must display good performance in terms of cost, benefit and
eco-compatibility. In conclusion, fabrication conditions to an ideal carrier should be;
scalable, low cost, reproducible and low batch-to-batch variability. [91]
 54

2.6. ADVANTAGES AND DISADVANTAGES OF NANO-SIZED DRUG

DELIVERY / OBSTACLES

Nano-technology has been increasingly used in the area of drug development in

recent years. Nanoparticle-based treatments offer the ability to overcome biological
barriers and effectively deliver drugs and biologics to the preferred target sites. Drug
delivery systems are engineered devices which utilized to transport a pharmaceutical
compound throughout the body in order to release its cargo in a controlled way. Nano-
encapsulation of bioactive formulations helps to reduce the frequency of dosing required
during treatment. Also they offer physical protection to the drug during storage prior to its
usage for controlled release or cargo. Most significant advantage which is presented by
nano-delivery systems is, controlled drug release. This phenomenon means not only to a
specific location, also time dependent releasing via active or passive targeting. Passive
targeted nano-carriers are designed based on pathophysiological features from the targeted
are which permits the accumulation of the nano-sized delivery system on it. Whereas,
active targeting refers to the using surface-active ligands onto the surface of the drug
carriers, which are able to recognize and interact with a receptor in the target cell. [92]

However, despite these significant advantages, only a small number of nanoparticle-

based medicines have been approved for clinical use. The most overwhelming obstacle
about drug delivery is to accomplish the release of the drug agents at the right time by a
safe way to a specific targeted area. About this concept, medicine and agriculture share
similar ideas and goals. Scalability and approval from regulatory governmental entities are
two major concerns when the goal is to release a product to the market. Approval process
includes numerous challenges at different stages of development. The complex form of
nanoparticles as multi-component three dimensional constructs demands careful design
and engineering, detailed orthogonal analysis methods and reproducible scale-up with
manufacturing process. These requirements are crucial to achieve a consistent product with
the intended physiochemical characteristics and biological behaviors. Also the safety and
efficacy of nano-medicines must be carefully examined in preclinical and clinical studies.
Specially in bio-distribution, targeting ability to intended sites and potential immune
toxicities. [92]
 55

The design process of nano-drug delivery particles can be separated into three
categories: nano-pharmaceutical design, preclinical evaluation and clinical evaluation for
commercialization. The key considerations and the obstacles about these stages are shown
in Table 2.7., 2.8. and 2.9. [93]

Table 2.8. Nano-pharmaceutical Design [93]

Key Considerations Current Obstacles

Route of administration Large-scale production according to Good
Manufacturing Practice standards
Reduce complexity in formulation design Quality control assays for characterization
Final Dosage form for human use
Bio-compatibility and bio-degradability
Pharmaceutical stability

Table 2.9. Preclinical Evaluation [93]

Key Considerations Current Obstacles

Need for validated and standardized assays Development of more specialized
for early detection of toxicity toxicology studies for nano-medicines
Evaluation in appropriate animal models of Adequate understanding of the interaction
disease of nanomaterials with tissues and cells
Adequate understanding of in vivo behavior Adequate structural stability of
such as cellular and molecular interactions nanomaterials following in vivo
administration
Limited degree of accumulation of nano-
medicines in target organs, tissues and cells
 56

Table 2.10. Clinical Evaluation for Commercialization [93]

Key Considerations Current Obstacles

Simplification of development pathways Lack of clear regulatory guidelines specific
from invention to commercialization to for nanomaterials
minimize time and expense
Evaluation of safety and toxicity in humans Complexity of nanomaterials patents
Evaluation of therapeutic efficacy in Limited understanding of the biological
patients interaction of nanomaterial with the
biological environment
Optimal clinical trial design

2.7. FUTURE PERSPECTIVES

Nano-sized drug delivery is currently one of the most fascinating areas. Many
research in this field in the last two decades has already summed up with a lot of patents
and completion of several dozens of clinical trials. Using various types of nanoparticles for
the delivery of the accurate amount of drug to the affected cells without disturbing the
normal cells, and application of nano-medicine and nano-drug delivery systems is the trend
that will remain to be the future arena or research for decades. [94]

The concept of controlled release of proper drugs to the proper areas, technology for
the accomplishment of these events, the effect of the drug in tissues/ cellular level, and the
theoretical mathematical models of them have not been perfected. The toxicity of
nanoparticles is another issue. For instance; in cancer treatment, toxicity of the quantum
dots is a significant obstacle for the development of a successful antitumor drug delivery
system. Cadmium contained semiconductors are the main component of quantum dots.
Unfortunately, cadmium is harmful and the toxicity studies of these cadmium contained
quantum dots in living cells is not evaluated yet. [94]

Research is still in progress to reduce the toxicity of existing nanocarriers and

discover the advanced nanocarriers with a low toxicity profile. Valuable data in drug
therapeutics and diagnosis researches will come from animal studies and multidisciplinary
studies that requires significant amount of time and resources. Future for more intelligent
 57

and multi-centered approach of nanomedicine and nano-drug delivery technology looks

bright. [94]
 58

3. CONCLUSION

Drug delivery is very significant subject that is necessary for the treatment of injured
cells, tissues or organs. If the drug is not delivered to the right locations at the right time
and the right amount, the patient may lose his/her life. Therefore, the content of the drug,
the delivery vehicle and its compatibility with the body and routes must be taken into
account for all the situations. The content of the drug is the most important topic. Each
disease or treatment has its own medication. Also it must be compatible with the patient’s
body. For that reasons the drug must be taken carefully no matter its type. Delivery
vehicles are called as drug carriers. Their role is to deliver the medication into the diseased
area through several routes with targeting strategies which are passive or active. There are
many drug carriers. Most known are vesicles, micelles and dendrimer. Each carrier has
own properties, advantages and disadvantages. Also not every carrier is able to treat every
disease. Furthermore, the drug can enter the body through the skin, through injection,
through the mouth and the eye, and through the lungs.

In human body, there are several significant biological barriers. Sometimes regular
drug carriers are not able to cross these barriers and deliver the therapeutic agent. In
treatment of brain and some types of cancer this issue may lead to death of the patient.
Thus, nano-sized drug delivery systems are considered as crucial for the few decades.
Their most important feature is offering controlled release of the drug. As organic and
inorganic, nano-sized carriers are separated into two subcategories. Organic ones are; solid
lipid nano-carriers, liposomes, dendrimers and polymeric micelles. Whereas the inorganic
ones are; carbon nanotubes, gold nanoparticles, mesoporous silica nanoparticles, magnetic
nano-carrier and quantum dots. In solid lipid nanocarriers, the type and amount of
surfactant are interrelated because they affect particle size and stability. In addition, the
choice of surfactant is also linked to application. The most important feature of the solid
lipid nanocarrier is that it allows the use of lipophilic and hydrophilic drugs together.
Nanoliposome carriers, which are another carrier and the most widely used, have
properties such as capturing and releasing hydrophilic and hydrophobic drugs, since they
are amphiphilic by nature. Nanoliposomes, which have the advantage of being produced
using natural ingredients, distinguish them from other carriers because of this advantage.
 59

Another nanocarrier with an amphiphilic structure such as nanoliposome is polymeric

micelles. But its difference from nanoliposome is that it is based on PEG. This nanocarrier
solubilized low solubility active substances. Thus, bioavailability increases and allows the
drug to circulate in the body for a longer time. The common features of carbon nanotube,
gold nanoparticle mesoporous silica nanoparticle and quantum dots are that they have a
large surface area. Due to their large surface area, carbon nanotubes can combine with a
variety of biological molecules. Gold nanoparticles can carry a large number of drug
molecules as they have large surface area to volume ratios. On the other hand, mesoporous
silica nanoparticles allow the addition of different functional groups because of their large
surface area. Quantum dots has multiple binding sites for drug targeting, which is one of
the advantages of having a large surface area. Mesoporous silica nanoparticles have very
strong Si-O structure. Because of these strong bonds, they are more stable against
degradation and mechanical stress compared to other nanocarriers. That is, this feature is
the biggest advantage that distinguishes it from other nanocarriers. The properties of
magnetic nanocarriers also distinguish it from other carriers. Magnetic drug targeting of
the drug to the tissues and, on the other hand, reaching living cells using magnetic
resonance imaging technology are its strongest advantages. Applications of nano-sized
drug delivery systems are treatment of cancer, targeting to brain, diagnostic testing, HIV
and AIDS treatment and nutraceutical delivery.

Besides all these advantages, nano-sized drug delivery systems have several
drawbacks. Their usage in treatment is an expensive technology. The carriers may have
toxicity. Also their design is complicated, requires great knowledge of several departments.
Engineering, chemistry, biology and medicine should be brought together in order to
accomplish. By using the correct technology, advanced nano-carriers with low toxicity
could be demonstrated.
 60

REFERENCES

1. Stephen W Page and Jill E Maddison, Principles of clinical pharmacology, pp. 3-4,
2009

2. Janja Marc, Pharmacogenetics of drug receptors, pp.48, University of Ljubljana, 2008

3. Georges Vauquelin,Cell membranes and How Long Drugs May Exert Beneficial
Pharmacological Activity in Vivo, British journal of Pharmacology, pp. 3-5, 2016

4. Amit K. Nayak, Syed A. Ahmad, Sarwar Beg,Tahseen J. Ara and Mohammad S.

Hasnain, Drug delivery: present, past, and future of medicine, pp.1-2, Shri
Venkateshwara University, 2018

5. Chong Li,a, Jiancheng Wang,b, Yiguang Wang,b, Huile Gao,c, Gang Wei,d, Yongzhuo
Huang,e, Haijun Yu,e, Yong Gan,e, Yongjun Wang,f, Lin Mei,g, Huabing Chen,h,
Haiyan Hu,i, Zhiping Zhang,j, and Yiguang Jink, Recent Progress in Drug Delivery,
pp.1146, China, 2019

6. National Institute of Biomedical Imagining and Bioengineering, What is Drug Delivery

System, pp.1, 2016

7. Danielle S.W.Benoit, Clyde T.Overby, Kenneth R.Sims Jr., Marian A.Ackun-Farmmer,

Drug Delivery Systems, pp.1238-1240, University of Rochester, Newyork,2020

8. Aaron Z. Garza, Sharon B. Park; Remek Kocz, Drug elimination, pp.1-3, Buffalo
Newyork, 2020

9. Pragasam Viswanathan, Yuvashree Muralidaran, Gokulakannan Ragavan, Challenges

in oral drug delivery: a nano-based strategy to overcome,pp.174-186, VIT University,
Vellore, India, 2017
 61

10. Piyush Mandhar, Gayitri Joshi, Development of Sustained Release Drug Delivery
System, pp.179-181, Uttarakhand, India, 2015

11. K.P. Sampath kumar, Debjit Bhowmik, Shweta Srivastava, Shravan Paswan and A.S.
Dutta, Sustained Release Drug Delivery System Potential,pp.48-51, India,2012

12. Sahilhusen I Jethara, Mukesh R Patel and Alpesh D Patel, Sustained Release Drug
Delivery System, pp.1-3, India, 2014

13. Modi Kushal, Modi Monali, Mishra Durgavati, Panchal Mittal, Oral Controlled
Released Drug Delivery Systems, pp. 70-71, India,2013

14. Debjit Bhowmik, Harish Gopinath, B. Pragati Kumar, S. Duraivel, K. P. Sampath

Kumar, Controlled Release Drug Delivery Systems, pp.24, India, 2012

15. J. S. Patil, S. Sarasija, Pulmonary drug delivery strategies: A concise, systematic

review, pp.45-46, India ,2017

16. Alex Berezov, Structure of Upper and Lower Lungs, 2019

17. Stephen P Newman, Drug Delivery to the Lungs: Challenges and Opportunities,
pp.647-648, UK,2017

18. Siraj Shaikh, Syed Nazim,Afsar Shaikh, Tarique Khan, Md. Zameeruddin, Quazi
Majaz and Shailesh Chalikwar, Recent Trends in Application of Pulmonary Drug
Delivery, pp. 16-17, India, 2011

19. Ahlam Zaid Alkilani, Maelíosa T.C. McCrudden, and Ryan F. Donnelly, Transdermal
Drug Delivery: Innovative Pharmaceutical Developments Based on Disruption of the
Barrier Properties of the Stratum Corneum, pp.439-440, UK,2015
 62

20. M. Wang and C.Xu, Inorganic Nanoparticles for Transdermal Drug Delivery and
Topical Application, pp 1 , USA, 2016

21. M.R.Prausnitz, Transdermal Drug Delivery, pp 1, Georgia Institute of Technology,

2008

22. J. Prettman and Medsurg Nurs, Sustained- Release Injectable Drug Delivery, pp 93-
98, USA, 2005

23. A. Jostel and S.M.Shalet, Sustained Release Injectable Drug Delivery,‘’Types of

Injectable Routes of Administration’’, pp 1399-145, USA, 2006

24. FDA Approves First Extended-Release Injectable Drug Regimen for Adults Living
with IDS, pp.1, USA, 2021

25. Vials of the HIV Treatment Cabenuva, USA, 2021

26. A.Patel, K.Cholkar, V.Agrahari and A.K.Mitra, Ocular Drug Delivery Systems, pp.1-
3, University of Missouri-Kansas City, 2013

27. Pralay Maiti, Drug-delivery Vehicles and Their Efficiency Toward Cancer Treatment,
pp.1-2, India, 2020

28. Shikha Jain, Vikas Jain, and S. C. Mahajan, Lipid Based Vesicular Drug Delivery
Systems, pp. 1-2, India, 2014

29. Norman Weinerl, Frank Martin and Mohammad Ria, Liposomes as a Drug Delivery
Systems, pp. 1524-1528, University of the Punjab, Pakistan, 2008

30. Vijaykumar Nekkanti, Sandeep Kalepu, Recent Advances in Liposomal Drug Delivery,
pp.36, India, 2015
 63

31. Melis Çağdaş, Ali Demir Sezer and Seyda Bucak, Liposomes as Potential Drug
Carrier Systems for Drug Delivery, pp. 9-11, Istanbul, 2014

32. Maria Laura Immordino, Franco Dosio, and Luigi Cattel, Stealth liposomes: Review
of the Basic Science, Rationale, and Clinical Applications, Existing and
Potential,pp.297-301, Italy,2006

33. Shreya Mahesh Suthar and Bhargavi Ankit Rathva, Development of Liposomal
Formulation: From Formulation Sterilization, pp.1567, India, 2019

34. Miriam Sharpe, Stephanie E Easthope, Gillian M Keating, Harriet M Lamb,

Polyethylene glycol-liposomal doxorubicin: a review of its use in the management of
solid and haematological malignancies and AIDS-related Kaposi's sarcoma,pp.2091,
New Zealand, 2002

35. Didem Ag Seleci, Muharrem Seleci, Johanna-Gabriela Walter, Frank Stahl, and
Thomas Scheper, Niosomes as Nanoparticular Drug Carriers: Fundamentals and
Recent Applications, pp. 2-5, Germany, 2016

36. Didem Ag Seleci, Viktor Maurer, Frank Stahl, Thomas Scheper and Georg
Garnweitner, Rapid Microfluidic Preparation of Niosomes for Targeted Drug
Delivery,pp. 2, Germany, 2019

37. Mehrdad Hamidi & Hosnieh Tajerzadeh, Carrier Erythrocytes, pp.9-10, Canada,2002

38. Larisa Koleva, Elizaveta Bovt , Fazoil Ataullakhanov and Elena Sinauridze,
Erythrocytes as Carriers: From Drug Delivery to Biosensors, pp. 1-2, Russia, 2020

39. Mehrdad Hamidi & Hosnieh Tajerzadeh, Carrier Erythrocytes, pp.9-14, Canada,2002

40. Begum S. Gousia, D Mustafa, S Pareen, An Advanced Review on Resealed

Erythrocytes, pp.55-57, India, 2019
41. Regina Bailey, Structure of Red Blood Cells (Erythrocytes), 2019
 64

42. Vito Annese, Anna Latiano, Luigina Rossi, Giovanni Lombardi, Bruno Dallapiccola,
Sonia Serafini, Giancarlo Damonte, Angelo Andriulli, Mauro Magnani, Erythrocytes-
mediated delivery of dexamethasone in steroid-dependent IBD patients-a pilot
uncontrolled study, pp.1, 2005

43. M.R. Carvalho, R.L.Reis and J.M.Oliveira, Dendrimer Nanoparticles for Colorectal
Cancer Applications, ‘’ Dendrimer Nanoparticles’’, pp. 2-3, 2020

44. Jain and N. K. Jain, IPN Dendrimers in Drug Delivery, pp.1, 2020

45. P.Vega-Vasquez, N.S.Mosier and J. Irudayaraj, Nanoscale Drug Delivery Systems:

From Medicine to Agriculture, ‘’Nanogels’’,pp.8-9, Purdue University, 2020

46. ’What are Drugs?’’, pp.1, Australia,2019

47. M.Bihari, Drug Classes, pp.1, 2020

48. Celia JA Morgan, L.A.Noronha and H.V.Curran, Harms and Benefits Associated with
Psychoactive Drugs, pp.1-10, University College London, 2013

49. Z.Zhao and A.Ukidve, Targeting Strategies for Tissue-Specific Drug Delivery, pp.1-3,
Harvard University, 2020

50. V.P.Torchilin, Strategies and Means for Drug Targeting, pp.1-2, USA, 2002

51. M.F.Attia and N. Anton, An Overview of Active and Passive Targeting Strategies to
Improve the Nanocarriers Efficiency to Tumor Sites, pp.1-6, Universite de Strasbourg,
2019

52. NBIB, What are Drug Delivery Systems, pp.1- USA, 2016
 65

53. N.Muhamad, T.Plengsuriyakarn, Application of Active Targeting Nanoparticle

Delivery System for Chemotherapeutic Drugs, Thammasat University, 2019

54. J.K.Patra, Nano Based Drug Delivery Systems: Recent Developments and Future
Prospects, pp.1-3, Republic of Korea, 2018

55. B.Mukherjee, Nanosize Drug Delivery System, pp.1, Indıa, Vol.4, 2013

56. Munusamy Chamundeeswari, John Jeslin1, Madan Lal Verma, Nanocarriers for drug

delivery applications, pp. 850, Switzerland,2018

57. Yongtao Duan,a Abhishek Dhar,b Chetan Patel,c Mehul Khimani,c Swarnali Neogi,b
Prolay Sharma,b Nadavala Siva Kumar d and Rohit L. Vekariya, A Brief Review on
Solid Lipid Nanoparticles: Part and Parcel of Contemporary Drug Delivery Systems,
pp. 26786, China, 2020

58. Fakhar ud Din,Waqar Aman,Izhar Ullah,Omer Salman Qureshi, Omer Mustapha,

Shumaila Shafiqueand Alam Zeb, Effective Use of Nanocarriers as Drug Delivery
Systems for the Treatment of Selected Tumors, pp.7292, Pakistan,2017

59. Sunil Khatak, Harish Dureja, Recent Techniques and Patents on Solid Lipid
Nanoparticles as Novel Carrier for Drug Delivery, pp.1, 2015

60. Raj Kumar, Ashutosh Singh and Neha Garg, Acoustic Cavitation-Assisted
Formulation of Solid Lipid Nanoparticles using Different Stabilizers,pp 13361, India,
2019

61. K.M.Aguilar-Perez, Insight into Nanoliposomes as Smart Nanocarriers for Greening

the Twenty-First Century Biomedical Settings, pp.2-4, School of Engineering and
Sciences, 2020

62. Alveola, Vita-Liposome Moisturizing Day Cream Structure

 66

63. Sushant S. Kulthe, Yogesh M. Choudhari, Nazma N. Inamdar & Vishnukant Mourya,
Polymeric Micelles: Authoritative Aspects for Drug Delivery, pp.466-468, India, 2012

64. Babita Baruwati, Studies on the Synthesis, Characterization, Surface Modification and
Application of Nanocrystalline Nickel Ferrite, pp. 31, Osmania University, India, 2007

65. Yifei Zhang, Yixian Huang and Song Li, Polymeric Micelles: Nanocarriers for
Cancer-Targeted Drug Delivery, pp.862, USA, 2014

66. Oluwadamilola Kolawole, The Self-assembly of Star Shaped Polymer (palmitoyl

groups grafted unto 8-armed polyethylene glycol) - Opportunities for Drug Delivery.
pp.23, London, 2010

67. Fereydoon Abedi-Gaballua,b,c , Gholamreza Dehghanb, Maryam Ghaffaria,b, Reza

Yektab, Soheil Abbaspour-Ravasjanid, Behzad Baradarana, Jafar Ezzati Nazhad
Dolatabadie,**, and Michael R. Hamblin, PAMAM Dendrimers as Efficient Drug and
Gene Delivery Nanosystems for Cancer Therapy, pp.2-4, USA, 2018

68. Ebelegi Newton Augustus, Ekubo Tobin Allen, Ayawei Nimibofa, Wankasi Donbebe,
A Review of Synthesis, Characterization and Applications of Functionalized
Dendrimers, pp. 9, Nigeria, 2017

69. Prashant Kesharwani, KeertiJain, Narendra KumarJain, Dendrimer as Nanocarrier for

Drug Delivery, pp.284, India, 2014

70. Pushpendra Kumar Tripathi, Shalini Tripathi, Dendrimers for Anticancer Drug
Delivery, pp. 134, India, 2020

71. Abdelbary M. A. Elhissi, Waqar Ahmed,Israr Ul Hassan,Vinod. R. Dhanak and

Antony D’Emanuele, Carbon Nanotubes in Cancer Therapy and Drug Delivery, pp. 1-
2, UK, 2011
 67

72. Sheikhpour M, Naghinejad M, Kasaeian A, Lohrasbi A, Shahraeini SS,

Zomorodbakhsh S, The Applications of Carbon Nanotubes in the Diagnosis and
Treatment of Lung Cancer, pp. 7069, Iran, 2020

73. M.Yafout, Gold Nanoparticles as Drug Delivery System for Standard

Chemotherapeutics, pp.1-2, University of Casablanca, 2020

74. K.Hussain, Gold Nanoparticles: A Boon to Drug Delivery System, pp.2-7, Indıa, 2015

75. C.Bharti, Mesoporous Silica Nanoparticles in Target Drug Delivery Systems, India,
2015

76. Mohammad Reza Zamani Kouhpanji 1,2 and Bethanie J. H. Stadler, A Guideline for
Effectively Synthesizing and Characterizing Magnetic Nanoparticles for Advancing
Nanobiotechnology, pp. 1-3, USA, 2020

77. B. Mehrafrooz, An Improved Method for Magnetic Nanocarrier Drug Delivery Across
the Cell Membrane, Iran, 2019

78. J.Nogueira, Magnetic Driven Nanocarriers for Ph-Respnsive Doxorubicin Release in

Cancer Therapy, pp.1-3, Portugal, 2020

79. M.N.Ganivada, Biodegradable Magnetic Nanocarrier for Stimuli Responsive Drug

Release, pp.1-8, India, 2014

80. Edis Z, Wagas MK, Nanocarriers-Mediated Drug Delivery Systems for Anticancer
Agents, ‘’Quantum Dots’’, pp.8, United Arap Emirates, 2021

81. S.B.Rizvi, Semiconductor Quantum Dots as Fluorescent Probes for in vitro and in
vivo bio-molecular and Cellular Imaging, pp.4, University College London, 2010

82. S.A.A.Rizvi,Applications of Nanoparticle Systems in Drug Delivery Technology,

USA, 2018
 68

83. W.H.De Jong, Drug Delivery and Nanoparticles: Applications and Hazards, pp.8-10,
The Netherlands, 2008

84. C.E.Lopez, Quantum Dots Fluorescence Quantum Yield Measured by Thermal Lens
Spectroscopy, Brazil, 2014

85. Destache C.J., Belgum T. Combination antiretroviral drugs in PLGA nanoparticle for
HIV-1. BMC Infect. Dis. 2009

86. Mohd. Gayoor Khan, The Novel Drug Delivery, pp. 477-478, India, 2017

87. Vivek Agrahar, Novel Drug Delivery SystemsDevices and Fabrication Methods,
pp.1,India,2017

88. Mohd. Gayoor Khan, The Novel Drug Delivery, pp. 485, India, 2017

89. Stephanie Farrel, Robert P Hesketh, An Introduction to Drug Delivery for Chemical
Engineers, pp. 198-202, Rowan University, 2002

90. Rohan Chipra, How is Chemical Engineering Used in Drug Delivery Mechanism, pp
1, 2007

91. P.V.Vasquez, Nanoscale Drug Delivery Systems: From Medicine to Agriculture, USA,
2020

92. N.Desai, Challenges in Development of Nanoparticle-Based Therapeutics, 2012

93. S. Hua, Current Trends and Challenges in the Clinical Translation of Nanoparticulate
Nanomedicines:Pathway of Translational Development and Commercialization, pp.7,
Australia, 2018

94. Edis Z, Wagas MK, Nanocarriers-Mediated Drug Delivery Systems for Anticancer
Agents ‘’ Future Perspectives’’,pp.8, United Arap Emirates, 2021