Ndds SK Project

“TUMOR SPECIFIC DRUG DELIVERY: NOVEL APPROCHES”
A REPORT OF PROJECT WORK
Submitted to
RAJIV GANDHI PROUDYOGIKI VISHWAVIDHALAYA, BHOPAL
In Partial Fulfillment of the Requirement for the Degree of
BACHELOR OF PHARMACY
2021-2022
SUPERVISED BY: SUBMITTED BY:

MRS. SADHNA MANGROLE SHAHNAWAZ KHAN
ASST. PROFESSOR B. PHARMACY VII SEMESTER
ENROLL NO: 0516PY181084
VIVEKANAND COLLEGE OF PHARMACY VIP CAMPUS,

RATIBAD, SIKANDARABAD BHOPAL, 462044
VIVEKANAND COLLEGE OF PHARMACY
VIP CAMPUS, RATIBAD, SIKANDARABAD BHOPAL, 462044
CERTIFICATE
This is to certify that Mr. SHAHNAWAZ KHAN Enrollment No. 0516py181084 a

student of B PHARMACY final year has satisfactorily submitted project on “TUMOR SPECIFIC
DRUG DELIVERY : NOVEL APPROCHES" under my Supervision.
He has collected the literature very sincerely and methodically and his work his authentic.
PROJECT INCHARGE
Mrs. ABHILASHA DELOURI
ASSO. PROFESSOR
FORWARDING LETTER
Mr. SHAHNAWAZ KHAN has completed his project work entitled “TUMOR SPECIFIC DRUG
DELIVERY: NOVEL APPROCHES” Under the Supervision and Guidence of Prof. Mrs .Sadhna
mangrole fulfillment for the degree of Bachelor of Pharmacy.
The project is forwarded to RGPV Examiner for evaluation.
Dr. VIVEKANAND KATARE

(Principal)
DECLARATION
This is to certify that the dissertation word entitled “TUMOR SPECIFIC DRUG DELIVERY :
NOVEL APPROCHES" for the award of carried by our laboratories and library under the
guidance and supervision of DR. VIVEKANAND KATARE.
It also declare that present work embody has not the basic award for any degree or fellowship
previously. The particular given in this project is true to be best knowledge.
Dr. VIVEKANAND KATARE SHAHNAWAZ KHAN

(Principal) Enrollment. No. 0516py181084
ACKNOWLEDGEMENT
The completion of any project depends upon the co-operation, co-ordination

and combined efforts of several resources of knowledge, inspiration and energy. Therefore
I approach the important matter of project through these lines trying my best to give full
credit where it deserves.
I wish to express my deep sense of gratitude to my guide, Asst.Prof. Sadhna

mangrole, VCP Faculty of Pharmacy for his valuable guidance and support for this major
project. I am heartily thankful to her for providing me her valuable suggestions and
remarks to complete these major projects. I think without her guidance this thesis work
could not be so successful.
I express my profound indebtedness to Dr. Vivekanand Katare, Principal VCP

Faculty of Pharmacy, Bhopal for providing all facilities required for making the project
successful It gives me an immense pleasure to thanks and expresses my deep sense of
gratitude to my Teaching staff of college, who has been an invariable source of
inspiration to me.
I am also thankful to my Non-Teaching Members, who always helped me in al

situations.
I express my sincere grautude to my ever loving, affectionate, Parents, and my

friends who has been soils pillar of everlasting support and inspiration.
STUDENT
SHAHNAWAZ KHAN
INDEX
ABSTRACT…………………………………………………………………………..…07
INTRODUCTION………………………………………………………………….…08
NOVEL DRUG DELIVERY SHYSTEM……………………………………..…10
TUMOR…………………………………………………………………………..……..12
TARGETED DRUG DELIVERY………………………………………………...16
TUMOR TARGETED THERAPY…………………………………………..….19
TUMOR TARGETING DRUG DELIVERY SYSTEM………………….....21
APPROCHES TO TARGETING TUMOR
PASSIVE TARGETING…………………………………………………………………..23
ACTIVE TARGETING……………………………………………………………………25
INVERSE TARGETING………………………………………………………………….26
PHYSICAL TARGETING,LIGAND MEDIATED TARGETING…………….27
DUAL TARGETING, Double Targeting…………………………………………28
TARGETED DRUG DELIVERY CARRIERS…………………………..29
Liposomes………………………………………………………………………………….31
Dendrimers………………………………………………………………………………..34
Hydrogels…………………………………………………………………………………..37
Lipid-polymer hybrid nanoparticles (LPNs)………………………………38
Polymer-drug conjugates…………………………………………………………..39
Magnetic nanoparticles (MNP)…………………………………………………..40
Quantum dots (QDs)…………………………………………………………………..41
Lipid-based ……………………………………………………………………………….42
Inorganic Nanoparticles…………………………………………………………….43
Nucleic Acid/ Peptide based………………………………………………………44
Transdermal approach in drug Transportation………………………...46
Folate Targeting………………………………………………………………………...47
INTRACELLULAR TARGETING
Targeting the cytomembrane…………………………………………………….48
Lysosomal targeting…………………………………………………………………..49
Targeting the endoplasmic reticulum………………………………………..50
Targeting the mitochondria……………………………………………………….51
Targeting the cell nucleus………………………………………………………….53
Targeting the tumor microenvironment……………………………………54
DRUG DELIVERY SYSTEM-MWCNTS/DOX/TC

Multiwalled carbon nanotubes………………………………………………….55
DOXORUBICIN,TAT-chitosan conjugate (TC)……………………………..56
DRUG-LOADING AND RELEASE STUDIES IN VITRO…………………….57
In vivo monitoring of DOX release and antitumor efficiency……..59
Simultaneous monitoring of drug release and the antitumor
effect of MWCNTs/DOX/TC by non-invasive imaging………………61
Advantage of NDDS over conventional………………………………….63

ADVANTAGES, DISADVANTAGES…………………………………………..64
LIMITATIONS OF TUMOR TARGETING DRUG DELIVERY…….…64
CONCLUSION………………………………………………………………………...65
REFERENCES………………………………………………………………………...66
ABSTRACT
Currently, a majority of cancer treatment strategies are based on the removal

of tumor mass mainly by surgery. Chemical and physical treatments such as chemo- and
radiotherapies have also made a major contribution in inhibiting rapid growth of
malignant cells. Furthermore, these approaches are often combined to enhance
therapeutic indices. It is widely known that surgery, chemo- and radiotherapy also inhibit
normal cells growth. In addition, these treatment modalities are associated with severe
side effects and high toxicity which in turn lead to low quality of life. This review
encompasses novel strategies for more effective chemotherapeutic delivery aiming to
generate better prognosis. Currently, cancer treatment is a highly dynamic field and
significant advances are being made in the development of novel cancer treatment
strategies. In contrast to conventional cancer therapeutics, novel approaches such as
ligand or receptor based targeting, triggered release, intracellular drug targeting, gene
delivery, cancer stem cell therapy, magnetic drug targeting and ultrasound-mediated drug
delivery, have added new modalities for cancer treatment.
These approaches have led to selective detection of malignant cells leading to
their eradication with minimal side effects. Lowering multi-drug resistance and involving
influx transportation in targeted drug delivery to cancer cells can also contribute
significantly in the therapeutic interventions in cancer.
Keywords: Cancer; Cell Penetrating Peptides; Chemotherapeutics; Efflux Pumps; Gene therapy;
Immunotherapy; Stem cells; Targeted Drug Delivery; Tumor.
TUMOUR SPECIFIC DRUG DELIVERY SYSTEM
INTRODUCTION
Cancer is a group of diseases involving uncontrolled growth and spread of

abnormal cells. Such cells undergo transformations to obtain inexhaustible replication and
thus traverse to other organs leading to malignancy. Failure to regulate or prevent such a
spread of cancerous cells often leads to death of the patient. Cancer represents the most
common cause of death in the US, and accounts for nearly 1 of every 4 deaths [3].
Approximately, 14.5 million Americans with a history of cancer were surviving on January
1, 2014. Survival statistics vary with cancer type and diagnosis stage. In U.S., 1,658,370 new
cancer cases are expected to be diagnosed in 2015 and about 589,430 Americans are
expected to die of cancer. Within the years 2004–2010, the relative survival rate for all
cancers diagnosed was 68%, compared to 49% in 1975–1977 [3].
Several internal and external factors are responsible for this deadly disease
External factors include infectious organisms, unhealthy diet, pesticides, environmental
toxins and tobacco while internal factors includes inherited genetic mutations, immune
conditions and hormones. These factors may act together or in series to develop cancer.
There are several stages in cancer progression which is generally established with tumor
size, extent of primary tumor and spreading capability to nearby lymph nodes or other
organs. Diagnosis and staging are essential elements to initiate therapy. The conventional
cancer treatment methods include surgery, radiation and chemotherapy.
Several differences in normal and cancer biology render cancer therapy as
a multidisciplinary task. Targeted therapy based on distinct tumor type aiming to
maximize efficacy and minimize toxicity has remained extremely challenging. Targeted
therapy has not been particularly effective in treating certain tumors.
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The cancer genome atlas (TCGA) was founded to explore opportunities that
may provide a holistic approach for classification. TCGA researchers hypothesized a
multiplatform analysis of 12 cancer types, unravelling similarity of tumors based on
genetics and molecular biology.
This analysis generated a reclassification of approximately 10% of tumors

based on their cell origin instead of tissue site. Interestingly, TCGA’s integrative analysis
unified classification of 12 cancer types into 11 major subtypes
Eleven major cancer types include lung adenocarcinoma (LUAD), lung

squamous cell carcinoma (LUSC), breast adenocarcinoma (BRCA), uterine corpus
endometrial carcinoma (UCEC), glioblastoma multiforme (GBM), head and neck squamous
cell carcinoma (HNSC), colon and rectal carcinoma (COAD, READ), bladder urothelial
carcinoma (BLCA), kidney renal clear cell carcinoma (KIRC), ovarian serous carcinoma
(OV) and acute myeloid leukemia (AML) which were standardized according to their
mutational data from 3281 tumors. Analysis revealed that some tumors are molecularly
heterogeneous while others are homogenous.
As mentioned above, histological classification includes 100 different types of

cancer that are classified into 6 major categories: i.e. carcinoma, sarcoma, myeloma,
leukemia, lymphoma and mixed types.
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NOVEL DRUG DELIVERY SYSTEM
Novel drug delivery systems is the new system Recent advances in the
understanding of pharmacokinetic & pharmacodynamic behaviour of drug have offer a more
rational approach to the development of optimal drug delivery system. the novel drug delivery
systems (NDDS) are carriers which maintain the drug concentration in therapeutic range for
longer period of time There are several advantages of novel drug delivery systems over
conventional drug delivery.
 Optimum therapeutic- drug concentration in the blood or in tissue may be maintained

over a prolonged period of time.
 Pre- determined release rates of extended period of time may be achieved.
 Duration for short half- life drug may be increased
 By targeting the site of action, side effects may be eliminated.
 Frequent dosing and wastage of the drug may be reduced or excluded.
 Better patient compliance may be ensured.
Various drug delivery systems have been developed and some of them under
development with an aim to minimize drug degradation or loss, to prevent harmful side effects
and to improve drug bioavailability and also to favour and facilitate the accumulation of the drug
in the required bio- zone (site). There are no. Of novel carries which have been established and
documented to be useful for controlled and targeted drug delivery. It is important to critically
evaluate different terms used under the different broad categories of novel drug delivery system.
 Sustained- or controlled- drug delivery systems provide drug action at a pre determined rate
by providing a prolonged or constant (Zero-order) release respectively, at the therapeutically
effective levels in the circulation.
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 Localized drug delivery devices provide drug action through spatial or temporal control of
drug release (usually rate- limiting) in the vicinity of the target.
 Rate- pre-programmed drug delivery systems provide drug action by manipulating the
release of drug molecules by system design which control the molecular diffusion of drug
molecules.
 Targeted drug delivery provides drug action by using carries either for passive or active
targeting or one base or self programmed approach, usually anchored with suitable sensory
devices, which recognize their receptor at the target.
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TUMOR
A tumor is an abnormal lump or growth of cells. When the cells in the tumor are
normal, it is benign. Something just went wrong, and they overgrew and produced a lump.
When the cells are abnormal and can grow uncontrollably, they are cancerous cells, and
the tumor is malignant.
To determine whether a tumor is benign or cancerous, a healthcare provider can

take a sample of the cells with a biopsy procedure. Then the biopsy is analyzed under a
microscope by a pathologist, a healthcare provider specializing in laboratory science.
If you have been diagnosed with a tumor, the first step your healthcare provider
will take is to find out whether it is malignant or benign, as this will affect your treatment
plan. In short, the meaning of malignant is cancerous and the meaning of benign is
noncancerous. Learn more about how either diagnosis affects your health.
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BENIGN TUMOR: NONCANCEROUS
If the cells are not cancerous, the tumor is benign. It won't invade nearby tissues or spread
to other areas of the body (metastasize). A benign tumor is less worrisome unless it is
pressing on nearby tissues, nerves, or blood vessels and causing damage.
Fibroids in the uterus or lipomas are examples of benign tumors.
Benign tumors may need to be removed by surgery.1 They can grow very large, sometimes
weighing pounds. They can be dangerous, such as when they occur in the brain and crowd
the normal structures in the enclosed space of the skull. They can press on vital organs or
block channels.
Some types of benign tumors such as intestinal polyps are considered precancerous and
are removed to prevent them from becoming malignant. Benign tumors usually don't recur
once removed, but if they do, it is usually in the same place.
MALIGNANT TUMOR: CANCEROUS
Malignant means that the tumor is made of cancer cells, and it can invade nearby tissues.
Some cancer cells can move into the bloodstream or lymph nodes, where they can spread
to other tissues within the body—this is called metastasis.2 Cancer can occur anywhere in
the body including the breast, intestines, lungs, reproductive organs, blood, and skin.
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For example, breast cancer begins in the breast tissue and may spread to lymph nodes in
the armpit if it's not caught early enough and treated. Once breast cancer has spread to the
lymph nodes, the cancer cells can travel to other areas of the body, like the liver or bones.
The breast cancer cells can then form tumors in those locations. A biopsy of these tumors
might show characteristics of the original breast cancer tumor.
PATHOGENESIS :
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TUMOR TARGETING
Approaches for targeted delivery of therapeutics in cancer typically involves systemic

administration of therapeutics packaged in nanocarriers (NCs) or localized delivery of
therapeutics to the diseased tissue. Encapsulation of therapeutic molecules (e.g., small
molecule inhibitors, chemotherapy, RNAi, etc.) in NCs can improve their solubility and
bioavailability, alter their bio-distribution, and can also facilitate entry into the target cell.
“Passively” targeted NCs, which utilize the enhanced permeability and retention (EPR)
effect1, are the most extensively explored strategy for targeting cancer systemically.
However, only a small percentage of these NCs accumulate even in high-EPR xenografted
tumors (less than 1% according to a recent meta-analysis study2). This could be due to
multiple physiological barriers (Fig. ) and a high degree of stochasticity involved in NCs
extravasation through the tumor vasculature2. A major proportion of NCs are also cleared
by the mononuclear phagocytic system (MPS); some get physically “stuck” in the sinusoids
of the liver and others are taken up by hepatocytes and Kupffer cells
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 Targeted drug delivery system is achieved with the advantage of morphology and
physiological differences between the normal cells and tumor cells.
 An ideal anticancer drug delivery system should fulfill the following requirements
Effectively kill tumor cells
 Be non-toxic for healthy organs, tissues, and cells
 Not induce multidrug resistance
MOLECULAR TARGETS FOR TUMOR THERAPY
 Altered expression of cell adhesion molecules.
 Altered expression of receptors during certain stages of cellular differentiation, like

transferrin receptors, folate receptors, etc.
 Altered expression of certain growth factors like epidermal growth factor receptor
(EGFr).
 Expression of tumor vasculature epitopes.
 Expression of surface determinants on malignant cells, like tumor
 associated genes(TAA).
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DRUG TARGETING TO TUMOR IS BASED ON:
 EPR effect(Enhanced Permeability and Retention).

 Nanoparticle properties and design.
 Ligand-receptor interactions.
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TUMOR TARGETED THERAPY
 Hormone therapies
o Hormone therapies slow or stop the growth of hormone-sensitive tumors, which require
certain hormones to grow Hormone therapies act by preventing the body from producing
the hormones or by interfering with the action of the hormones. Hormone therapies have
been approved for both breast cancer and prostate cancer.
 Signal transduction inhibitors

o Signal transduction inhibitors block the activities of molecules that participate in signal
transduction, the process by which a cell responds to signals from its environment. During
this process, once a cell has received a specific signal, the signal is relayed within the cell
through a series of biochemical reactions that ultimately produce the appropriate
response(s). In some cancers, the malignant cells are stimulated to divide continuously
without being prompted to do so by external growth factors. Signal transduction inhibitors
interfere with this inappropriate signalling.
 Gene expression modulator

o Gene expression modulators modify the function of proteins that play a role in controlling
gene expression.
 Apoptosis inducer
o Apoptosis inducers cause cancer cells to undergo a process of controlled cell death called
apoptosis. Apoptosis is one method the body uses to get rid of unneeded or abnormal cells,
but cancer cells have strategies to avoid apoptosis. Apoptosis inducers can get around
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these strategies to cause the death of cancer cells.
 Angiogenesis inhibitor
o Angiogenesis inhibitors block the growth of new blood vessels to tumors (a process called
tumor angiogenesis). A blood supply is necessary for tumors to grow beyond a certain size
because blood provides the oxygen and nutrients that rumors need for continued growth
Treatments that interfere with angiogenesis may block tumor growth Some targeted
therapies that inhibit angiogenesis interfere with the action of vascular endothelial growth
factor (VEGF), a substance that stimulates new blood vessel formation. Other angiogenesis
inhibitors target other molecules that stimulate new blood vessel growth.
 Immunotherapies
o Immunotherapies trigger the immune system to destroy cancer cells. Some
immunotherapies are monoclonal antibodies that recognize specific molecules on the
surface of cancer cells. Binding of the monoclonal antibody to the target molecule results
in the immune destruction of cells that express that target molecule. Other monoclonal
antibodies bind to certain immune cells to help these cells better kill cancer cells.
 MONOCLONAL ANTIBODIES
o Monoclonal antibodies that deliver toxic molecules can cause the death of cancer cells
specifically. Once the antibody has bound to its target cell, the toxic molecule that is linked
to the antibody-such as a radioactive substance or a poisonous chemical is taken up by the
cell, ultimately killing that cell. The toxin will not affect cells that lack the target for the
antibody ie, the vast majority of cells in the body.
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TUMOR TARGETING DRUG DELIVERY SYSTEM
 Targeted drug delivery system is achieved with the advantage of morphology and
physiological differences between the normal cells and tumor cells.
 An ideal anticancer drug delivery system should fulfill the following requirements
o Effectively kill tumor cells
o Be non-toxic for healthy organs, tissues, and cells
o Not induce multidrug resistance.
APPROCHES TO TARGETING TUMOR
Drug targeting is defined as the ability of a drug molecule to accumulate in

the target organ or tissue selectively such that the concentration of the drug at the disease
site is high, while its concentration in nontarget organs and tissues is low, preferably,
below certain minimal level so as to prevent any toxic effect. Thus, drug targeting can
overcome the non-specific toxic effect of conventional drug delivery. This may also reduce
the amount of drug required to dose. A drug can be targeted on the level of a whole organ,
on the level of certain cells specific for a given organ, or even on the sub-cellular level of
specific tissue.
The concept of drug targeting was first mentioned by Paul Ehrlich when he
suggested the hypothetical “magic bullet” as an entity consisting of two components — the
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first one should recognize and bind the target, while the second should provide a
therapeutic action in this target. Currently, the concept of ‘magic bullet’ includes a
coordinated behavior of three components – drug, targeting moiety and pharmaceutical
carrier.
Various pharmaceutical carriers explored for targeting drug include

polymeric micelles, liposomes, nanoparticles such as solid lipid nanoparticles, gold
nanoparticles, quantum dots, etc. All these carriers can be made targeted in one way or
another. The most widely-used approach involves utilizing specific targeting moieties.
However in certain cases, physical principles or some physiological features of the target
area may be utilized for a successful targeting of pharmaceuticals and pharmaceutical
carriers.
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PASSIVE TARGETING
This is based on the accumulation of drug at areas around the site of interest,
such as tumor tissues, in higher quantities when compared to healthy body parts . Such an
accumulation at an area of interest is called Enhanced Permeability Retention (EPR) effect.
Solid tumors have inherent abnormalities of tumor vasculature. Conventional anticancer
drugs rely on passive targeting due to the fact that comparatively higher concentration of
the drug is accumulated in cancerous cells due to faster and higher blood supply to them.
This is due to the stimulation of blood vessel growth by signaling out

angiogenic factors. These abnormalities of tumors can be further exploited for passive
targeting of anticancer drugs, particularly nanoparticulate anticancer drugs. Nano-sized
macromolecular anticancer drugs are relatively large and hence those administered
intravenously can escape renal clearance.
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These large-sized drugs are unable to penetrate through tight endothelial

junctions of normal blood vessels and hence their concentrations build up in the plasma to
result in long plasma half-life for these drugs. They are then forced out of blood to
concentrate in tumor tissues since the latter have abnormal vascular nature.
This result is progressive building up of nanoparticulate drugs in tumors up

to severalfold higher concentrations than that in plasma. The build-up is further facilitated
since the solid tumors have no efficient lymphatic drainage. Another example for passive
targeting is the ability of anti-malarial drugs to be targeted for the treatment of microbial
infections such as leishmaniosis, candidiasis and brucellosis.
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ACTIVE TARGETING
As described above, some drugs, particularly nanoparticulate drugs have

their own passive targeting. Targeting can be enhanced by deliberately introducing ligands
having high affinity to receptors either to drugs or by co-encapsulating the drug and
required ligands in nanoparticles to result in ligand-receptor interactions in order for drug
to find the receptor site more efficiently and effectively.
However, interactions between a ligand and a receptor work only when the
two are in close proximity of around less than 0.5 nm. As such, active receptor targeting
actually occurs only after blood circulation and extravasation of the drug to the cancerous
cells. One classic example is the folic acid-folate receptor interactions. Folate receptors
(FRα, FRβ and FRγ) are glycoproteins which have cysteine-rich cell-surfaces
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These receptors have high affinity to folate and hence they mediate
cellular uptake of folate. Folate receptors such as FRα are present in very low levels in
ordinary tissues but they are expressed at high levels in many cancers in order to meet the
folate demand of rapidly dividing cells under low folate conditions. This is exploited in the
administration of anti-FRα antibodies, high-affinity antifolates, folatebased imaging agents
and folate-conjugated drugs and toxins.
As such, folate can be coencapsulated with the active drug or combination
of drugs in porous nanoparticles for active targeting of the formulation to cancer cells.
Active targeting can be sub-divided into three different targeting levels; First Order, Second
Order and Third Order Targeting. In the first order targeting, the drug is distributed to
capillary beds of general target sites such as organ or tissue. In lymphatic tissues,
peritoneal cavity, pleural cavity, cerebral ventricles, eyes and joints are such targeting sites.
In the second order targeting, the targeting of drugs is aimed at specific sites such as the
tumor cells. One such example is the targeting of drugs to Kupffer cells in liver . Third order
targeting is the next type of drug targeting wherein the drug is intracellularly localized at
the target site via endocytosis or through receptor-based ligand mediated interactions.
INVERSE TARGETING
When the passive uptake of colloidal carrier is avoided by Reticulo Endothelial

Systems (RES) the process is called inverse targeting of drugs. In order to achieve this,
regular function of the RES is suppressed by pre-injecting a large amount of blank colloidal
carriers or macromolecules such as dextran sulphate. This approach facilitates the
saturation of RES and suppression of defense mechanism. This type is commonly
considered as an effective approach to target drug(s) to non-RES organs of the body
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PHYSICAL TARGETING
Physical targeting utilizes some characteristics of environment conditional

changes like pH, temperature of the system, light intensity, magnetic field, electric field or
ionic strength and other small and even specific stimuli like glucose concentration or
gaseous concentration are used to localize the drug carrier to predetermined site [40]. This
approach is the most preferred one in nanoparticulate drug targeting to tumors as well as
in cytosolic delivery of entrapped drug or genetic materials. This is because these physical
factors can indeed help control release of the drug at the site of the cancer.
LIGAND MEDIATED TARGETING
 Ligands are carrier surface group(s) which can selectively direct the carrier to the pre-
specified site(s) housing the appropriate receptor units to serve as "homing device to the
carrier/drug.
 Most of the carrier systems are colloidal in nature & can be specifically functionalized using
various biologically-relevant molecular ligands including antibodies, polypeptides,
oligosaccharides, viral proteins & fusogenic residues.
 The ligands confer recognition & specificity upon drug carrier & endow them with an
ability to approach the respective target selectivity & deliver the drug.
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DUAL TARGETING
The specialty in this targeting approach is that the carrier molecule itself has
its own therapeutic activity and hence increases the therapeutic effect and the activity of
the drug. For instance, a carrier molecule with its own antibacterial or antifungal activity
can be loaded with antibacterial drug or antifungal drug and the net synergistic effect of
drug conjugate or the composite can be observed. For example, ZnO nanoparticles have
antibacterial activities and when antibacterial drugs are loaded in porous ZnO
nanoparticles both the carrier and the drug are effective against the bacteria and hence the
corresponding TDD is dual targeting.
Double Targeting
When temporal and spatial methodologies are joined to target a carrier system
then it is termed dual targeting. Here, the spatial placement targets drugs to specifically
identified organs, tissues, cells or even subcellular compartments and temporal delivery
enables controlling the rate of drug delivery to target site of interest
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TARGETED DRUG DELIVERY CARRIERS
Targeted drug delivery requires specific carrier systems. TDD carrier is

a special molecule, particle, composite or system, essentially required for effective
transportation of loaded or encapsulated drug up to the targeted site. They are purposely
engineered vectors capable of retaining the drug inside or onto them either via
encapsulation and/or via bonding with the help of a spacer moiety. These drug-containing
carriers should be able to preferentially transport to the vicinity of target cells. Any drug
delivery system includes a target and the drug carriers or markers essential for it. Here,
the target means an organ or a tissue or a cell or a receptor which is in need of treatment.
An ideal drug delivery vehicle should even have the following requirements.
They should be capable of crossing even tenacious sites such as a blood-

brain barrier, easily recognized by the target cells, and the drug-ligand complex, if formed,
should be stable, non-toxic and biodegradable after completion of the task assigned to it.
Biodegradable nature of drug carrier is essential so that it can be cleared away by the body
through physiological mechanisms, thus avoiding any chance of their accumulation within
cells that may lead to cytotoxicity. Nanotechnology-based delivery systems are now
studied for their utilization in the field of TDD. Recently, nanomedicine has emerged as a
powerful field of applications of nanotechnology in medical sector. Drug delivery at
nanoscale has now become possible due to the development and fabrication of various
nanostructures . These nanostructures are capable of protecting drugs from their
fragmentation by various enzymes of the gastrointestinal tract and carry the drug right
into the target in safest possible manner. These particles or structures can easily penetrate
tissues and are readily taken up by cells.
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This allows for effective targeted delivery. The uptake of nano-sized

particles is reported to be about 15-250 times higher in comparison to microparticles .
Advantages of nanoccarier based TDD over conventional DD include higher surface area to
volume ratio, higher and more reactive activity centers, stronger adsorption capacity and
other characteristics such as morphological preferences. Nanoparticle-based TDD to
specific organs is commonly used by modifying antibodies, aptamers such as
oligonucleotide or peptide molecules, folic acid and other biological molecules such as
DNA, RNA . These carriers have relatively unique and specific mode of controlling and
releasing drugs to the targeted sites. Mode of controlling and releasing drugs of
nanocarriers is initially an outbreak release, and finally, leading to a constant release for a
long period of time. Hence, nanocarriers for drugs can significantly extend the efficiency of
drugs at limited concentration, deliver at lesser intervals with significantly lower doses and
considerably reduced side effects with less suffering of patients from various types of
diseases.
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Liposomes
Liposomes are the first to be discovered as drug delivery vehicles. These are
vesicles consisting of an aqueous core bounded by a hydrophobic lipid bilayer as
diagrammatically shown in Fig.
Figure: Cross-section through liposome (Adapted from Philcha [Public

domain], via Wikimedia Commons). Accessed on 04/02/2018 @ Peradeniya, Sri Lanka.
Solutes such as polar drug molecules entrapped inside the core are so tightly entrapped so
that they find it difficult to overcome the hydrophobic barrier . The bilayer permits the
absorption of hydrophobic molecules so that liposomes can carry both hydrophilic and
hydrophobic molecules. Therefore, they are termed amphiphilic carriers. Different
liposomes may differ in their biochemical composition, size, and number of layers.
They can have a single bilayer or multiple bilayers. Drugs held and delivered
by liposomes have significantly enhanced pharmacokinetic properties with high
therapeutic index; i.e., the ratio between the amounts of a therapeutic agent that causes the
therapeutic effect to the amount that causes toxicity. Other advantages of liposomes are
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that they have a fat metabolic action and lower toxicity apart from in vitro and in vivo anti-
cancerous activity. Once drugs are encapsulated in the core of liposomes, the drugs are not
in contact with biological fluids containing enzymes, acidity etc. Therefore, the drugs are
protected from untimely degradation. Additionally, liposomes can be coated with polymers
such as poly(ethylene glycol) (PEG) to enable the entrapped drugs to have increased half-
life. In order to intensify target-specificity, liposomes can be associated with ligands or
antibodies. Such liposomal drugs are already in the clinical use. For example, DOXIL
(Doxorubicin.HCl liposome injection) is doxorubicin hydrochloride (Fig. ), which is an
anthracycline topoisomerase II inhibitor, encapsulated in STEALTH® liposomes
(Illustrated in Fig. ) for intravenous use which was given the approval in 1995 as a remedy
for AIDS-related Kaposi’s sarcoma in patients after failing prior systemic chemotherapy or
intolerance to such therapy . The STEALTH liposome carriers are composed of cholesterol
(3.19 mg/mL), fully hydrogenated soy phosphatidylcholine (HSPC) (9.58 mg/mL) and N-
(carbonylmethoxypolyethylene glycol 2000)-1,2- distearoyl-sn-glycero-3-
phosphoethanolamine sodium salt (MPEG-DSPE) (3.19 mg/mL). Each milliliter also
contains ammonium sulphate (~ 0.6 mg), histidine as a buffer; hydrochloric acid and/or
sodium hydroxide for pH control and sucrose to maintain isotonicity. It is important to note
that greater than 90% of the drug is encapsulated in the STEALTH liposomes.
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Figure : Structure of doxorubicin.HCl [(8S,10S)-10-[(3-amino-2,3,6-

trideoxy-α-Llyxohexopyranosyl) oxy]-8-glycolyl-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-
methoxy-5,12 naphthacenedione.hydrochloride.
Figure : Pictorial representation of STEALTH liposome DOXIL, in combination

with bortezomib, is indicated for the treatment of patients with multiple myeloma who
have not previously received bortezomib and have received at least one prior therapy
[https://www.rxlist.com/doxil-drug.htm]. Therapeutic potency of drugs is enhanced by
their targeted delivery through ligand-conjugated liposomes. Pervasive pre-clinical studies
have further proved the importance of targeted liposomes in TDD which can be considered
as an improved drug potency. However, it is well known that liposomes are not appropriate
for sustained release of drugs, which is a limitation in liposome-based TDD .
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Dendrimers
Dendrimers (Dendritic polymers) are another type of drug carriers used

in TDD. They are synthetic, unimolecular, branched nanostructures (~ 20 nm in size)
comprising of a core or focal point and multiple branched layers of repeated units with
high density of function terminal groups. The specific characteristics of dendrimers
include uniform and controlled size parameters, monodispersity, and modifiable surface
group functionalities useful in biomedical applications. The terminal groups can be
functionalized with several therapeutic, targeting, and imaging agents in a specific and
controllable manner. Dendrimers attain a spherical or globular shape with internal cavities
after 3rd and 4th generation of dendrimer series are introduced. These are used to
physically encapsulate guest molecules. In Fig. , chemical structure of polyethylenimine
dendrimer belonging to the 4th generation is illustrated . The internal void volume can be
used to encapsulate hydrophobic guest molecules and drugs. The resulting
drugencapsulated functionalized dendrimers have important properties such as water
solubility and biocompatibility.
Figure 6: Chemical structure of Polyethylenimine Dendrimer Generation 4 (G4)
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Dendrimers can be used as TDD vehicles to carry different drugs. The drugs
may either be encapsulated in the core via hydrogen bonding, hydrophobic interactions,
and chemical bonding or else via covalent bonding on the terminal groups. Bioactive
molecules such as DNA can be carried using electrostatic interactions. The use of
dendrimers for delivering photosensitizers in photodynamic therapy of cancer treatment
was reported by Zhang et al.
Recently, Generation 3 (G3) PAMAM-implanted porous hollow silica
nanoparticles (PHSNPs) have been developed for carrying photosensitizers for
photodynamic therapy .Poly(amidoamine) (PAMAM) dendrimes are particularly used for
delivering low molecular weight anti-cancer drugs, such as, methotrexate, cisplatin,
doxorubicin, 5-FU, and anti-inflammatory drugs including ibuprofen, piroxicam,
indomethacin (The structural formulae of these drugs are given in Figs.
The potential of these dendrimers can be intensified by attaching targeting
ligands to their multivalent surface. As an example, PANAM dendrimer conjugated with
folic acid and methotrexate drug was shown to selectively bind and kill KB tumor cells that
overexpress folate receptor (FR) in vitro and in vivo. Surface charge of the dendrimers also
have profound effect on drug interactions. For example, positively charged surface of (G4-
PAMAM-NH2) and neutral surface (G4 PAMAM-OH), were found to be able to inhibit
enzymatic activity of pepsin which has negatively charged surface while negatively
charged dendrimer (G3.5 PAMAMCOOH) was not able to inhibit the enzymatic activity of
pepsin. This indicates important role played by electrostatic interactions between
dendrimers and the proteins.
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Hydrogels
Hydrogels are three-dimensional structures composed of cross-linked

networks of water-soluble polymers. Hydrogels can be made from any water-soluble
polymer so that they are associated with wide range of chemical compositions as well as
bulk physical properties. Additionally, hydrogels can be readily changed to various
physical forms such as microparticles, nanoparticles, coatings and films. As such, hydrogels
are commonly used in wide range of applications, including tissue engineering and
regenerative medicine, clinical practice, experimental medicine, diagnostics, cellular
immobilization, separation of biomolecules or cells.
Drug delivery applications of hydrogels are mainly based on their unique
physical properties. The affinity of the hydrogels and the density of cross-links in the gel
matrix tune their porous structure. The loading capacity of the drug mainly depends on the
porosity of the gel matrix. Hydrogels are also generally extremely biocompatible.
Biocompatibility is endorsed by the high water content of hydrogels and their
physiochemical resemblance. Biodegradability is designed into hydrogels via enzymatic,
hydrolytic, or environmental such as pH, temperature, and electric field or magnetic field
pathways.
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Lipid-polymer hybrid nanoparticles (LPNs)
To overcome the limitations of polymeric nanoparticles and liposomes in

their individual basis, a new generation of delivery vehicles called lipid–polymer hybrid
nanoparticles (LPNs) have been developed. The specificity of LPNs, is that they combine
the characteristics of both polymeric nanoparticles and liposomes together to have
synergistic effects. They have three components; viz. a polymer core in which the
therapeutic drugs are encapsulated, an inner lipid layer inclosing the polymer core, and an
outer lipid-PEG layer. The outer lipid-PEG layer acts as a stealth coating that extends in
vivo circulation time of the LPNs while providing steric stabilization. The inner lipid layer
functions as a molecular boundary that reduces leakage of the encapsulated drugs.
The inner lipid layer also helps to reduce the polymer degradation rate by
limiting inward water diffusion. In other words, it improves for the sustained release
kinetics of the drugs. It is clear therefore that the lipid-polymer hybrid nanoparticles act as
a platform to unite the merits of liposomes and polymer nanoparticles. Several of them
have been developed by now. Recently, characterization of polymeric nanoparticles with a
lipid coating, comprising a core of PLGA, a shell of PEG and a monolayer of lipid, has been
carried out. Results are that the core can carry sparingly water soluble drugs, the shell
enhances circulation half-life of the drug and the lipid monolayer at the interface of core
serves to maintain sustained release of the drug from the core and boost the drug retention.
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Polymer-drug conjugates
Polymer–drug conjugates (P-DCs) have been developed to replace

traditional small molecule therapeutics and offer numerous significant advantages over
the traditional methods. These conjugates have been designed to have a covalent bond
between a water-soluble polymer and a bioactive molecule. The polymer can safeguard the
drug from degradation or chemical reactions with components present in the path. It,
therefore, increases drug circulation time, helps control release of drug triggered by
differences in pH, temperature, enzyme concentration, or attached ligands for targeting of
the desired site of therapeutic need.
Further, the polymer-drug conjugates have a specific advantage of increased
reduction in the uptake by reticuloendothelial system (RES) or macrophages due to stealth
effect of the polymer. In 1975, Ringsdorf was the first to propose a model for
pharmacologically active polymers. A multitude of drug-conjugates, employing linear
polymers, have been recently manufactured. Most widely explored ones are those made
using polyethylene glycol (PEG and N-(2-hydroxypropyl)methacrylamide (HPMA)
copolymers. PEG-protein conjugates are of significant interest, since PEG can provide
protection against enzymatic degradation of proteins and also helps to lower the
absorption by the reticuloendothelial system.
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Magnetic nanoparticles (MNP)
The targeted delivery of anti-tumor agents adsorbed on the surface of MNPs

is a favorable alternative to conventional chemotherapeutic methods. MNP can be used to
treat cancers in three different ways. Basically, specific antibodies can be conjugated with
the MNPs to selectively bind to particular receptors and prevent tumor growth. Targeted
MNPs can also be used for hyperthermia for tumor therapy.
Drugs can be loaded onto the MNPs for targeted therapy. The drug/carrier
complex is then injected into the body either via intravenous or intra-arterial injection.
High-gradient, external magnetic fields are used to guide and concentrate the drugs at
tumor locations. The magnetic carrier of interest is concentrated at the specific target site
in vivo manner. Therapeutic agent is then released from the magnetic carrier, either by
variations in physiological conditions such as pH, osmolality, or temperature or via
enzymatic activity conditions leading to increased uptake of the drugs of interest by the
cancerous cells at the target sites.
These are micro-and nano-scale magnetic particles loaded or conjugated with
drugs that get activated when exposed to an active magnetic field. They release the drug at
the specific target site. It is an extremely controllable and effective arrangement of drug
targeting. In addition to delivery process, these particles are appropriate for safe image
guided drug delivery also. MNPs avoids RES clearance and provide image guided delivery
with magnetic resonance imaging (MRI). It controls releasing of the drug with
exceptionally high targeting. Drawbacks of MNPs are gradient loss for deep seated tissues,
accumulation of magnetic material at particular targeted site and requirement for
specialized manufacturing. Magnetic particles up to 100 nm are generally phagocytosed
through liver cells. Iron oxides with core/shell structure are the widely used sources of
magnetic materials.
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Quantum dots (QDs)
Quantum dots are currently found to be significant enough to carry out

different industrial applications (Fig. 9). They can also be used in TDD and concurrent
imaging. This is particularly useful in the case of cancer diagnosis and treatment. Quantum
dots, made up of zinc oxide doped with Mn2+ (ZnO:Mn2+), loaded with drugs and enclosed
in chitosan, possess a great potential for delivering drugs specifically targeted to tumors.
They can report the process of drug delivery at the same time due to their luminescence
effects. Apoptosis of tumor cells is expected to improve by the use of ZnO:Mn2+ quantum
dots. Ideal QD nanomaterials should have the following specific properties.
They should not react with the drugs, should have high drug loading capacity
and high encapsulation efficiency. There should be an appropriate preparation and
purification methods for the QD. QDs that we prepare for targeted drug delivery should
have good biocompatibility and should not be toxic to the human body. They should have
required mechanical strength and stability and best morphological properties such as
appropriate particle size and shape. QDs are 0-D nanomaterials which have unique optical
and electrical properties, due to their quantum-size effects such as quantum confinement
effect, dielectric confinement effect, and macroscopic quantum tunneling effect. They have
size- and shape-dependent properties and unique surface effects such as surface Plasmon
resonance effect. These give rise to many optical properties such as tunable emission,
photostability, and brightness, and have a very broad application prospect in biological
fluorescent probes and functional materials. Hence, QDs will have diversified biomedical
applications in the continued development of life sciences and targeted drug delivery
system development (Fig. 9).
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Figure 9: ZnCdSeS alloyed Quantum dots with vivid colours stretching from violet to deep
red.
Lipid-based
Liposomes are commonly used for targeting water insoluble drugs, enabling
them to be used as targeted delivery systems particularly for such drugs. For example, the
biocompatibility and possible diversity with structures and compositions make them
suitable for a number of TDD applications. There are several types of liposomes that are
used in the biomedical field. These include conventional liposomes, stimuli-responsive
liposomes, stealth liposomes, targeted liposomes, and polymer composite liposomes.
Liposome-based drug delivery systems enable passive/active targeting and easy and rapid
internalization. They also have low immunogenicity. Another important advantages are
high bioavailability and high biocompatibility. But there are some drawbacks as well. Rapid
degradation of liposomes in the cell system (uptake by RES (reticuloendothelial system),
poor scale-up ability, need for extensive modifications of liposomes for different tasks, are
some of those drawbacks.
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Targeted liposomes and environment- sensitive liposomes are the ones with
maximum potential for targeting to cancers and treating neurodegenerative disorders.
Several of such prevailing chemotherapeutics have been entrapped in stimuli-responsive
liposomes for successful drug targeting.
Inorganic Nanoparticles
Nanostructured materials have exceptional properties and capabilities to

make specific interactions with biological systems which can be harnessed predominantly
in TDD applications. Several organic nanoparticles have been developed successfully using
polymers, liposomes and micelles. But, they have some disadvantages such as low chemical
stability, inappropriate drug releasing rates, possibility of microbial contamination, and
the effects of the organic solvents used. On the other hand, inorganic nanoparticles are non-
toxic, more stable than organic materials, hydrophilic, and biocompatible, and also they
have high cellular uptake capacity and non-immunogenic response. Electromagnetic,
optical and catalytic properties of metal nanoparticles depend on their shape and size and
hence tailor-made material can be made.
Biomedical applications of metal nanoparticles emerged as a result of the
development of metalbased nano-conjugates. They were eventually used for drug delivery
applications as vehicles for delivering drugs, proteins, peptides, plasmids, nucleic acids for
detection, diagnosis and various therapeutic processes. Recently, many industries are
developing nanotechnology-based materials for the applications for anticancer drug
encapsulation, as prostheses and implants, implanted insulin pumps, and in gene
therapeutic applications.
Various inorganic nanoparticles such as calcium phosphates, iron oxide
nanoparticles and fullerenes have been synthesized and developed as excellent drug
delivery matrices.
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Carbon nanotubes and nanoparticles and different types of nanoconjugates have been
studied as drug delivery carriers. As their size confines to the nanometer range, they can
move effortlessly inside the body. Drugs can be either introduced into the nanotube or
attached externally or internally on to the particle surface. These nanomaterials include
silica, metal nanoparticles, metal hydroxides, carbon and so on. A number of
multifunctional, inorganic nanoparticles are being developed for TDD and imaging
applications. Carbon-based nanoparticles and gold-based (AuNPs) nanoparticles are very
much common in TDD. They have inherent optical properties enabling them in imaging
applications. Silica/Alumina/ZnO nanoparticles, quantum dots, metal/oxide/sulfide-based
nanoparticles are some such examples. Drawbacks are mainly the issues with regard to
toxicity and non-biodegradability leading to accumulation of chemicals in the body.
Inorganic nanoparticles with multiple functionalities can be developed which will prompt
further research for development of effective cellular delivery systems. Gold-based colloids
and nanoshells are currently used in clinical trials for cancer applications.
Nucleic Acid/ Peptide based
Peptides are short chains of amino acid monomers (lesser than 50 amino acids) connected
by peptide (amide) bonds. The covalent chemical bonds are formed from the reaction of
carboxyl group of one amino acid with the amino group of another. Dipeptides are the
shortest, consisting of 2 amino acids joined by a single peptide bond. Tripeptides,
tetrapeptides can be synthesized by the linkage of respective amounts of amino acids
reacting with each other. A polypeptide is a long, continuous, and unbranched peptide
chain. With the development and the popularization of recombinant proteins and effective
protein purification methods, exquisite potency of the peptide based drug delivery systems
has been realized. A new protein-based drug classification was introduced.
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It is referred to as ‘Biologics’ which include molecules such as engineered

antibodies, insulin hormone, etc. Peptides and proteins bind with exquisite specificity to
their in vivo targets. This reduces unnecessary side effects. Huge array of structural and
functional diversity of these molecules possess high degree of selectivity in their specific
interactions. So, it is easy to fine tune the peptide-based molecules for binding with
biologically specific targets. Normally, injection methods are used to deliver current
peptide therapeutics. Some examples for the peptide based drugs currently used are
oxytocin, Fuzeon (antiretroviral), calcitonin (hypercalcemia, osteoporosis), teriparatide
(parathyroid hormone analog, osteoporosis) and growth-hormone releasing hormone.
However, applications of chemically synthesized different peptides have been severely
restricted due to factors such as their low systemic stability, poor membrane permeability,
and so on . But, in a work done by the Kessler group, a research on cyclic N-methylated
somatostatin analogs associated to the Veber-Hirschmann peptides were developed (Fig.
11). They were able to synthesize about 30 compounds by varying degrees of methylation
of the secondary amides enclosed in the starting macrocycle . Furthermore, in vitro
evaluation studies have shown that specific methylation of D-Trp8, Lys9, and Ph11
considerably enhances the cell membrane permeability. This is also considered as an oral
biocompatible compound according to rat studies.
Figure 11: General structure of the Veber–Hirschmann peptides.

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Transdermal approach in drug Transportation
Transdermal drug delivery systems, such as the use of patches, ointments and
creams, have been around for several years. These systems enhance the skin permeation
of low molecular weight usually < 500 Da, lipophilic drugs that are effective at low doses.
However, improvements to this approach is required for hydrophilic molecules and
macromolecules. In order to make the transdermal drug delivery methodology suitable for
large, hydrophilic molecules and macromolecules, nano-carriers made of lipids, metals, or
polymers have been successfully used. Nanocarriers increase penetration of drugs or
vaccines. In this way, it is possible to achieve controlled drug release and also to target
drugs to specific areas of skin in vivo. A transdermal drug delivery carrier can be of a
passive design or an active design.
It provides an alternative pathway for administering drug to specific site
where the drug is delivered across the skin barrier. The passive approach relies on the
optimization of formulation or drug carrying vehicle to increase skin permeability.
However, passive methods are not very suitable for large drug molecules of over 500 Da
molecular weights. Active methods rely on physical or mechanical methods of enhancing
drug delivery and hence active methods have been shown to be much superior to passive
methods. Active methods have been used for the delivery of drugs of differing lipophilicity
and molecular weight.
These include proteins, peptides, and oligonucleotides. Electrical methods such
as iontophoresis, electroporation, mechanical methods such as abrasion, ablation,
perforation, and other energy-related techniques such as ultrasound and needless
injection have been successfully used in active transdermal drug delivery. Transdermal
delivery id associated with significant advantages compared with the oral pathway.
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Folate Targeting
Folate targeting is a method invented by Christopher P. Leamon and Philip

S. Low for TDD process [95]. This involves the attachment of the vitamin, folic acid
(Structure of folic acid is given in Fig. 12) to a molecule or drug to form folate conjugates
Folates are a kind of B vitamin which are involved in purine synthesis. Most cells get the
folate they need via reduced folate carrier anion channel which has a low affinity for folates.
As such, there is only very little or no expression of folate receptors in most normal cells.
However, cancer cells require a large amount of folate and hence they have excess folate
receptors on their surfaces. As such, folate receptor proteins (FRPs) are commonly
overexpressed in the surfaces of many human cancers. Folic acid has a specific binding
ability to these FRPs. When folic acid is bound to drugs forming drugfolate conjugates they
also have high affinity for FRPs in human cancer cell surfaces and trigger cellular uptake
via endocytosis.
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INTRACELLULAR TARGETING
Targeting the cytomembrane
The cell membrane is a biological protective barrier that surrounds the

cell surface and is mainly composed of membrane lipids and proteins. An intact cell
membrane could maintain the relative stability of the microenvironment within cells and
thus sustain the normal life activity. It also has critical roles in many biological processes
such as cell recognition, signal transduction as well as the exchange of substances and
energy.
The composition and structure of the cell membrane changes significantly
during canceration of cells. Studies show that some characteristics of tumor cells, such as
invasion and migration, could also be associated to the abnormal changes found on the cell
membrane.24 Based on this, the specific antigens or receptors overexpressed on the
tumour cytomembrane could be used as specific target sites for targeted tumor therapy. In
a typical targeted drug delivery process, the nanocarriers are functionalized with the
corresponding ligand or antibody to target over-expressed receptors or antigens on the
cell surface. After nanocarriers are leaked from the vessel, they can accumulate in the
tumor tissue and then be internalized through specific recognition effect between receptor
and ligand (or antigen and antibody).
This targeted strategy not only achieves the targeted delivery of drugs but
also greatly increases the endocytosis amount. For example, an elevated concentration of
sialic acid was found due to the unusual sialyl behaviour on the surface of tumor cells.
Benzene boric acid, which has a strong affinity with sialic acid, has been used to target
tumor cells.24 Notable examples of commonly used targeting ligands include folic acid,
transferrin, low-density lipoprotein, endothelial growth factor and various antibodies.
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Lysosomal targeting
Lysosomes are an important organelle in cells and are essentially

monolayered cystic particles. Lysosomes contain large amounts of hydrolase, within which
more than 60 kinds of hydrolytic enzymes have been found so far, such as proteolytic
enzymes, nucleic acid hydrolase, lipase, glycosyl hydrolase, etc. Its main function is to
decompose intracellular macromolecules and proteins. When foreign substances enter the
lysosome, they are decomposed by the hydrolase within. Should the membrane integrity
of the lysosome be damaged.
Its abundant hydrolases would be released into the cell, leading to cell auto
lysis. Studies have indicated that cationic substances and external stimuli (such as
surfactants and heat, etc.) can lead to increased permeability of the lysosomal membrane,
as a result of which the enzymes are released into the cytoplasm, causing cell death.
Compared with other targeting strategies, the specific targeting of lysosomes is relatively
simple to achieve because most of the nanoparticles will enter the lysosome after cellular
uptake. Specifically, after the surface ligand modification, the nanomaterials are
endocytosedin to primary endosomes.
The ligandand receptor eventually fuse with the lysosome., the destabilizing
agents,can readily initiate the permeabilization of a variety of hydrolytic enzymes through
the lysosomal membrane, resulting in the effective cell apoptosis.
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Targeting the endoplasmic reticulum
The endoplasmic reticulum (ER) is a closed-mesh piping system

comprising primarily of internal membranes. It is responsible for the synthesis, folding and
assembly of nascent peptide chains. A broad range of diseases is the direct result of ER-
misfolded protein. The endoplasmic reticulum can also maintain homeostasis of
intracellular calcium ions, which are important intracellular signalling substances stored
in the ER. ER will release calcium ions and initiate caspase-8-related program apoptosis
when subjected to external stimuli.30,31 Typical ER stresses, such as protein misfolding32
and environmental stimulation (incubation with anticancer drug),33 could induce certain
biological response of ER and then lead to cell death through the initial programmed
apoptosis pathway.34,35 This applies to many cancer cells. Therefore, the endoplasmic
reticulum is also a potential target for tumor therapy;36 however, current research in this
area remains underdeveloped.
Ligand-mediated endoplasmic reticulum localization is a common
targeting approach for tumor therapy that relies on the conjugation of ER-targeting signal
peptides. Previous research has confirmed that a dilysine signal derived from type I
membrane proteins could be used as an efficient targeting ligand.37 Furthermore, the
hydrophobic poly-(propylene oxide) (PPO) block could bypass the lysosome stage and
enter the ER with high specificity.38
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Targeting the mitochondria
Mitochondria can control programmed cell death via regulating the

membrane potential.40 However, in most tumor cells, mitochondria are in a constant
dysfunctional state, such as poor membrane permeability and abnormal release of
apoptotic signals a highly negative membrane potential that is derived from its function in
the cell. Mitochondria provide ATP energy to support various cellular activities. They are
constantly pumping out protons (H+, Na +, etc.) from the intima. Moreover, the
proliferation ability of cancer cells is higher than that of normal cells ,so cancer cells need
more energy supply to meet the growth of cells.
Consequently, the membrane potential of mitochondria in tumor cells is
more negative than that of normal cells. Therefore, mitochondria-targeted therapy could
be developed based on this characteristic. Triphenylphosphine (TPP), a lipophilic cationic
substance, is currently under extensive investigation for mitochondria targeting. TPP can
efficiently attach to mitochondria due to electrostatic attraction between the positively
charged TPP moiety and the negatively charged mitochondrial membrane.42,43 Similarly
,dequaliniumchloride(DQA), a dibasic cationic amphiphilic compound, could deliver small
molecular drugs or nanocarriers to the mitochondrial matrix.44
Almost all mitochondrial proteins are synthesized with a precursor
protein in the ribosome as the template. The precursor proteins are transported to the
mitochondria with the help of a targeting signal sequence. The signal sequence is typically
located in the N-terminal of transport protein, and they are rapidly hydrolysed after
entering the mitochondria. These signal sequences are referred to as mitochondria-
targeting sequences (MTSs).45 Therefore, nanoparticles modified with MTSs can achieve
the mitochondrial targeting.
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TAT protein transduction domain (PTD) produced from human immune

deficiency virus type1(HIV-1)can not only carry oligonucleotides, proteins or
nanoparticles and pass through cell membranes quickly, but also has the ability to enter
the mitochondria without depending on the MTS pathway.46 Based on these advantages,
PTD has also been studied for potential mitochondria-targeted drug delivery, although the
detailed mechanism still needs to be further clarified.
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Targeting the cell nucleus
The cell nucleus is the control centre of a cell and plays an important role
in cell metabolism, growth and differentiation. It is also the main storage site of genetic
materials. More importantly, the action sites of most therapeutic anticancer drugs, such as
DNA intercalators and topoisomerase inhibitors, are in the nucleus.
Thus, directly targeting drug delivery to the nucleus can effectively increase
the therapeutic effect due to the bypassing of drug efflux pumps, which makes nuclei-
targeting an important delivery strategy for tumor therapy. From a structural perspective,
the nuclear membrane is constituted by two layers of membrane and decorated by nuclear
pore complex (NPC) on the membrane surface.48 Nanoparticles witha diameter
oflessthan9 nm could gain entry nuclear area via NPC.49 However, such small
nanoparticles would be easily removed from blood circulation before they could even
reach the tumor site. Large nanoparticles can be delivered to the nucleus through NPC
facilitated by the nuclear localization signal (NLS). The NLS is a signal sequence located in
the C-terminal of nucleo plasmins. It usually contains 4–8 amino acids and is positively
charged. NLS complexes with NPC and forms a hydrophilic channel on the nuclear
membrane.
Subsequently, the cargo that previously bound to NLS can enter the nuclear
area in an energy-dependent manner.51 In addition, there are adequate amounts of
glucocorticoid receptors on the nucleus;52 therefore, small molecular glucocorticoids such
as dexamethasone,53 triamcinolone acetonide,54 betamethasone,55 etc. could be used as
nucleus-targeting molecules. More interestingly, when the nanoparticles are transported
to the nucleus mediated by glucocorticoid, the NPC channel could be expanded up to 60
nm, so that the nanoparticles may enter the nucleus more easily.
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Targeting the tumor microenvironment

The tumor microenvironment is closely related to the pathological state of
tumors. It mainly consists of the surrounding blood vessels, fibroblasts, lymphocytes,
immune cells and the extracellular matrix (ECM). It is widely involved in tumor occurrence,
growth, invasion and metastasis. Thus, the tumor microenvironment sensitivity is another
extensively studied area in the field of tumor-targeted DDS, taking advantage of the
numerous differences in tumor microenvironments to the surrounding normal tissues,
including pH value, vascular abnormalities and ECM composition.
Meanwhile, many distinctive characteristics have been discovered in
cancerous ECM, including slightly acidic environment and low oxygen concentration,
which differ greatly from the normal tissue ECM and could facilitate the development of
novel targeted TDDSs.60,61 Ji et al. reported that optimized zwitterionic nanoparticles
rapidly aggregated in cancerous ECM in response to the slight pH change from 7.4 to 6.5,
which could be utilized for tumor-targeted therapy.62 A similar pH-sensitive TDDS was
reported by Li et al.63 These examples consistently demonstrate that cancerous ECM can
be used as potential target for tumor therapy.
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DRUG DELIVERY SYSTEM-MWCNTS/DOX/TC
Multiwalled carbon nanotubes:

Multiwalled carbon nanotubes (MWCNTs) are
seamless hollow tubes formed by rolling of multiple layers of graphene, which have
recently gained popularity as potential delivery vehicles for therapeutic/diagnostic agents
due to their unique structural, optical, electronic and chemical properties (Qin et al., 2011a;
Sajid et al., 2016). Owing to their high surface area ratio, MWCNTs have strong loading
capacity for a variety of agents including biomolecules (proteins or nucleic acids) and
chemical drugs (either hydrophilic or hydrophobic) (Li et al., 2014; Qi et al., 2015). They
can also increase the bioavailability of these molecules by controlling their release or
protecting them from degradation or alleviate their toxicity and harmful side effects
through targeted delivery (Mu et al., 2009; Li et al., 2016; Mehra & Palakurthi, 2016). These
features make it possible to develop multifunctional drug carriers to further improve the
efficacy of therapeutic/ diagnostic agents.
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DOXORUBICIN :
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from
cultures of Streptomyces peucetius var. caesius. Doxorubicin binds to nucleic acids,
presumably by specific intercalation of the planar anthracycline nucleus with the DNA
double helix.
Mechanisms of action:
 Doxorubicin forms complexes with DNA by intercalation between base pairs.
 It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex.
 It preventing the religation portion of the ligation-religation reaction that
topoisomerase II catalyzes.
TAT-chitosan conjugate (TC) :

Chitosan (CS), a cationic polysaccharide obtained
from deacetylation of chitin, has attracted intense attention for application as a drug/gene
delivery vehicle (Misra et al., 2012) or tissue engineering scaffold (Depan, 2014) because
of its hydrophilicity, biocompatibility, biodegradability and low immunogenicity
properties. TAT (transactivator of transcription) peptide, a widely recognized cell-
penetrating peptide, can drive macromolecules to penetrate the cell membrane and target
the cell nucleus (Liu et al., 2008; Qin et al., 2011b; Mei et al., 2014), while causing no damage
to the cell membrane.
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DRUG-LOADING AND RELEASE STUDIES IN VITRO
Cellular uptake :
Briefly, BEL-7402 cells were seeded into 96-well plates at the density of
104 cells per well and allowed to grow overnight and subsequently incubated with
different concentrations of MWCNTs/DOX/TC or free DOX for 4h and 12h, the cells were
then washed three times with PBS and fixed with immune staining fix solution for 20min
at room temperature, followed by the labeling of the intracellular microfilament with actin-
tracker green and subsequent staining of the nucleus with DAPI (Beyotime Institute of
Biotechnology, Shanghai, China). The cellular uptake of MWCNTs/TC/DOX or DOX was
analyzed with the GE IN Cell Analyzer 2000 High-Content Cellular Analysis System
Drug-loadingand release behavior isone of themost important factors

determining the application potential of drug delivery systems. Previous reports have
shown that DOX can be absorbed onto the surface of modified SWCNTs via –interactions
(Liu etal., 2007). It was also reported that the DOX-loading efficiency was influenced by the
zeta potentials of the drug carrier (Zhang etal., 2009), illustrating that the electrostatic
interactions played an important role in the absorption process. Our preliminary study
found that modification with positively charged TC molecules significantly attenuated the
DOX-loading capacity of MWCNTs (data not shown). Therefore, to achieve higher DOX-
loading capacity, DOX was first loaded onto the surface of MWCNTs, followed by further
coating of the MWCNTs/DOX complexes with TC for higher cellular uptake of the drug
delivery system. The drug-loading capacity and efficiency of the MWCNTs/DOX/TC with
different DOX to MWCNTs mass ratios (3/1, 1/1 and 1/2, respectively) were further
investigated. The data revealed that the DOX-loading capacity was improved with
increasing DOX/MWCNT ratio (about 24%,
58 | P a g e

33% and 50% for mass ratio of 1/2, 1/1 and 3/1, respectively), whereas the loading
efficiency demonstrated the opposite trend (about 63%, 50% and 35% for mass ratio of
1/2, 1/1 and 3/1, respectively). As shown in Figure 2, that the DOX release rate was
increased with increasing DOX/MWCNTs ratio in PBS at pH of both 7.4 and 5.5. It was also
found that DOX
was released at a significantly lower rate at pH 7.4 from MWCNTs/DOX/TC than that at pH
5.5, which is beneficial for intracellular drug delivery and release. Coating of MWCNT/DOX
with TC significantly slowed the release efficiency of DOX from MWCNTs/DOX/TC by
comparing with MWCNTs/DOX at each condition.
59 | P a g e

In vivo monitoring of DOX release and antitumor efficiency
Balb/c nude mice (6 weeks, male) were purchased from Peking Union
Medical College. All animal procedures were conducted following the protocol approved
by the Institutional Laboratory Animal Ethics Committee, and all animal experiments were
performed in compliance with the Guiding Principles for the Care and Use of Laboratory
Animals, Peking Union Medical College. Luciferaseexpressing Bel-7402 cells (1106) in
0.1mL normal saline (NS) were injected into the armpit region of Balb/ c nude mice. When
the volume of tumors reached to 100mm3, the mice were divided into different treatment
groups (6 mice/group) and free DOX or MWCNTs/DOX/ TC at the dose of 10mg/kg,
20mg/kg or 30mg/kg DOX were injected into the center of tumor with NS-treated mice as
the negative control. Fluorescence imaging was conducted to monitor the drug release
process using an live animal imaging system (IVIS Lumina system, Xenogen, Alameda, CA)
until the fluorescence signal disappeared, with excitation wavelength being set at 532nm.
To investigate the antitumor effect, luminescence imaging was conducted 5min after
intraperitoneal injection of 200mL luciferin (15mg/mL) using the IVIS Lumina imaging
system for a period of 25 days.
Cellular uptake observation:

Cellular uptake of MWCNTs/DOX/TC or free DOX was
analyzed with IN Cell Analyzer 2000. Figure 3 showed the intracellular fluorescence
intensity of DOX after incubating BEL-7402 cells with MWCNTs/DOX/TC or free DOX for 4
or 12h. The intracellular fluorescence intensity of DOX after incubation for 12h was
stronger than that for 4h, which indicated that MWCNTs/DOX/TC could efficiently enter
the tumor cells.
60 | P a g e

Quantitative analysis further demonstrated that the mean florescence

intensity of free DOX group is slightly higher than that of MWCNTs/DOX/TC group with
equivalent concentration of DOX after incubation for 4h, which might be due to the fast
cellular internalization of DOX through the cell membrane by a passive diffusion
mechanism (Prabaharan etal., 2009). However, after incubation for 12h, the florescence
intensity of DOX for MWCNTs/DOX/TC group was higher, which indicated that more DOX
was still retained in the tumor cells due to the prolonged DOX release from the drug
delivery system. More importantly, most of the nucleus of the MWCNTs/DOX/TC treated
cells was filled with DOX, indicating the successful release of DOX from the delivery system,
as our previous study demonstrated that MWCNTs/ TC could efficiently enter the tumor
cells and mainly accumulated in the cytoplasm, but cannot cross nuclear membranes. All
these results implied that MWCNTs/DOX/ TC led to more efficient DOX delivery and
release in tumor cells.
61 | P a g e

Simultaneous monitoring of drug release and the antitumor effect of

MWCNTs/DOX/TC by noninvasive imaging.
Current in vivo imaging modalities include ultrasonography (US),

computed tomography (CT), single-photon emission computed tomography(SPECT) and
magnetic resonance imaging (MRI) (Othman et al., 2012;Fischerauer et al., 2013), etc.
For monitoring the in vivo release process of DOX from the
MWCNTs/DOX/TC delivery system, taking advantage of the unique fluorescence property
of DOX. In the meantime, the location of tumor and the change of tumor volume could be
determined precisely by assessing the radiance efficiency of luciferaseexpressing BEL7402
cells through bioluminescence imaging. To investigate the in vivo drug release efficiency
and antitumor effect of MWCNT/DOX/TC more accurately, different concentrations of
MWCNTs/DOX/TC or free DOX were injected into the center of tumor, and fluorescence
imaging and bioluminescence imaging were simultaneously conducted for the evaluation
of the delivery system.
The change in fluorescence or bioluminescence intensity can be
monitored noninvasively in a real-time manner to reflect the drug releaserate and
inhibition of tumor growth simultaneously. As shown in Figure 5, the release of DOX can
be tracked by fluorescence imaging. By quantitative analysis of the total fluorescence
intensity in the efficiency region of tumor tissues, the relative release of DOX can be
monitored drastically. It was revealed by the fluorescence imaging that a slower release
rate was achieved for MWCNTs/DOX/TC group, and MWCNTs/DOX/TC significantly
elongated the retention time of DOX in the tumor tissues at each concentration (10mg/kg,
20mg/kg or 30mg/kg of DOX) as compared with free DOX. No fluorescence signal was
observed one day after injection of 10 lg/mL free DOX, whereas the fluorescence remained
for more than 24h and a faint fluorescence signal could still be detected after 2 days in the
MWCNTs/DOX/TC group with equivalent amount of DOX.
62 | P a g e

Similarly, at the concentration of 20 lg/mL, 50% fluorescent signal remained in the tumors
in MWCNTs/DOX/ TC group versus a 35% remanence in the free DOX group on the first
day. The fluorescence signals in the free DOX group disappeared completely 4 days after
injection, while around 20% of the fluorescence intensity still remains at day 4 in the
63 | P a g e

MWCNTs/DOX/TC group. When DOX was at 30 lg/mL, approximately 60%

of the fluorescence intensity still remained in the tumors at day 4 for the
MWCNTs/DOX/TC group, while the fluorescence in the tumors disappeared completely for
the free DOX group. All these results indicated that MWCNTs/DOX/TC realized a
conspicuously sustained release of DOX, and the sustained release of DOX could be
extended by increasing DOX concentration. More importantly, it was also demonstrated
that the difference in the release process of different DOX concentration group could be
intuitively and clearly observed by fluorescence imaging.
Advantage of NDDS over conventional

 The conventional dosage forms provide drug release immediately and it causes
fluctuation of drug level in blood depending upon dosage form.
 Therefore to maintain the drug concentration within

therapeutically effective range need novel drug deliverysystem.
 It provide optimum dose at the right time and right location.
 Efficient use of expensive drugs, excipients and reduction in production cost.
 Beneficial to patients, better therapy, improved comfort and standard of living
64 | P a g e

ADVANTAGES DISADVANTAGES
 Reduced toxicity. o Rapid clearance of targeted system.
 Bypass hepatic first pass o Immune reactions against i.v

metabolism. administered carrier system.
 Reduced dose and dosing o Diffusion and redistribution of

intervals. released drug.
 No peak and valley plasma o Drug deposition at the target site

concentration. may produce toxicity symptoms.
 Enhancement of the o Difficult to maintain stability of

absorption of target dosage form.
molecules.
LIMITATIONS OF TUMOR TARGETING DRUG DELIVERY
 Cancer cells can become resistant to them. Resistance can occur in two ways
 The target itself changes through mutation so that the targeted therapy no longer
interacts well with it.
 The tumor finds a new pathway toachieve tumor growth that does notdepend on
the target.
65 | P a g e

CONCLUSION
Cancer has emerged as a leading cause of death worldwide. Although

conventional chemotherapy has been the keystone to combat cancer, it is associated
with normal cell toxicity. Due to lack of specificity, conventional cancer treatments often
cause severe side effects and toxicities. Severity of cancer makes it imperative to
develop novel approaches to treat such diseases. New chemo preventive agents may
be delivered through novel cell targeting approaches. Focus of such novel approaches
is based on cancer treatment with innovative methods. Consequently, these promising
technologies offer new opportunities for cancer prevention and treatment with
minimal/lower toxicity to normal cells which can be realized in the clinic in the very near
future.
Targeted drug delivery is developing as one of the most advanced
technique in the medical sciences in the diagnosis and treatment of diseases. TDD is
associated with many advantages which include minimal dosage requirement and
minimal side effects with maximal bioavailability and high efficacy of the drugs. In this
review, we attempted to highlight problems associated with conventional drug
administration methods and shown that targeted delivery as a solution to these
problems.
An effective anticancer drug delivery vehicle MWCNTs/DOX/TC was
developed with high drug loading effectiveness and pH-dependent controlled release.
The in vivo release process of DOX and antitumor effect were monitored simultaneously
by non-invasive fluorescence and luminescence imaging, which demonstrated the
application potential of MWCNTs/DOX/TC for cancer therapy.
 Such approaches have been investigated to overcome the limitations of

conventional therapy.
66 | P a g e

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“TUMOR SPECIFIC DRUG DELIVERY: NOVEL APPROCHES”

A REPORT OF PROJECT WORK

SUPERVISED BY: SUBMITTED BY:

VIVEKANAND COLLEGE OF PHARMACY VIP CAMPUS,

This is to certify that Mr. SHAHNAWAZ KHAN Enrollment No. 0516py181084 a

The project is forwarded to RGPV Examiner for evaluation.

Dr. VIVEKANAND KATARE

Dr. VIVEKANAND KATARE SHAHNAWAZ KHAN

The completion of any project depends upon the co-operation, co-ordination

I wish to express my deep sense of gratitude to my guide, Asst.Prof. Sadhna

I express my profound indebtedness to Dr. Vivekanand Katare, Principal VCP

I am also thankful to my Non-Teaching Members, who always helped me in al

I express my sincere grautude to my ever loving, affectionate, Parents, and my

DRUG DELIVERY SYSTEM-MWCNTS/DOX/TC

Advantage of NDDS over conventional………………………………….63

Currently, a majority of cancer treatment strategies are based on the removal

Cancer is a group of diseases involving uncontrolled growth and spread of

VIVEKANAND COLLEGE OF PHARMACY

This analysis generated a reclassification of approximately 10% of tumors

Eleven major cancer types include lung adenocarcinoma (LUAD), lung

As mentioned above, histological classification includes 100 different types of

VIVEKANAND COLLEGE OF PHARMACY

NOVEL DRUG DELIVERY SYSTEM

 Optimum therapeutic- drug concentration in the blood or in tissue may be maintained

VIVEKANAND COLLEGE OF PHARMACY

VIVEKANAND COLLEGE OF PHARMACY

To determine whether a tumor is benign or cancerous, a healthcare provider can

VIVEKANAND COLLEGE OF PHARMACY

BENIGN TUMOR: NONCANCEROUS

Fibroids in the uterus or lipomas are examples of benign tumors.

MALIGNANT TUMOR: CANCEROUS

VIVEKANAND COLLEGE OF PHARMACY

VIVEKANAND COLLEGE OF PHARMACY

VIVEKANAND COLLEGE OF PHARMACY

Approaches for targeted delivery of therapeutics in cancer typically involves systemic

VIVEKANAND COLLEGE OF PHARMACY

 Be non-toxic for healthy organs, tissues, and cells

 Not induce multidrug resistance

MOLECULAR TARGETS FOR TUMOR THERAPY

 Altered expression of cell adhesion molecules.

 Altered expression of receptors during certain stages of cellular differentiation, like

 Expression of tumor vasculature epitopes.

 Expression of surface determinants on malignant cells, like tumor

VIVEKANAND COLLEGE OF PHARMACY

DRUG TARGETING TO TUMOR IS BASED ON:

 EPR effect(Enhanced Permeability and Retention).

VIVEKANAND COLLEGE OF PHARMACY

TUMOR TARGETED THERAPY

 Signal transduction inhibitors

 Gene expression modulator

VIVEKANAND COLLEGE OF PHARMACY

these strategies to cause the death of cancer cells.

VIVEKANAND COLLEGE OF PHARMACY

TUMOR TARGETING DRUG DELIVERY SYSTEM

o Effectively kill tumor cells

o Be non-toxic for healthy organs, tissues, and cells

o Not induce multidrug resistance.

APPROCHES TO TARGETING TUMOR

Drug targeting is defined as the ability of a drug molecule to accumulate in

VIVEKANAND COLLEGE OF PHARMACY

Various pharmaceutical carriers explored for targeting drug include

VIVEKANAND COLLEGE OF PHARMACY

This is due to the stimulation of blood vessel growth by signaling out