Medicine in Drug Discovery 15 (2022) 100134

Contents lists available at ScienceDirect

Medicine in Drug Discovery

journal homepage: www.elsevier.com/locate/medid

Review Article

Nano-based drug delivery systems: Conventional drug delivery routes, recent

developments and future prospects
Afreen Sultana a, Mina Zare a,b,⇑, Vinoy Thomas c, T.S. Sampath Kumar d, Seeram Ramakrishna a,⇑
a
Center for Nanotechnology and Sustainability, Department of Mechanical Engineering, National University of Singapore, Singapore 117581, Singapore
b
Department of Food and Nutrition, P.O. Box 66, 00014, University of Helsinki, Finland
c
Department of Materials Science and Engineering, University of Alabama at Birmingham, Birmingham, AL, USA
d
Medical Materials Laboratory, Department of Metallurgical and Materials Engineering, Indian Institute of Technology Madras, Chennai 600036, India

A R T I C L E I N F O A B S T R A C T

Keywords: Drug delivery can be defined as the group of approaches a drug or pharmacologically active agent can be trans-
Target drug delivery ported to the target cell to treat disease or health issue. Conventional routes for drug delivery are oral, buccal,
Nanocarriers rectal, subcutaneous, intranasal, intramuscular, intravenous, pulmonary and transdermal. These are the com-
Pharmacokinetics monly used methods for treatment of various medical problems but have certain limitations such as instability,
Pharmacodynamics
risk of displacement, uncontrolled release, side effect such as irritation and pain, slow absorption, enzymatic
Nanomedicine
Smart drug delivery
deterioration and many others. Incorporation of drug into nanocarrier is one of the efficient methods for tar-
geted and sustained delivery of drug. Applications of nanocarriers such as solid nanoparticles, liposomes, den-
drimers, polymeric nanoparticles, polymeric micelles, virus like nanoparticles, carbon nanotube and
mesoporous silica nanoparticles are discussed in this review. To overcome drawbacks of drug delivery, inno-
vative delivery systems are designed usually termed as smart drug delivery systems which include nucleic
acid‐based drug delivery system, cell‐based drug delivery system, self‐nano emulsifying drug delivery system,
self‐micro emulsifying drug delivery system, chemical and physical stimuli‐based drug delivery system, nano-
needles, patches, ultrasound drug delivery and microchip technology. This article focuses of the basic mecha-
nism of drug delivery, pharmacokinetic study, recent innovations and future trends of the drug delivery system.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2. Mechanism of targeted drug release . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2.1. Linker cleavage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
2.2. Control of carrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3. Pharmacokinetics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.1. Absorption . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.2. Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.3. Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
3.4. Elimination. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4. Pharmacodynamics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
5. Classification of drug delivery systems based on routes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
6. Role of nanocarriers in drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
6.1. Solid lipid nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
6.2. Liposomes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
6.3. Dendrimer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
6.4. Polymeric nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
6.5. Polymeric micelles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

⇑ Corresponding authors.
E-mail addresses: zare.mina@yahoo.com (M. Zare), seeram@nus.edu.sg (S. Ramakrishna).

https://doi.org/10.1016/j.medidd.2022.100134
Received 5 February 2022; Revised 13 May 2022; Accepted 15 May 2022
Available online 20 May 2022
2590-0986/© 2022 The Author(s). Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
A. Sultana et al. Medicine in Drug Discovery 15 (2022) 100134

6.6. Virus-based nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

6.7. Carbon nanotubes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
6.8. Mesoporous silica nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
7. Smart drug delivery systems. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
7.1. Nucleic acid-based drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7.2. DNA nanotechnology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
7.3. Spherical nucleic acid . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.4. Exosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.5. Lipid nanoparticle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.6. Aptamer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.7. Cell-based drug delivery system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.8. Self-nano emulsifying drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.9. Oil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
7.10. Surfactant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.11. Co-solvent. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.12. Self-micro emulsifying delivery system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.13. Physical stimuli responsive drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.14. Chemical stimuli responsive drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
7.15. Nanoneedle patches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7.16. Ultrasound drug delivery. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7.17. Microchip technology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7.18. Nano vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7.19. Dry vaccine delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7.20. Bioceramic nanoparticles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
7.21. Nanogels. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
7.22. Fullerenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
8. Ethics and regulatory affairs in nano-drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
9. Future scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
9.1. Drug delivery for future viruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
9.2. Safety and efficacy of drug . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
9.3. Symbiotic drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
9.4. Gender sensitive drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
9.5. Affordable . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
9.6. Greener drug delivery system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
9.7. Intelligent drug delivery system. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
10. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Author contributions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Funding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Ethical statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

1. Introduction via constrain mesh. In osmotic pump system, drug is released due to
change in osmotic pressure through hole/ holes in impermeable mem-
Drugs are defined by FDA, in part, as “intended for use in the diag- brane. In erodible material, drug is released when the material gets
nosis, cure, mitigation, treatment, or prevention of disease” and “arti- dissolved1. Self‐emulsifying drug delivery system are composed of
cles (other than food) intended to affect the structure or any function oil, surfactant, co‐surfactant and drug and when diluted with water
of the body of man or other animals. It is expected that the drugs are result in micro or nano emulsion [3]. Implementation techniques are
capable of targeting the disease‐causing cell with an exact therapeutic medium via which drug can be delivered such as microsphere (spher-
concentration in an effective manner. However, in contrast, it is ical particle with diameter in range between 1–1000 μm) [4] and tubu-
observed that release rate, stability and cell‐ and tissue‐specific target- lar vesicles (persistent length is greater than microsphere) [5]. Clinical
ing ability are uncontrolled and cannot be monitored [1]. To overcome application involves the investigation of drug validity as per the clin-
challenges, drug delivery system is designed. Drug delivery system has ical view point [2].
the capability to regulate drug release rate and improves the effective- There are various conventional ways to transport drug to the target
ness of the drug (Fig. 1) [2]. cell, but all these methods have certain limitations. This has led to the
Designing of drug delivery system includes the study of engineering development of smart drug delivery system which is capable of over-
concepts, material design, implementation techniques and clinical coming the shortcoming of conventional methods. This review focuses
application. Engineering concepts focuses on the diffusion, erosion, on the mechanism involved in targeted delivery of the drug, discusses
degradation, shear, swelling, binding kinetics, passive cell uptake, sur- the four important steps involved in movement of drug and the con-
face area and active cell uptake. Material design includes two systems‐ ventional and smart drug delivery systems. This study is impactful
controlled drug delivery system and self‐emulsifying system [2]. Con- for the researchers to understand the basics and future advances in
trolled drug release system is classified as matrix, reservoir, degrad- the drug delivery system.
able material, hydrogel, osmotic pump and erodible material. In
matrix system, drug is released through interconnected pores. In reser- 2. Mechanism of targeted drug release
voir system, drug permeates through the semipermeable membrane. In
degradable material system, the material degradation causes porous Targeted drug delivery system is system in which pharmacokinetic
structure leading to extrusion of drug. Hydrogel system release drug drug is transported to the site of action and prevents the unnecessary

2
A. Sultana et al.
Fig. 1. Schematic illustration of factors involved in designing of effective drug delivery system. These factors include safety, efficacy, preparation technique and
adsorption.
interaction with other healthy tissue to avoid side effects [6]. Non‐
targeted drug delivery such as chemotherapeutic drug used for cancer
treatment leads to undesirable effect on healthy cells. Targeted drug
delivery improves the uniformity of the drug effect and reduces the
drug dosage [7]. Targeted drug release is a three‐step process: (i)
through multivalent receptor–ligand interactions nanocarrier binds
with the receptors of the target cell, (ii) through endocytosis drug
nanocarrier enters into the cell and (iii) in the last step drug release
takes place. Targeted drug delivery can take place in cytosol and cell
membrane by interacting with lipid membrane (Fig. 2) [8].
Drug release can be performed via two methods: linker cleavage
and control of carrier which are further discussed in this section [8].
2.1. Linker cleavage
Constituent of fusion proteins which are capable of separating mul-
tiple domains in a single protein is known as linker [9,10]. Linkers are
of two types cleavable and non‐cleavable. Cleavable linkers easily
break bond in the presence of suitable condition. For instance, anti-
body–drug conjugates enter into to the lysosome via endocytosis. Lyso-
some has an environment where pH is low and contains hydrolytic
enzymes which promotes the cleavage. Cleavage of non‐cleavable link-
3
Medicine in Drug Discovery 15 (2022) 100134
ers is not triggered by any chemical trigger [11]. Linker cleavage plays
a vital role in targeted delivery of drug which is further discussed in
this section. The drug release through the linker cleavages can be per-
formed via various mechanisms such as ester hydrolysis, amide hydrol-
ysis, hydrazone hydrolysis, disulphide exchange, hypoxia activation,
mannich base, self‐immolation, photochemistry, azo reaction and
thermolysis.
Ester linkers work well at basic pH as well which is useful for con-
trolled release [12]. Amide linker can be used for formation of drug
conjugate with nanocarrier. For chemical hydrolysis of amide bond,
high temperature along with strong acid or base is needed [13].
Hydrazone bond is stable at 7.4 pH and the optimal pH for cleavage
is equal to or more than five [8]. Disulphide bond cleavage takes place
in cytoplasm due to electrochemical reaction or disulfide exchange
reaction and is triggered by thiol group [14–17]. Hypoxic condition
is the one in which oxygen supply is low in tissue and cell such as
tumor microenvironments [18,19]. Mannich base acts as a prodrug
for the parent drug which helps in enhancing the pharmacokinetics
attributes of the drug [8]. Self immolative linker system does not
release drug directly instead involves intervening linker. Once the
reaction is triggered, triggering moiety is excluded from the linker,
leading to activation of free spacer and spontaneously causing drug
A. Sultana et al.
Fig. 2. Schematic illustration of target drug release system in cytosol and cell membrane. It shows that nanoparticles get linked to the receptors, then via
endocytosis enters the cell and ultimately leads to release of drug.
release. It has an advantage over other mechanisms that is it amplifies
the release frequency by repetitive release of numerous drug units per
reaction cascade8. Photochemistry involves the use of photocleavable
linker and this reaction is activated in the presence of light [20,21].
Azo reaction involves cleavage of azo linker via biological mechanism
which can be used to activate anti‐inflammatory group of azo‐linked
prodrugs of 5‐aminosalicylic acid [22,23]. Thermolysis refers to cleav-
age of chemical bond of drug linker where thermal stimuli act as a trig-
ger [8].
2.2. Control of carrier
Non‐covalent mechanism can be used for drug loading and release.
It can be performed via encapsulation or interaction with the carrier
where particle size, shape and geometry have a vital role in regulating
biological mechanism [24–27]. In encapsulation mechanism, drug is
loaded into the carrier and the drug is released via diffusion in a con-
trolled way [8].
3. Pharmacokinetics
The essence of pharmacology is the relationship between the dose
of a drug given to a patient and the resulting change in physiological
state (the response to the drug). The absorption, distribution, metabo-
lism, and excretion of a molecule define its pharmacokinetics, and
many of these processes, in turn, are controlled by the physicochemi-
cal properties of the molecule. Pharmacokinetic helps in understand-
ing these four important processes [28].
3.1. Absorption
Absorption step refers to the movement of drug from the adminis-
tration site to the body circulation system. Absorption of drug to the
systemic circulation can occur via five routes such as transcellular
absorption, pinocytosis, transport protein mediated absorption, para-
cellular, and endocytosis [29]. Low aqueous solubility and poor per-
meability of drug are the main obstructions in drug absorption [30].
Adsorption of an nanocarrier occurs via internally interacting with
organism or permeating through biobarriers [31] (Su et al., 2019).
4
Medicine in Drug Discovery 15 (2022) 100134
In a study it was reported that permeability of transdermal drug deliv-
ery can be improved by using microneedle in the presence of ultra-
sound [32]. Nanostructures are also one of the ways to overcome
these drawbacks [33]. Nanostructures can be fabricated using electro-
spinning to improve efficacy and avoid loss of effectiveness of active
component [34].
3.2. Distribution
At distribution stage, drug moves from systemic circulation to the
tissue. Nanocarrier helps in prolonging the blood circulation and pro-
mote target delivery [31] (Su et al., 2019). One of the major challenges
in drug distribution is blood brain barrier, which can be improved by
intranasal administration, transcytosis or direct injection of drug to the
central nervous system [35]. For instance, in a study, it was recorded
that on exposure to ultrasound, permeability improved, releasing the
ultrasmall super‐paramagnetic iron oxide nanoparticles from the
microbubles and opened the blood brain barriers [36].
3.3. Metabolism
Metabolism is a process of breaking down drug using enzymes,
which can occur in liver, gastrointestinal tract, kidneys, lungs or skin.
There are two phases for metabolism of drug, but in some cases both
the phase occurs simultaneously for complete metabolism [37,38].
Nanocarrier are removed from the body via structural degradation
[31] (Su et al., 2019). In a study it was reported that immobilization
of Cytochrome P450 onto electron can eliminate the need of NADPH.
Hence, it can enhance the metabolism process by reducing the compli-
cations [39]. Thus, these factors need to be considered while designing
of drug [40,41].
3.4. Elimination
Elimination of drug and metabolites can occur via several routes
but the most significant is via kidney. Elimination via kidney involves
glomerular filtration, secretion of active tubular and then reabsorbs
tubular [42]. Excretion can occur via sweat, bile, urine, breast milk
and saliva [43]. Elimination of nanocarriers depends on shape, size
and charge of the nanocarriers [31] (Su et al., 2019).
A. Sultana et al. Medicine in Drug Discovery 15 (2022) 100134

Targeted delivery of nano drug can be obtained via intercellular
transport, intracellular transport, controlling particle size, enhanced
permeability and retention, coating with hydrophilic component (un-
hygenic) and conjugating with other materials such as peptide. These
methods facilitate the adsorption, metabolism, distribution and excre-
tion of drug. It also helps in reducing the cytotoxicity against normal
cells and enhances the efficacy [44].
The pharmacokinetics profile of nanocarriers is different in terms of
biodistribution, degradation, and the drug release behaviour and it
also affects the pharmacodynamic profile. The nanodrug gets accumu-
lated in target sites through two pathways, one in which the nanocar-
rier drug gets diffused in the target cell and second is in which
nanocarrier loaded with drug gets distributed to the target site and
releases the drug [46] (Liu et al., 2016).

5. Classification of drug delivery systems based on routes

4. Pharmacodynamics
Pharmacodynamics is the process to determine the magnitude and
type of drug responses when it reaches the site of action using quanti-
tative tools. Drug response can be defined as the chemical interaction
between drug and binding site. Binding site (its known as receptors if
it consists of functional activity) are the sites at which drugs bind to
macromolecule. Drug binding leads to activation of receptors and
influences the intracellular messengers or proteins.
Receptors are classified into five categories: (i) ligand gated ion
channels: ligands bind to channel to regulate the flow of ions through
the cell membrane (example: nicotinic acetylcholine receptor), (ii)
voltage gated sodium channel: aqueous pore is formed by agglomera-
tion of subunits of receptors through which sodium ions flow, (iii) G
protein coupled receptor: it converts extracellular stimuli into intracel-
lular signals, (iv) Enzyme linked receptors: cytosolic enzyme activity
gets inhibited or activated when ligands bind to such receptors and
(v) intracellular receptor: ligands has to permeate into the cell to inter-
act with these receptors [45].
Drug can be administered through several routs such as oral, buc-
cal, rectal, subcutaneous, intravenous, intranasal, intramuscular, pul-
monary and transdermal. These drug delivery systems have some
advantages and limitations as well which are mentioned in the
Table 1.
As mentioned in the table, all the drug delivery systems have cer-
tain shortcomings for which various studies are being performed to
overcome such challenges. In a recent study, smart microencapsulation
system is designed to overcome challenges in oral drug delivery. In this
research oil in water emulsion solvent evaporation method was used to
fabricate hollow microparticles (Eudragit S100 polymer) consisting of
environmental pH sensitive macrospores [62]. In an investigation,
mussel inspired mucoadhesive film was developed to attain effective
attachment to buccal tissue [63]. In a study, mucoadhesive chitosan
hydrogels were prepared to study the effect on treatment of ulcerative
colitis. It was concluded that catechin‐ chitosan incorporated with sul-
fasalazine is an effective way to treat ulcerative colitis via rectal route
[64]. Treatment of brain tumor via intravenous drug delivery is chal-

Table 1
List of advantages and disadvantages of various drug delivery systems.

Drug delivery systems Advantages Disadvantages Ref.

Oral drug delivery system Non-requirement of skilled person. Challenging for patients of pediatric, geriatric, and mentally [47,48]
Non-invasive. retarded population.
Cost effective. Difficulty in consumption.
Instability of drug under environmental conditions of
gastrointestinal tract.
Unnecessary accumulation leads to low bioavailability.
Buccal drug delivery Good blood supply and perfusion rate promotes rapid absorption. Residence time. [49–52]
system Improved bioavailability. Some drugs are instable at buccal pH.
Safe from degradation due to environmental conditions of Risk of displacement.
gastrointestinal tract. Drugs which require high dosage cannot be administered.
Lesser dose frequency needed and has small treatment period.
Rectal drug delivery Absence of enzymes helps in avoiding enzymatic degradation. Rectal irritation [53,54]
system Can be administered by patients of pediatric, geriatric, and mentally Absorption can be interrupted by defecation
retarded population.
Effectiveness of localized treatment of problems such as constipation is
enhanced.
Intravenous drug delivery Short latent period. May cause undesirable immune reaction (in case of protein and [55,56]
system Fast achievement of blood concentration required for drug effective peptides).
functioning. May cause thrombophlebitis and tissue necrosis.
May also lead to air embolism.
Subcutaneous drug Sustainable absorption of drug Rate of absorption is slow. [56,57]
delivery system Can be conveniently self-administered May cause pain and irritation at the injection site.
May lead to tissue damage due to accretion of unabsorbed drug.
Intramuscular drug Rapid and uniform absorption. It may cause pain at injection site. [56,58]
delivery system Larger amount of drug can be injected comparatively to subcutaneous Quantity injected depends on the mass of the muscle.
drug delivery method. May cause hematoma.
Accidental rupture of blood vessel may lead to incorporation of
drug into the blood.
Intranasal drug delivery Rapid onset of action. Intolerance in nasal mucosa. [59]
Convenient to use. Poor permeability is observed for hydrophilic agents.
Prevents interaction with gastrointestinal tract.
Pulmonary drug delivery Vascularization and circumvention promote enhanced absorption of Aerodynamic filter inhibits the efficient deposition. [56,60]
system the drug. Mucus lining moves the deposited agents towards the throat.
Inhibits the risk of side effects due to targeted delivery.
Requires lesser dosage
Transdermal drug delivery Prevents deterioration of drug due to gastrointestinal interaction Skin is impermeable to hydrophilic components. [61]
system Convenient to administer May cause enzymatic deterioration.
Incomplete utilization of the drug.

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A. Sultana et al. Medicine in Drug Discovery 15 (2022) 100134

Fig. 3. Schematic illustration of nanocarriers used in drug delivery which includes solid nanoparticles, liposomes, dendrimers, polymeric nanoparticles, polymeric
micelles, virus like nanoparticles, carbon nanotube and mesoporous silica nanoparticles.

lenging because of blood–brain barrier. Wireless electronic tion, focused ultrasound along with microbubbles has proved to open
doxorubicin‐loaded patch was experimented on nude mice via human blood brain barrier. Results showed that 7.2 µl microbubbles/kg/min
xenograft glioblastoma model. The results showed decrease of tumor or below were able to consistently open blood brain barrier without
recurrence and survival rate was increased [53]. In another investiga- causing any damage [65]. One of the challenge subcutaneous drug

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A. Sultana et al. Medicine in Drug Discovery 15 (2022) 100134

Table 2 Table 4
Summary of the SLNs for improved drug delivery. List of drugs loaded in dendrimers for effective drug delivery.

Drug loaded Results Ref. Drugs Dendrimers Results Ref.

in SLN
Human Polyamidoamine This model showed the [94]
Carbendazim According to release profile, 30% of Carbendazim was [78] epidermal inhibition of mammosphere
released by 6th day from SLN, suggesting the sustained growth factor formation of MDA-MB-231
release receptor-2 and MDA-MB-231/
(HER2) HER2 + cells. Suggesting
Paclitaxel After 24 hours of treatment IC50 (i.e., 50% inhibitory [79]
selective cancer killer gene
concentration) of Paclitaxel SLN on B16F10 cells was
therapy
recorded as 200 nM and 7.7 mM approximately for
Poly (propylene FTIR report suggest that 5 µg [95]
dacarbazine
imine) maltose- per day of G4-His-Mal
Enrofloxacin SLN loaded enrofloxacin accumulated 27.06–37.71 times [80] histidine (G4-His-Mal) dendrimers decreased the
more efficiently than free enrofloxacin. 0.24 and 0.06 μg/ dendrimers formation of amyloid
mL SLN loaded enrofloxacin was effective in inhibition of aggregates
Salmonella CVCC541
Doxorubicin L-cysteine modified Under acidic condition, drug [96]
Berbamine 25 μM of Berbamine loaded SLN inhibited the invasion of [81] G4.5 dendrimer release from dendrimer was
A549 and MDA-MB-231 cells. After 12 days of treatment, increased to approximately
melanoma tumor volume in C57BL/6 mice model for 16%. It inhibited the
control and Berbamine loaded SLN was recorded above proliferation of HeLa cells in
1500 mm3 and below 1000 mm3 respectively zebrafish
Myricetin 0.8 mg kg−1 of myricetin loaded SLN reduced focal sweat [82] SN-38 L-Lysine dendrimer Three times weekly dose of [97]
by 55% (anticancer 4 mg/kg of SN-38 showed
drug) regression of almost complete
tumor. Maximum weight loss
in treated samples was
Table 3 observed as 3.6%
List of drugs incorporated in liposomes for effective drug delivery.
Doxorubicin CXCR4 targeted At pH 5 faster drug release [98]
Drugs Liposome type Results Ref. (LFC131- dendrimers was observed compared to at
DOX-D4) pH 7.4. It binds to breast
Paclitaxel Chitosan Inhibited 86.4% of tumor [87] cancer cell suggesting the
oligosaccharide effective way for cancer
conjugated Pluronic therapy
P123 polymers
Bupivacaine Unilamellar Sustained drug release was [88]
recorded for 6 days
for efficient insertion of drug‐loaded dissolving microneedles (DMNs)
ZL006 HAIYPRH conjugated Drug loaded in Liposome was [89]
via skin. As per the drug release profile comparison data, DMNs micro-
PEGylated liposomes capable of penetrating into the
brain parenchyma via the lancer are much more effective than DMNs loaded patch even for hairy
endothelial cells and effective in skin. After 2 hours of exposure, DMNs patch has released only 56% of
treating ischemic stroke insulin while microlancer released 92% into the skin. In case of hairy
Paclitaxel Glutamic oligopeptides- HAP binding % showed that [90] skin, same value was observed for DMNs microlancer while for DMNs
RGD peptide (PTX- Paclitaxel (from PTX-Glu6-RGD- patch only 26% of insulin was delivered after 2 hours [70].
Glu6-RGD-Lip) Lip) in metastatic bones was 5–8
times higher than free drug.
Suggesting improved targeting 6. Role of nanocarriers in drug delivery
efficacy
Doxorubicin Thioether The minimum average tumor [91] Nanotechnology is the advanced way to cure cancer, infections and
phosphatidylcholines weight was recorded as 0.78 g by neurological disorders [71]. Drug can be delivered using organic
liposomes samples treated with Doxorubicin nanocarriers and inorganic nanocarriers. Organic nanocarriers include
loaded liposome. In the presence
of 10 mM H2O2, 80% of the drug
solid liquid nanoparticles, liposomes, dendrimers, polymeric nanopar-
was released observed suggesting ticles, polymeric micelles and virus‐based nanoparticles. Inorganic
the improved reactive oxygen nanoparticles include carbon nanotubes and mesoporous silica
species (ROS) triggered release nanoparticles. Fig. 3 represents the schematic representation of vari-
ous nanocarriers used in drug delivery.

delivery is limited volume of drug can be delivered (maximum 3 mL).
To overcome which high concentration injectables of more than
100 mg/mL need to be designed and studied [66]. Zhang and few
others performed a study to compare the efficacy of Mecobalamin
intramuscular injections vs oral tablets for treating diabetes peripheral
neuropathy. It was concluded that Mecobalamin intramuscular injec-
tion is more effective in treating diabetes peripheral neuropathy com-
pared to oral tablet [67]. One of the challenges in intranasal drug
delivery is observed as poor permeability for polar molecules. To over-
come this issue, in a research hypergravity was found to be an effective
way of improving nasal drug delivery efficiency [68]. In an investiga-
tion, rifampin was loaded into mesoporous silica nanoparticle to attain
efficient pulmonary drug delivery. Drug release data showed that, after
24 hours 95% of drug was released by drug‐loaded mesoporous silica
nanoparticles [69]. In research, patchless microlancer was designed
6.1. Solid lipid nanoparticles
Size of solid lipid nanoparticles (SLNs) ranges between
50–1000 nm which is prepared by melting solid lipids in water and
emulsifier is added to form stabilized solution [72,73]. Heat liable
drugs, drugs with poor physicochemical compatibility and low phar-
macokinetic profile can be delivered using SLNs [74,75]. SLNs are cap-
able of eliminating various complications in targeted and sustained
drug delivery some. In a study, 5‐Fluorouracil was incorporated into
SLN via high pressure homogenization with 81% of entrapment effi-
ciency. Results showed that 5‐Fluorouracil SLN had 3.6 times higher
area‐under plasma concentration–time curve compared to5‐
Fluorouracil. According to tumor efficacy study, mean tumor volume
for control, 5‐Fluorouracil and 5‐Fluorouracil SLN (20 mg/kg) was
recorded as 375 mm3, 300 mm3 and 200 mm3 respectively. Hence,

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Table 5
List of drugs incorporated in polymeric nanoparticles for effective drug delivery.

Drugs Type of polymeric nanoparticle Results Ref.

Hydrophobic curcumin Chitosan polymeric nanoparticle
Doxorubicin-triphenylphosphine Polylactic-co-glycolic acid (PLGA)
wrapped with bovine serum albumin
Curcumin Poly(lactic-co-glycolic acid)-poly
(ethylene glycol) (PLGA-PEG)
Ofloxacin Polycaprolactone
Sustained release for 3 hours from the polymeric nanoparticle was observed. Highest [103]
inhibition zone for Pseudomonas aeruginosa was recorded as 3.2 cm
After 12 hours of treatment, MCF-7 cell, at pH 6.5 caused 74% of cell apoptosis. Tumor [104]
volume was reduced from 26 mm3 to 23 mm3.
Drug loaded polymeric nanoparticle have 14 fold higher diffusivity in brain parenchyma [105]
compared to PLGA. Median area loss for drug loaded PLGA-PEG was recorded as 12.3%
Sustained release of drug for six hours was recorded [106]

5‐Fluorouracil SLN is capable of inhibiting HCT‐116 subcutaneous it was observed that efficacy, distribution and concentration of drug at
tumor in mouse [76]. The bioavailability of oral drug administration targeted site can be enhanced by using thermosensitive liposomes
can be improved by encapsulating Amphotericin B and Paromomycin which releases drug on increasing the temperature of tumor via ultra-
in SLN via emulsion solvent evaporation. Entrapment efficiency of sound [86]. Several ongoing researches are found to improve the effi-
Amphotericin B and Paromomycin was recorded as 90% and 96% cacy of drug delivery via liposomes among which some are mentioned
respectively. According to in vitro anti‐leishmanial study, 1 µg/ml of in the Table 3.
modified dual drug loaded solid lipid nanoparticles showed 96.22%
of inhibition against the growth of Leishmania donovani [77]. Table 2.
6.3. Dendrimer
Represents the some of the SLNs studied for improved drug delivery.
Dendrimer consists of several arms originating from core which are
6.2. Liposomes prepared using sugar, nucleotides and amino acids [83]. Dendrimer
are effective method for treating cancer as it depletes bioavailable cop-
Liposomes are spherical vesicle composed of lipid bilayer enclosing per from tumours. Conventional method for synthesis of dendrimer is a
aqueous core which are capable of carrying bioactive agent such as tedious process, therefore effective method was designed to produce
drug [83]. Manufacturing of liposome, loading of drug and removal
of undesirable components can be performed in the continuous process
Table 7
via two microfluidic devices [84]. Although liposomes are effective
List of drugs incorporated in virus-based nanoparticles for effective drug
drug delivery system but lack in on‐demand content release. For this
delivery.
reason, X‐ray‐triggerable liposomes are designed incorporated with
verteporfin and gold nanoparticles. In this investigation it was Drugs Type of virus like Results Ref.
nanoparticles
reported that 6 MeV of X‐ ray triggers the photosensitive vertopoerfin
to produce singlet oxygen and this causes destabilization of liposomal DOX Truncated hepatitis B Within 24 hours almost [120]
membrane causing release of cargos [85]. Similarly, in another report virus core antigen the entire drug was
(tHBcAg) loaded with released. And at pH 5.4,
drug and conjugated more efficient drug
with folic acid release was observed.
Table 6
The IC50 DOX values of
List of drugs incorporated in polymeric micelles for effective drug delivery. virus like nanoparticle
Drugs Copolymer Results Ref. for HT29, Caco-2 and
CCD-112 cells were
Paclitaxel Poly(l-histidine) Minimum increase tumor [110] recorded as 0.14, 2.02
volume (95 mm3) was and 8.10 μM receptively
observed in shielded
Streptokinase Tobacco mosaic virus It enhanced thrombolysis [121]
polymeric micelles loaded
with drug DOX MS2 spheres, tobacco Survival days of mouse [122]
mosaic virus disks and bearing small tumor was
Doxorubicine Diselenide-crosslinked Drug loaded micelles [111]
nanophage filamentous recorded around
micelles (DCM) delivered 3.73-fold higher
rods 40 days days for mouse
quantity of drug compared to
treated with tobacco
free drug in tumor bearing
mosaic virus disks.
mice. Tumor volume for free
drug treated and DOX-DCM Monomethyl Plant virus Potato virus X Reduction in off target [123]
treated samples were 680.86 auristatin drug delivery is
and 210.19 mm3 respectively observed. Median
survival of drug loaded
Doxorubicine Poly(ethylene glycol) At pH 5 drug release was [112]
virus like nanoparticle
observed to be increased two
treated sample was
folds. But the highest
recorded as 54 days
releasewa recorded on
addition of Glutathione Maleimide- Physalis mottle virus More than 83% of [124]
functionalized platinum was released at
Doxorubicine Biotin-Poly(ethylene Cell viability of COS7 cells in [113]
cisplatin pH 5.2 within 48 hours.
glycol)-blocked-poly(L- the presence of micelles was
prodrug More than 90% of mice
lysine) grafted with recorded as 85% and it didn’t
containing Pt (having tumor), treated
matrix possess cytotoxicity
(IV) with drug loaded virus
metalloproteinases suggesting the targeted
like nanoparticles
delivery
survived till 38 days
IR-780 DSPE-PEG2000 Analysis showed; lymphatic [114] while, all control samples
metastasis suppression by were succumbed to
88.2% disease by 28 days

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Table 8
List of drugs incorporated in carbon nanotube for effective drug delivery.

Drugs loaded in CNTs Results Ref.

Silibinin 3T3 cell viability ranged between 69 and 98%. Chitosan coated muliti-walled CNTs showed the highest thermal stability. Sustained release of [133]
drug was observed for 2500 minutes
Doxorubicin In the presence of cathepsin B and at pH 6.5, 85% of the drug was released within 48 hours. Efficient reduction of HCT116 tumor cells by carbon [134]
hydrochloride nanotube was observed
Droxidopa Drug was loaded into the carbon nanotubes efficiently and absorption energy was recorded as −0.714 eV. Bioavailability was enhanced. [135]
Methotrexate On increasing the CNTs, burst release rate decreased. Addition of 0.5% of CNT decreased cell proliferation. Combination of CNT (0.1%) with [136]
hydrogel improved antitumor effect
Formononetin IC50 of Formononetin loaded CNTs for MCF-7 cells and Hela cells was recorded as 17.9% and 21.7% respectively, suggesting the improved [137]
cytotoxicity. Higher release rate was observed at Ph 7.4 than at 5.3 Ph

poly(acyl thiourea) and polythiourea dendrimers. This method
involves isothiocyanate–amine coupling and thiol‐methacrylate
Michael addition reaction to produce one dendrimer generation within
four hours [92]. Several studies have been performed on utilizing the
beneficial effect of dendrimer in drug delivery. Such as in an investiga-
tion, dendrimer incorporated with N‐acetyl‐L‐cysteine (DNAC) was
studied for controlling preterm birth risk. DNAS was capable in reduc-
ing the recruitment of CD3 + T‐ cell to the placenta. According to
analysis, 10 mg/kg of DNAC showed more potent results in decreasing
preterm birth rate than 100 mg/kg of N‐acetyl‐L‐cysteine [65]. Den-
drimers are effective gene delivery system but lacks the application
due to cytotoxicity. One of the methods to overcome this shortcoming
is PEGylation of dendrimers. For instance in an investigation, PEGy-
lated dendrimers showed lesser cytotoxicity on B16F10‐Luc cells com-
pared to unmodified dendrimers [93]. Table 4 represents the list of
various dendrimers used for effective drug delivery.
[109]. Table 6 represents the list of various polymeric micelles used
for effective drug delivery.
6.6. Virus-based nanoparticles
Virus‐based nanoparticles are strong protein cages prepared by self‐
assembly which can encapsulate protein, peptide, nucleic acid and
drug [72,115,116]. These protein cages are much small in size which
leads to difficulty in functionalizing with virus‐binding moieties. To
overcome this problem, DNA origami triangular tiles was designed
with the ability of self‐assembly into icosahedral shells [117]. Virus‐
based nanoparticles plays a vital role in targeted delivery of hydropho-
bic drug to tumor cells for therapy. For instance, virus‐like particles of
Flock House Virus was used to design a viral vector. In this system
2 kDa PEG spacer arm protected the nanoparticle from immune reac-
tion and tLyP‐1 promotes the delivery of drug to the site of action

6.4. Polymeric nanoparticles

Table 9
List of drugs incorporated in mesoporous silica nanoparticle for effective drug
Polymeric nanoparticles are colloidal particles composed of
delivery.
biodegradable polymer which can exist in two forms nanocapsule
and nanosphere. Nanocapsule is prepared by dissolving or dispersing Drugs Nanocarrier design Results Ref.
the drug in liquid core (oil or water) which is encapsulated with poly- Arsenic MSNs coated with PTX was released at pH 6.5 [143]
meric membrane. Nanosphere is fabricated by entrapping drug in poly- trioxide polyacrylic acid and pH- and ATO was released at
meric matrix [99]. Preparation of nanocapsule is a complex process, to (ATO) and sensitive lipid pH 5 effectively
paclitaxel
combat this challenge one‐step self‐assembly strategy was developed.
(PTX)
In a study it was used for encapsulating doxorubicin hydrochloride
ML336 Lipid coated MSNs Dose of 0.11 g LC-MSNs/ [144]
and NaYF4:Yb,Er@NaGdF4 in poly (DL‐lactic‐co‐glycolic acid).
kg/day for four days didn’t
Release profile was dependent on pH, at pH 5, 35.7 wt% and at pH show any toxicity. After 24
7.4, 14.58 wt% of drug was released [100]. In a study, docetaxel‐ hours of treatment, viral
loaded hyaluronic acid nanocapsules were prepared and release profile load was decreased by 4
suggested sustained release of docetaxel for 24 hours [101]. Das and orders of magnitude

colleagues fabricated a poly‐L‐glutamic acid embedded mesoporous DOX MSNs were grafted with After 72 hours, 70% of the [145]
bioactive glass nanosphere. Daunomycin was loaded into the nano- Triphenylphosphine, DOX drug was released and on
was incorporated and addition hyaluronidase,
sphere and results showed higher release at 5.5 pH than at 7.4 pH.
capped with hyaluronic release was increased.
Thus, it can be used for localized drug delivery [102]. Table 5 repre- acid More than 80% of cell
sents the list of various polymeric nanoparticles used for effective drug viability was observed at
delivery. concentration 25 μg/mL
Clofazimine Drug is chaperone by Release efficiency of drug [146]
acetophenone was recorded as 47.2%.
6.5. Polymeric micelles Antibacterial study showed
that 22 µg/mL drug loaded
Polymeric micelles are spherical shell which self assembles using clofazimine was capable of
amphiphilic di‐ or tri‐block copolymers in aqueous media [107]. In a killing 90% of
Mycobacterium
study, controlled radical polymerization was used to prepare amphi- tuberculosis
philic diblock copolymer micelles having hydrophobic core and hydro-
Silver MSNs is incorporated with Minimum inhibition [145]
philic shell. It was observed that on increasing the degree of silver boron nanoparticles concentration of MSNs-
polymerization, release rate of doxorubicin for nine hours decreased (MSNs-AgBrNPs) AgBr NPs to inhibit
from 11.3% to 6.12% [108]. In an investigation, camptothecin was Mycobacterium
incorporated into core of the polymeric micelles and AS1411 aptamer tuberculosis growth was
recorded as 31.25 μg/mL
was covalently attached. Results showed 93% of inhibition of tumor

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A. Sultana et al.
Fig. 4. Schematic illustration of DNA nanostructure which acts as the one of the effect methods for drug delivery and is further classified as DNA tile, DNA origami
and DNA wireframe.
[118]. Virus‐based nanoparticles acts as a promising scalable nanopar-
ticle platform technology for imaging or detection of disease [119].
Such drug delivery can be used to prevent off target delivery and
achieve sustained release of drug some of them are mentioned in the
Table 7.
6.7. Carbon nanotubes
Carbon nanotubes (CNTs) are prepared by folding grapheme sheet
into tube like structure whose diameter is nanoscale and length is
thousand times the diameter [125,126]. CNTs are flexible and possess
electrical conductivity and biocompatibility [127]. It can be single
walled or multiple walled, such as for DOX has stronger bond with
multiple walled CNTs and facilitate better drug release from single
walled CNTs [128]. In a study, Magnetospirillum magneticum bacteria
were used to fabricate carbon nanotubes. Capacitance of this scaffold
was improved to six times higher than the pure carbon nanotubes
[129]. Dehaghani and collegues encapsulated Isatin in a single walled
carbon nanotube. Results showed that eleven molecules of Isatin was
easily absorbed in 30 Å long single walled carbon nanotube and
remained encapsulated till the end of molecular dynamic simulation
[130]. Hence, carbon nanotubes are capable of holding drug to obtain
targeted drug delivery. In an investigation, Doxorubicin was loaded in
N‐isopropyl acrylamide Carbon nanotube. It was observed that poly-
mer of short chain length has better stability, interaction and release
of doxorubicin [131]. In another research, doxorubicin (loaded with
folic acid) was incorporated into the carbon nanotube and blended
with silk protein to develop injectable hydrogel system. Results
showed sustained release of doxorubicin for 14 days [132]. Such
nanocarrier can be used in design of system capable of reducing sys-
temic side effects. Such drug delivery can be used to prevent off target
delivery and achieve efficient drug some of them are mentioned in the
Table 8.
6.8. Mesoporous silica nanoparticles
Mesoporous silica nanoparticles (MSNs) are silica material with
structure similar to honeycomb and it can be synthesized in varying
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Medicine in Drug Discovery 15 (2022) 100134
size consisting of different pore sizes [138,139]. Sol‐gel process is
the commonly used method to synthesize MSNs which involves
hydrolysis and condensation of silicon alkoxide precursors [140].
Delivery of drug before it reaches target is one of the commonly faced
issue, but using MSNs it can be overcome as the exposure to internal or
external stimuli would trigger the pore opening and permit drug
release [141]. In an investigation, anti‐carbonic anhydrase IX antibody
was bonded on the surface of MSNs and doxorubicin hydrochloric was
loaded. According to in vivo therapeutic efficacy, drug loaded in MSNs
showed the least tumor growth at 11th day of treatment. The inhibit-
ing concentration 50% values for 24 h for drug loaded in MSNs was
recorded as 1.1 μg/mL. It was also observed that addition of 10 mM
glutathione, increased release of doxorubicin at pH 5 was from 28%
to 80%, suggesting redox‐responsive release [142]. Such drug delivery
can be used to design effective drug delivery, some of them are men-
tioned in the Table 9.
Nanocarrier drug delivery helps in improving bioavailability,
enhances permeability, reduces drug dosage, prevents degradation,
active and passive targeting, reduces the risk of side effects due to
aggregation and speed up the curing of disease [146,147]. Apart from
various advantages of nanocarrier, its application is limited due to tox-
icity, difficulty in scaleup process and low drug loading efficacy [148].
7. Smart drug delivery systems
Although conventional drug delivery systems are widely used tech-
niques for treatment of health issues but certain limitations have led
the demand for advanced version for delivery of drug known as smart
drug delivery systems. Smart drug delivery system can be defined as
system which has controlled release rate and provides spatiotemporal
resolution. Drug release in such systems takes place as a response to
exogenous stimuli such as electric field, ultrasound and magnetic field,
and endogenous stimuli such as enzyme, pH and retention effect
[149]. This review focuses on the impactful smart drug delivery sys-
tems such as nucleic acid, cell‐based, self‐nano emulsifying, self‐
micro emulsifying drug delivery system, physical, chemical stimuli‐
based drug delivery system, nanoneedle patches, ultrasound drug
A. Sultana et al. Medicine in Drug Discovery 15 (2022) 100134

Fig. 5. Schematic representation of formation of aptamer from RNA or DNA which fold into three-dimensional conformation and then binding to the target
resulting in target aptamer complex formation.

Fig. 6. Schematic representation for cell-based drug delivery system which is designed as an inspiration from erythrocytes, platelets, macrophages, leucocytes
(monocytes and neutrophils), T cells, stem cell and bacterium.

delivery system, microchip technology, nano vaccine, dry vaccine drug
delivery system and bioceramic nanoparticles.
7.1. Nucleic acid-based drug delivery system
canonical nucleic acid can be used for diverse structural designing of
DNA nanostructures due to its high degree of conformational polymor-
phism [153]. Recent development has led to the exploration of three
pillars of nucleic acid‐based drug delivery system which are DNA nan-
otechnology, spherical nucleic acids, and aptamers [151].

Nucleic acids are negatively charged, hydrophilic polymer which

are impotent of permeating through the cell, enzymatically unstable,
may lead to undesirable biological responses and hence, broadly not
considered as a good option to be used for drug delivery [150,151].
But the modified nucleic acid has proved the ability to activate the
innate immune system at low concentration [152]. For instance, non-
7.2. DNA nanotechnology
DNA is a nanoscale material which has the ability to carry genetic
information. DNA nanotechnology is an excellent method for drug
delivery but has the limited use due to its susceptibility to nuclease

11
A. Sultana et al.
[154]. Advantages of DNA nanotechnology include its precise defined
particle architecture, stimuli‐responsiveness and absence of intrinsic
toxicity. DNA nanotechnology can be further classified as tile‐based
assembly, DNA origami, and DNA wireframes (Fig. 4) [151].
Tile‐based assembly is composed of double DNA duplexes with
crossovers [155]. Thermal annealing process is used to fabricate
DNA origami structure, in which staple strand is amalgamated with
numerous scaffold segments to develop double helical structure
[156]. In a study, DNA origami is incorporated with 2‐[3‐(1,3‐
dicarboxy propyl)‐ureido] pentanedioic acid and then loaded with
Doxorubicin via intercalation. Results showed that DNA origami
helped in selectively delivering Doxorubicin to the prostate‐specific
membrane antigen cancer cell line LNCaP [157]. Designing of DNA
wireframe structure involves three steps: graphical representation
(2D or 3D) of target structure, network rendering of nodes (vertices
of arms) and edges (variable length), separation of edges and sequence
production [158]. In a study, wireframe DNA origami with honeycomb
edges were designed and it was concluded that structural fidelity is
improved [159].
7.3. Spherical nucleic acid
Spherical nucleic acids are compact structure composed of DNA
layers positioned vertically on the center core (silica, quantum dots,
liposomes, polymers, or even empty cavity) [160–165]. In this system,
nucleic payloads and co‐delivery of drug occur in synchronized man-
ner which has beneficial effect on enhancement of stability and solu-
bility, allows delivery without carrier and improved drug loading
[151].
7.4. Exosomes
Exosomes are extracellular vesicles composed of proteins, mRNAs,
lipids and miRNAs. Exosomes which is lipid molecules (30–100 nm
wide) used for transportation of smaller molecules [166]. Earlier, exo-
somes were considered as cellular waste but research has proved its
application in intracellular connection which has effect on functioning
and activity of recipient cell [167,168]. Formation of exosomes
includes four basic steps budding, invagination, formation of multi-
vesicular bodies and secretion of multiple vesicle structures [169].
Exosomes play a vital role in pathogenesis and progression of health
ailments such as cancer.
7.5. Lipid nanoparticle
Lipid nanoparticle are non‐viral gene delivery system which can
deliver siRNA, mRNA, DNA, or gene‐editing complexes [170]. These
nanoparticles are useful in transportation of hydrophobic and hydro-
philic molecules. It reduces the toxicity, controlled release and
increase in drug action [171]. Lipid nanoparticles are profound deliv-
ery system for anticancer drug and as well as environmentally friendly
[172].
7.6. Aptamer
Aptamers can be defined as a single stranded oligonucleotide which
have the ability to bind to target cells through their 3D structure
[173,174]. Aptamer conjugates are considered as the most effective
nucleic acid‐based drug delivery system [151]. Nucleic acid can be
prepared using SELEX (Systematic Evolution of Ligands by Exponential
enrichment), which involves the separation of initial nucleic acid bin-
ders from oligonucleotide library, followed by amplification via poly-
merase chain reaction [175] (Fig. 5).
Aptamers have lesser toxicity, can be easily modified depending on
the requirement, easily bind to tumor biomarkers and inexpensive
(production cost) when compared to antibiotics [176,177]. In an
12
Medicine in Drug Discovery 15 (2022) 100134
recent study, DNA nanoscale precision‐guided missile was designed
which consist of two parts: warhead (rod‐like DNA nanostructure
which acts as a drug carrier) and a guidance/control (aptamer‐based
logic gate). This DNA nanostructure was capable of specific recogni-
tion and targeted delivery of doxorubicin for cancer therapy [178].
7.7. Cell-based drug delivery system
For designing of cell‐based drug delivery system, erythrocytes, pla-
telets, macrophages, leucocytes (monocytes and neutrophils), T cells,
stem cell and bacterium act as inspiration because of their unique
transportation mechanism (Fig. 6) [179].
Erythrocytes are red blood cells which due to their special structure
and circulating attribute are considered as the efficient source of drug
delivery system [180]. Platelets are cell whose maximum portion of
cytoplasm is composed of thrombosthenin and nucleus is absent. Pla-
telets have a vital role in hemostasis, whenever there is any injury pla-
telet acts as source of repairement via four step mechanism: adhesion,
activation, aggregation, and wound repair. Monocytes are leucocytes
with diameter in the range of 50–80 μm, unilobar nuclei and granu-
lated cytoplasm and have the ability to migrate into the infected site
by following inflammatory signals. Macrophages are cells with the
diameter of around 21 μm and have the ability to engulf via phagocy-
tosis and degrade foreign substances. Macrophages have an important
role in innate immunity and adaptive immunity. Neutrophils are gen-
erated by the stem cells in bone marrow and belong to polymorphonu-
clear cell family. Neutrophils play a vital role in innate immunity and
are well known due to their ability of deformability and chemotaxis. T
cells are those which mature in the thymus and further divide into sub-
sets. A T cell recognizes epitopes of foreign substance and leads to cell
death. It has the ability of releasing cytokines and enhances immune
system by promoting generation of antibodies via B cells [179]. Stem
cells are unspecialized cells which can differentiate into any cell [181].
In a study it was observed that stem cells are capable of targeting
tumor foci [182]. Bacteria have the ability to locomote along the mole-
cules providing signals and this attribute can be used to carry drug to
specific area [179].
For instance, in an investigation, macrophage was used as a pul-
monary drug delivery system. Doxorubicin was loaded into cellular
vectors via electroporation and passively for comparison. In release
study it was found that, 80% of payloads were released within 2 hours
for passively loaded samples and within 6 hours for electroporation
loading [183].
7.8. Self-nano emulsifying drug delivery system
Self‐nano emulsifying drug delivery system (SNEDDS) refers to a
blend, composed of oils, surfactants and co‐solvent which when agi-
tated in aqueous condition results in oil in water nano emulsions
[184–186]. The resulting nano emulsion droplet ranges between
20–200 nm and is used for efficient movement of active component
across the intestinal membrane [187]. Fig. 7 represents the compo-
nents of SNEDDS and formation of nano emulsion.
The three major components of SNEDDS are further discussed
below:
7.9. Oil
Oil considered for SNEDDS is usually medium to long chain triglyc-
erides and should possess good solubility for drug as it facilitates drug
absorption and formulation‐loading capacity [188]. In contrary, a
study reported that low solubility of drug in oil has better absorption
property [189]. Some of the usually considered oils are such as poly-
ethylene glycol, hydrogenated castor oil, sorban esters, glyceryl mono-
linoleate and triglycerides of capric/caprylic acids [190].
A. Sultana et al.
Fig. 7. Schematic illustration of the four major components of SNEDDS which
are surfactant, co-surfactant, drug and oil. When dissolved in water it results in
formation of nano-emulsion.
7.10. Surfactant
Surfactants are the substance which reduces surface tension to sta-
bilize the nanoemulsion. Surfactants can be classified based on charge
(ionic and non‐ionic) and hydrophilic‐lipophilic balance (HLB) (lipo-
philic and hydrophilic) [191]. Surfactants which are non‐ionic and
have hydrophilic‐lipophilic balance more than 12 are considered as
the best option for SNEDDS because they enable unconstrained nano
emulsification mechanism [190].
7.11. Co-solvent
Co‐solvent or co‐surfactant is required because surfactant alone
cannot always facilitate nano‐emulsification and it helps in attaining
stability and homogeneity [192]. Co‐solvent and surfactant weight
ratio has an important role in designing efficient SNEDDS. The mini-
mum quantity of co‐solvent is considered to prevent drug precipitation
which is usually caused due to polarity of co‐solvent which leads to
migration towards water [193].
In an investigation, andrographolide was loaded into SNEDDS to
study its effect on oral dissolution and bioavailability. The results
showed 1.2 folds increase in the AUC (area under the curve) and
1.26 folds increase in Cmax (maximum concentration) for SNEDDS sam-
ples when compared to plain andrographolide. Hence, it was con-
cluded that SNEDDS is effective means for enhancing dissolution and
bioavailability [194]. Some of the advantage and disadvantages are
mentioned in the Table 10.
Table 10
List of some of the advantages and disadvantages of self-nano emulsifying drug
delivery system.
Advantages/Disadvantages
Advantages Protects sensitive drug components
Improved bioavailability and reduces dose intake
Rapid distribution throughout gastrointestinal tract and
reduces irritation in gut due to frequent drug intake
Disadvantages It is thermodynamically unstable
Medicine in Drug Discovery 15 (2022) 100134
7.12. Self-micro emulsifying delivery system
Self‐micro emulsifying drug delivery systems (SMEDDS) are com-
posed of oil, water, surfactant and co‐surfactants or co‐solvents which
results in isotropic microemulsion. This blend can be incorporated into
capsule and injested and when it contacts with the gastrointestinal
tract it results in oil in water microemulsion [197]. Major components
of SMEDDS are drug, oil, surfactant and co‐surfactant. Drug used
should not have first pass metabolism and minimal dose is considered.
Medium chain triglyceride moves directly to the circulatory system,
and usually considered for lipid‐based drug due to rapid solubility
and ability to prevent oxidation. Surfactant used should have HLB
value more than 12 to obtain effective emulsification. Medium chain
alcohols are usually considered co‐surfactant. Co‐surfactants are help-
ful in reducing interfacial tension to negative value [196].
One of the examples of SMEDDS includes a study in which oral
bioavailability of cathepsin K inhibitor (HL235) was improved. It
was designed using 5.0% of Capmul MCM EP, 20.0% of Carbitol and
75.0% of Tween 20. The size of the droplet obtain via microemulsion
was 10.7 mm. And the results showed that bioavailability was
improved to 3.22‐fold when compared to control [198]. Some of the
advantage and disadvantages are mentioned in the Table 11.
7.13. Physical stimuli responsive drug delivery system
Two widely studied physical stimuli responsive drug delivery sys-
tems are thermo and light responsive drug delivery systems. In thermo
responsive drug delivery system, temperature plays a critical role, drug
release depends on temperature change [199]. For instance, in a study
poly(Nisopropylacrylamide) was used to encapsulate antibacterial
peptide of G(IIKK)3I‐NH2 at lower temperature. On increasing the
temperature above 33 ℃ resulted in release of drug [200]. In light
responsive drug delivery system, drug release is triggered by the light.
For instance, copolymers of N‐Isopropylacrylamide and N‐
(hydroxymethyl) acrylamide were loaded with sodium copper chloro-
phyllin. On exposure to green laser light for 2 minutes, controlled drug
release was attained to kill cancer cell via 5‐FU loaded nanogel [201].
7.14. Chemical stimuli responsive drug delivery system
Chemical stimuli responsive drug delivery systems are dependent
on pH, redox potential and enzyme response. pH responsive drug
delivery system is based on pH‐controlled release of drug. For exam-
ple, chitosan nanoparticles were incorporated with Tamoxifen can be
used for targeted drug delivery for tumor treatment. It was observed
that Tamozifen released more efficiently at 4 and 6 pH rather than 7
pH+. Change in redox potential also acts as trigger for controlled
and targeted drug release. For instance, concentration of glutathione
of cancer cell (2–10 mM) is ten times higher than in normal cells which
can act as potential gradient for drug release [202]. Enzyme such as
Cathepsin B (lysosomal protease) can also be used for provoking the
drug release. In an investigation it was observed that polyethylene
Table 11
List of some of the advantages and disadvantages of self-micro emulsifying drug
delivery system.
Advantages/Disadvantages Ref.
Ref. Advantages Improved bioavailability [196]
Thermodynamically stable
[195] Manufacturing of SMEDDS is easy
Food does not interfere with drug absorption
Disadvantages In vivo drug precipitation is observed
Handling complication while formulation
[196] It has bounded lymphatic uptake
Causes oxidation of unsaturated fatty acid
13
A. Sultana et al.
glycol‐Gly‐Leu‐Phe‐Gly‐Lys(C16)2 loaded with Doxorubicin resulted
in controlled drug released due to degradation by capthepsin B and
was effective in inhibition of Hep G2 cells viability by 60% [203].
7.15. Nanoneedle patches
Preparation of Silicon nanoneedle was performed by treating the
silicon wafer with buffered oxide etch and followed by fabrication of
silicon pillars via photolithography patterning and deep reactive ion
etching process. The passivation layer of (CxFy)n polymer is deposited
on the silicon pillar surface under radio frequency power of 800 W.
Size of silicon pillars is reduced to nanometer by immersing the silicon
wafer in potassium hydroxide solution. These silicon nanopillars are
removed from the wafer and embedded on the polydimethylsiloxane.
It has application in nanoinjection of biomolecules into cells and tis-
sues [204]. In an investigation, diamond nanoneedles are prepared
with aptamer based nano sensors. This nanoneedle is capable of isolat-
ing NF‐κB from intracellular region [205]. Diamond nanoneedle is cap-
able of enhancing the delivery of plasmid DNAs into neurons by eight‐
fold in transfection efficiency compared to lipofection. It is an efficient
method for vector free delivery to cytoplasmic matrix [206].
7.16. Ultrasound drug delivery
Ultrasounds are capable of permeating into the tissue at very low
amplitude. It can be used to trigger local anesthetic to combat pain
[207]. Ultrasounds can be used for targeted drug delivery because
when a nanoparticle embedded with drug is injected into the blood
vessel and irradiated with ultrasonic energy, the nanoparticles expand
and facilitate the release of drug [208]. Ultrasound can be used for
controlled drug delivery. For instance, in a study, tetrodotoxin and
protoporphyrin IX were encapsulated into micrometric liposomes.
Exposure of ultrasound showed formation of reactive oxygen species
(ROS). This ROS reacted with liposome membrane and leads to insta-
bility and releases tetrodotoxin [209].
In a study it was observed that ultrasound can be used to detect gas
vesicles present in the microorganism [210]. The mechanism behind
this is that ultrasounds are scattered when comes in contact with gas
vesicles which are recorded. But pressure pulses are capable of collaps-
ing the cell which causes disappearance of the ultrasound and can be
used for detecting the location of the cell containing gas vesicle [211].
In another investigation, ultrasound has also shown to favor the treat-
ment of Leptomeningeal metastases in athymic rats. Experiment was
divided into three groups: (i) samples with no treatment, (ii) samples
treated with trastuzumab and (iii) samples were treated with trastuzu-
mab and focused ultrasound combined with micron‐sized stabilized
bubbles. Magnetic resonance imaging report showed that group 1, sup-
pressed the tumor cells to 25 ± 17 mm3 and group 3, suppressed it to
8 ± 5 mm3 [212].
7.17. Microchip technology
Microchip is a micro‐scale device with wireless chipset, sensors and
drug delivery unit which can be used for pulsatile release of drug
[213]. Electric field can be used to provoke conducting material for
controlled release drug [214]. The four ways electric field can provoke
drug delivery system are: by opening the pores of conducting material
which covers the drug, by shrinking the nanoparticle which ultimately
release the drug in the presence of electric field, by enhancing the skin
permeability and by applying force on ions which enhances the move-
ment of surface‐charged small‐molecule drugs [149]. In a study n‐type
silicon wafer (resistance of 0.45 ± 0.75 Ω cm and diameter of 100 nm)
was used to prepare silicon chip. The efficiency of DNA electroporation
was recorded as 23.08% and 61.21% for neuronal SH‐SY5Y and
epithelial CHO‐K1 cells respectively. It was concluded that silicon
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Medicine in Drug Discovery 15 (2022) 100134
microchip was capable of double and serial transfection of the targeted
cells [215].
7.18. Nano vaccine
Nano‐vaccinology can be defined as science of nanoscale particles
which has opened an entrance to boundless hopes for treatment of var-
ious diseases [216]. Nanoscale vaccine is designed to achieve sustain-
able release, improved immunogenicity, improved antigen stability,
flexible physical characteristics and reduced immune‐toxicity [217].
Nanoscale technology is not so common among the present population
which makes it difficult to accept and leads to unwanted conspiracies
such as presence of nanorobotic chips in the vaccine. For covid‐19
treatment, viral and non‐viral nanoscale vaccine vectors are injected
which has undergone minimum 25 years of long development phase
towards clinical translation. Long term use of nano vaccine is still
not clear due to cost, duration of effectiveness is not understood, incor-
poration of new sequence against mutation of virus is not easy and
complicated manufacturing and logistics [218].
7.19. Dry vaccine delivery system
Vaccines are made up of antigens which are usually chemically and
physically unstable in liquid formulation [219,220]. Vaccine delivery
in the dry powder aerosol form is considered as a promising method
to prevent degradation of macromolecules present in vaccine [221].
In a study, spray freeze dried vaccine was analyzed for anthrax treat-
ment via nasal route. Formulated vaccine can be stored for two and
a half years at room temperature and results suggest it remains as fresh
as intramuscular injection in liquid formulation [222]. In another
study, Norwalk virus‐like particles was incorporated into dry powder
of polysaccharide derived from aloe vera for nasal delivery. It was
observed that nasal mucosal provides large surface area for immune
induction. This study concludes that dry vaccine is more immunogenic
than liquid formulation [223]. In a recent investigation, nanovaccine
(cubosomes with ovalbumin and Quil‐A) was spray dried. Powdered
form vaccine consisted of 10.6 ± 0.7% w/w ovalbumin, among which
65% was released with 20 minutes and complete release was recorded
in 24 hours [224]. Luczo and his colleagues developed powdered form
of live attenuated influenza vaccines by vapourization and reported
the minimum loss for 1 year at 25 ℃. And also suggests that this vac-
cine can be stored without refrigeration and do not require reconstitu-
tion and injection during administration [225]. Thus, dried form of
vaccine is one of the methods to develop vaccine with improved effi-
ciency and stability.
7.20. Bioceramic nanoparticles
Bioceramic nanoparticles can be used as a cargo for targeted drug
delivery and prevents enzymatic degradation [226]. Bioceramic
nanoparticles helps in sustained release of drug as reported in a study
sustained release of gentamicin for 70 hours was recorded poly
(epsilon‐caprolactone) coated calcium phosphate scaffolds [227]. Alu-
mina, pyrolytic carbons, zirconia, calcium phosphates and silica‐based
glasses or glass ceramics are the commonly known bioceramics [228].
Among all the bioceramic NPs, calcium phosphate is widely studied for
drug delivery due to their chemical similarity to biomineralized mam-
malian tissue leading to a high biocompatibility and inherent
biodegradation [229]. Calcium phosphate possess more reaction sites
for drug binding due to their high surface‐to‐volume ratios compared
to bulk form and high loading capacity [230]. Calcium phosphate NPs
can be synthesized via precipitation, sol–gel method, flame‐spray
pyrolysis, solid‐state reactions etc., with different properties, depend-
ing on morphology, size, and surface properties [231]. In an investiga-
tion, Platinum (IV) prodrug of cisplatin was loaded into hybrid
nanoparticles of human serum albumin (HSA) and calcium phosphate.
A. Sultana et al.
The pH responsive study showed that, at normal pH the hybrid is
stable and at pH less than or equal to 6, complete release of drug
was observed. According to in vitro cytotoxicity analysis, calcium
phosphate enhanced the cytotoxicity of hybrid [232]. Fig. 8 represent
the schematic illustration of bioceramic nanoparticle used for drug
delivery.
7.21. Nanogels
Nanogels are 3D nanoparticles obtained by crosslinking hydrophi-
lic or amphiphilic polymer chains which can be used for incorporation
of drug via hydrogen bonding, salt bond formation or hydrophobic
interaction [233]. Nanogels reduces toxic effects, enhance therapeutic
index of the drug and can be fabricated as stimuli‐responsive materials
[234]. It has scope in controlled drug release for cancer therapy such
as in an investigation sulfamide‐based zwitterionic monomer was used
to synthesise nanogels which showed controlled drug release and exhi-
bit prolonged blood circulation [235]. In another study, pH‐responsive
polypeptide‐based nanogels were developed which was stable at pH
7.4 and released doxorubicin under acidic (tumor) condition [236].
7.22. Fullerenes
Fullerenes are allotropes of the carbon and have a structure which
possess sp2 carbons. Fullerenes are useful in achieving controlled
release of drug to the targeted site, thus have scope for efficient treat-
ment of disease like cancer and HIV [237]. In an investigation por-
phyrin adducts of cyclohexyl‐fullerene were fabricated which
showed 80% recovery of hypoxia symptoms in one day [238]. Fullere-
nes can also be incorporated with hormone such as erythropoietin and
bioactive component such as warfarin [239,240]. It has antioxidant,
antibacterial and photodynamic effect and also acts as scaffold for drug
synthesis [241].
Smart drug delivery system has several advantages among which
one of the important factors is, it maintains the drug concentration
in the organ or tissue but decreases drug dosage frequency. Insufficient
information availability on in vivo trails, cost of drug, problem of
inconsistent pharmacokinetics between preclinical and clinical trials
are some of the factors which acts as shortcoming of the smart drug
delivery system [242].
8. Ethics and regulatory affairs in nano-drug delivery system
Variation in characteristics of nano scale particles may cause
unwanted effect on environment and human. Therefore it is important
Fig. 8. Schematic illustration of bioceramic nanoparticle which acts as a
carrier of drug for targeted drug delivery. It consists of target molecule,
surface stabilizing component and drug.
15
Medicine in Drug Discovery 15 (2022) 100134
to understand the interaction of drug with the environment, involve-
ment in biosystem, biodegradability, disposability and its accumula-
tion [243]. Establishment of regulatory authority is necessary for
nano‐drug delivery system because along with various benefits of
nano‐medicines some studies also suggest the negative impact on
health. This regulatory body needs to consider ethical, legal and social
impact as well as focus on possible and non‐possible risk of the drug.
Along with environmental impact, ethical impact is also need to be
considered which leads to design of strict rules and regulation. One
of the challenges is communication gap between developed nations
and under developed nations is related to risk an assessment and man-
agement measure which causes complication in designing standard
rules. Another challenge is the knowledge gap among scientist, public,
regulatory body and civil society which lead to inadequate risk evalu-
ation and administration [244]. Patenting of nano‐based drug is also
under confusion whether it should be patented or not. For this reason,
Europe has designed a “nanoscience and nanotechnology patent‐
monitoring system under European Patent Office [245]. Drug delivery
system requires proper and systematic rules and regulation followed
by ethical aspects, but currently implementation of such system is
absent due to global governance gap, communication gap and knowl-
edge gap.
9. Future scope
Drug delivery systems have advanced a lot from the normal basic
pill with unregulated release towards the systems with improved
bioavailability and reduced side effects. Still there are undergoing
researches focusing on targeted, controlled, monitored and convenient
drug delivery systems. Researchers need to focus on factors such as
drug delivery system for future viruses, safety, symbiotic delivery sys-
tem, gender sensitive delivery system, affordability, more greener drug
delivery system and system which resolves unmet clinical needs. These
factors are further discussed in details.
9.1. Drug delivery for future viruses
Viral infections are one of the health issues which are challenging
to treat due to increased drug resistance and barrier at cellular and
intracellular levels. For example, an effective treatment of herpes sim-
plex virus and herpes zoster are still under study. Frequently encoun-
tered pandemic situation around the world due to Covid‐19 is also an
example of unavailability of effective drug for treatment. Although
remdesivir was a hope for reducing the recovery of patients but still
many conflicting data is available [246]. Recent development has
led to the focus on nanaotechnology (nanoparticles, liposomes, nano-
spheres, nanogels, nanosuspensions and nanoemulsions) for drug
delivery [247]. For instance, in a study multiwalled carbon nanotubes
conjugated with virus‐specific nanobody and antiviral drug was inves-
tigated for treatment of virus induced central nervous system disease.
It was observed that the mortality of larvae was 100% for control and
27% for treated samples [248]. In an undergoing study, it was
reported that molnupiravir (an antiviral pill) can be used for effective
treatment of gamma, delta and Mu variants of corona virus. Such drugs
are the need for being ready to face future predicted health crisis.
9.2. Safety and efficacy of drug
It is reported that 80% of the drug used for human trail fail to show
safety and efficacy [249]. Such failure can be overcome by being open
about the failed trails which also help to speed up the research in drug
development [250].
A. Sultana et al.
9.3. Symbiotic drug delivery
Symbiotic drug delivery is an efficient way for targeted and con-
trolled drug delivery such as bacteria can be used for treatment of dis-
eased human tissue. In a study bacterium was used as vehicle to carry
antitumor drug which reduced toxicity and improved delivery effi-
ciency [251]. In another study, Lactobacillus acidophilus was
microencapsulated in alginate‐gelatin and alginate‐gelatin‐fructooligo
saccharides microbeads and results suggested improvement in viability
of microbes in gastrointestinal tract as well as when incorporated in the
yogurt [252]. Symbiosis of metal–organic frameworks was fabricated
and studied for efficient drug delivery. Drug release profile showed that
hydrogel release was completed within 5 days whereas, metal–organic
frameworks had sustained release for 7 days [253].
9.4. Gender sensitive drug delivery
Gender differences have effect on frequency and severity of phar-
macological side effects [254]. Difference in gender has variation in
physiological, hormonal, and genetic conditions which may act as a
reason for uneven pharmacological side effects. In a study adverse
event of antidiabetic drug was investigated based on difference in gen-
der. It was observed that 13 out of 17 system organ class level disor-
ders were common in women than in men [255]. In another study it
is found that compared to men, women encountered nervous system
disorders such nausea, headaches, insomnia [256]. Thus, it is neces-
sary to consider gender differences to design a tailored and more effec-
tive treatment for each individual [257].
9.5. Affordable
It has been observed that novel drug with even modest benefits
come with the increase price than the previous existing treatment. In
a report, four regulatory policies are proposed to induce transparency
and reduce unnecessary cost rise of drug. First is, to only allow those
drugs which have added therapeutic benefit. Second is, that all the
drugs should undergo head‐to‐head comparison with other treatments
which include mandatory active‐controlled randomized controlled tri-
als. Third is, that added therapeutic benefit should undergo indirect
comparisons. And the last step is to describe the comparison of a coun-
terfactual scenario with the bad or good effects of treatment [258].
9.6. Greener drug delivery system
Drug delivery fabricated using living organisms, biomolecules and
environmentally friendly are greener compared to the existing drug
delivery systems. For instance, oligonucleotide (polynucleotide DNA
or RNA chain) acts as a aptamer and could be used for treatment
due to its low adverse effect, high specificity, least chance for resis-
tance development and minimum cytotoxicity [259]. Natural compo-
nents such as curcumin, camptothecin, anthracyclins and collagen
can be incorporated into nanofiber via electrospinning and used for
treatment of cancer [260,261].
9.7. Intelligent drug delivery system
Intelligent drug delivery system involves the delivery of drug by
sensing the change based on stimuli [262].Intelligent drug delivery
helps in achieving targeted drug delivery via pH responsive, light sen-
sitivity, redox responsive, enzyme responsive, thermo responsive and
other responsive systems such as saccharide sensitive system, urea
responsive system, electro responsive system and may other [263].
For instance in a study mesoporous silica nanoparticles were coated
with poly(ethylene glycol) and poly(2‐(pentamethyleneimino)ethyl
methacrylate) to obtain pH triggered targeted drug delivery [264].
Near infrared light targeted drug delivery is reported in a study involv-
16
Medicine in Drug Discovery 15 (2022) 100134
ing incorporation of SrCl2 and black phosphorus nanosheets into poly
(lactic‐co‐glycolic acid) [265]. Intelligent drug delivery system is a
potential drug delivery system for future but requires focus on its tox-
icity, adequate intensity and in vivo evaluation of the performance.
Intelligent drug delivery system will have promising opportunities to
attain efficient targeted drug delivery [266].
10. Conclusions
Drug delivery system plays a vital role in terms of treatment of var-
ious health issues. The basic mechanism of drug release involves, bind-
ing of nanocarrier linked with drug to the receptor, entering the cell
via endocytosis and then the drug releases into the endosomes. Tar-
geted delivery of drug can take place either via linker mechanism or
encapsulation. The four basic steps involved in pharmacokinetics once
the drug is administered are absorption, distribution, metabolism and
elimination of drug.
This review discusses the various conventional drug delivery sys-
tems along with their benefits and shortcomings. Drug delivery system
has been evolving very fast with time through implementation of inno-
vative technology. Limitations of the existing or conventional drug
delivery systems can be overcome with the smart drug delivery system.
These smart drug delivery systems (such as nucleic acid‐based, cell‐
based, self‐nano emulsifying, self‐micro emulsifying drug delivery sys-
tems physical and chemical stimuli‐based drug delivery) are capable in
improving bioavailability, stability, better absorption and controlled
release of drug for effective treatment of health problems. With recent
advancement novel drug delivery system such as nanoneedle patches,
ultrasound‐based delivery, microchips and many other are widely
studied with future perspective for achieving targeted and controlled
drug delivery systems. This study has highlighted the seven major
issues which need to be focused for designing of potential and effective
drug delivery system and overcoming existing challenges for treatment
of health issues.
Author contributions
A.S collected data for the review article, prepared the initial draft of
the manuscript, and worked with the co‐authors to edit and refine the
manuscript before submission. M.Z., V.T., and T.S.S.K. revised and edi-
ted the manuscript. S.R. and M.Z. supervised the work, revised the
manuscript, and approved the final version to be published. All
authors have read and agreed to the published version of the
manuscript.
Funding
The authors received NO specific funding for this work.
Ethical statement
This study was conducted with integrity, fidelity, and honesty. No
humans or animals were harmed.
Conflicts of interest
The authors declare that there are no conflicts of interest.
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