Development Team

Prof. Farhan J Ahmad

Principal Investigator Jamia Hamdard, New Delhi
Dr. Vijaya Khader
Former Dean, Acharya N G Ranga Agricultural University
Dr. Sushama Talegaonkar
Paper Coordinator Jamia Hamdard, New Delhi

Dr. Honey
Content Writer Baba Farid University of Health Sciences,
Faridkot

Prof. Vivek Ran jan Sinha

Content Reviewer Panjab University, Chandigarh

Prof. Dharmendra.C.Saxena
SLIET , Longowal

Pharmaceutical Novel Drug Delivery Systems II

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 Content Reviewer

Dr. Vijaya Khader

Dr. MC Varadaraj
Description of Module

Subject Name Pharmaceutical Sciences

Paper Name Novel Drug Delivery Systems II

Module Name/Title Targeted Drug Delivery Systems-I

Module Id 26

Pre-requisites Internet, PC equipped with MS Word 2007 or 2010/Acrobat Adobe software

Introduction, Concepts, Description, Basic understanding, Advantages, Disadvantages and

Objectives
Carrier for targeting, Order of targeting

Keywords Target, drug delivery, carriers, order, magic bullet

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 TARGETED DRUG DELIVERY SYSTEMS
The origin of concept of targeting was first of all initiated by Paul Ehrlich, when he introduced the term
‘magic bullet’ as an entity consisting of two components- the first one should recognize and bind the
target, while the second should provide a therapeutic action towards its target as shown in Figure 1.
Hence, magic bullet comprises a coordinated behavior of drug, targeting site and pharmaceutical carrier.

Figure 1: Concept of drug targeting

After the decoding of human genome in 2002, targets of pharmacological interest amplified
from 482 to 8000, out of which 5,000 were found to be potentially hit by traditional drug substances,
2,400 by antibodies and 800 by protein pharmaceuticals (Drews and Ryser, 1997; Imming et al., 2006).
And on the basis of ligand-binding studies, 399 molecular targets were identified belonging to 130
protein families, and ~3,000 targets for small- molecule drugs were predicted to exist by extrapolations
from the number of currently identified such targets in the human genome (Park, 2014). Current
paradigms and focus of the targeted drug delivery systems include- enhanced permeation and retention,
drug distribution, multiple drug resistance and micro-environmental factors.

TARGETED TECHNOLOGIES

Targeted drug delivery systems are the engineered technologies to deliver the pharmacologically active
moieties or drugs at higher concentrations to a specific region/part of the body relative to others. The
prime focus of drug targeting techniques is to overcome the nonspecific toxic effect of conventional
drug delivery and thereby reducing the amount of drug required for therapeutic efficacy. The drug can
be targeted at organ, cellular and subcellular level of a specific tissue.
Figure 2 indicates the historical timeline in developing the clinical development of targeted
nanotechnologies:

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 Figure 2: Historical timeline in the development of targeted technologies (reprinted with
permission from Shi et al., Accounts of Chemical research, 2011, 44(10), 1123–1134; Copyright in
2011 by Ame rican Chemical Society).
Local and Systemic targeting
Targeting can be categorized into local targeting and systemic targeting. In locally targeted systems,
such systems are non- invasive in nature and the prime goal of the locally targeted therapies are to
deliver the drug at the local site for the management of local pathologies (such as IBD, inflammation,
ulceritis, colon cancer, gastritis, stomach cancer etc.). Local targeted systems encompass colon specific
targeted systems (pH sensitive, time dependent, combined pH and time dependent, microbially triggered
systems, coated systems, prodrug approaches), Gastroretentive systems, buccal adhesive systems etc.
However, In case of systemic targeting, delivery of such therapeutic systems occurs through the
invasive route such as intravenous administration of nanotechnological systems (liposomes, niosomes,
SLN’s, nanocrystals, dendrimers). Such systems deliver the drug via systemic circulation after the
distribution in the body. The major limitations of such systems are due to the adverse effects of the
drugs in the non-specific tissues.

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 Misconceptions about Targeting

The word ‘Target’ means any specific organ or a cell or group of cells, which in chronic or acute
condition need treatment. However, in today’s context, the term ‘targeting’ has been stereotyped
overwhelmingly by the scientific community. It has become quite confusing to use this term for delivery
of the drug. There is great difference in targeted drug delivery which refers to predominant drug
accumulation within a target zone that is independent of the method and route of drug administration;
however, targeted medicine/drug or therapy means specific interaction between a drug and its receptor
at the molecular level (Park and Bae, 2011).
To summarize the concept of TDDS, it can be stated that these systems encompasses cell
specific interaction mechanisms by which a drug is propelled or transported to its action site. There is a
specific interaction between drug carriers and diseased target cells those endow such ‘forced’
mechanisms for the carrier to select their target cells (Bae YH, 2012). Figure 3 shows the emergence of
diverse applications of targeted technologies in the field of theranostics and pharmaceutical sector.

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 Figure 3: Diverse nano-technological approaches in the field of theranostics (reprinted with
permission from Shi et al., Accounts of Chemical research, 2011, 44(10), 1123–1134; Copyright in
2011 by Ame rican Chemical Society).
Both FDA-approved and experimental targeted therapies for specific types of cancer are being studied in
clinical trials. Certain targeted therapies like hormone therapies, signal transduction inhibitors, gene
expression modulators, immunotherapies, apoptosis inducers, monoclonal antibody-conjugates have
been approved. Further, Table 1 depicts the summary of targeted technologies which are under clinical
development.

Table 1: Summary of targeted technologies under clinical development (Reprinted with permission
from Kamaly et al., Che m. Soc. Rev., 2012, 41, 2971–3010.6; Copyright in 2012 by Royal Society of
Che mistry)

Product Code Drug/API Ligand Target Carrier system

Antibody
MCC-465 Doxorubicin Tumor Antigen Liposome
fragment

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 Transferrin
CALAA-01 siRNA Transferrin Liposome
Receptor

Transferrin
MBP-426 Oxaliplatin Transferrin Liposome
receptor

Transferrin Antibody
SGT53-01 p53 gene Liposome
receptor fragment

Nicotine antigen, Toll like

Small Antigen Polymeric
SEL-068 receptor, agonist, T- helper cell
molecule presenting cells Nanoparticle
peptide

Prostate specific
Small Polymeric
BIND-014 Docetexal membrane
molecule Nanoparticle
antigen

PRINCIPLE OF TARGETING

The basic principle behind concept of drug targeting is to deliver the high concentration of drug/drug
carrier to the targeted site and lesser concentration of drug/carrier at the non-targeted area where the
toxicity may crop up. Thus, this restricted access of the parent drug to the non-specific tissues with
effective accessibility to targeted site could assist in maximizing the therapeutic potential of the drug at
lower dose, with minimizing side effects. Figure 4 illustrates the bioenvironmental factors and
contribution of drug access to the targeted vs non-targeted sites.

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 Figure 4: Schematic representation of principle of drug targeting (Adapted from Vyas SP and
Khar RK; Targeted and Controlled Drug Delivery: Novel Carrier Systems, CBS Publishers, 2004)

DESCRIPTION AND BASIC UNDERSTANDING

Rationale of TDDS

Pharmaceutically, TDDS are the advanced

technological delivery systems which are employed for
the consideration of three factors:

Pharmaceutical factors: Poor solubility of the drug

candidate, High drug instability (in
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acidic/alkaline/enzymatic conditions etc.).

Pharmacokinetic factors: Lower half- life, poor

bioavailability, low drug absorption
Novel and largerSystems
Drug Delivery volume II
Pharmaceutical
of distribution, high plasma
sciences protein binding.
Targeted Drug Delivery Systems-I
Pharmacodynamic factors: Lower specificity and low
 Objective of TDDS

 To provide selective, localized action of the drug with/without absorption.

 To enhance the therapeutic index/potential of the drug.
 To protect the drug from any alterations/interactions.
 To restrict the access of drug at undesirable sites (normal tissues) to prevent adverse effects.
In order to achieve successful targeting of the drug to its targeted site, system should use multi-
dimensional targeted approaches (i.e. dual use of active and passive targeted approaches) in order to
enhance the circulation time and provide the targeting agent sufficient time to interact with its targets.
Further, the carriers should also have the inherent potential to sustain the biological, physiological
elimination mechanisms (i.e. reticulo-endothelial clearance systems) in order to target the specific site.

Targeted drug delivery to the specific cell is governed by all the physical laws of transport like
blood flow, convectional transport, Brownian motion, concentration gradient, diffusivity and
permeability.

Ideal characteristics for effective TDD designing

 For the designing of TDDS, the polymers which shall be used as carriers for the delivery of drug must
be biocompatible, chemically inert, non-toxic, non-immunogenic and physically robust.
 The polymeric carrier system should not affect the drug distribution, release (i.e. loss of drug during
transit) or drug action.
 TDDS should have the capacity to confine the drug distribution to target cells or tissue or organ or
should have uniform capillary distribution.
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  TDDS should exhibit characteristics of a simple, reproducible and cost effective system having
predictable rate of drug release.
Factors which affect the designing of TDDS

Some of the factors which directly play a vital role in the designing of TDDS are given below in the
Table 2.

Table 2: Vital Components for the designing of a targeted drug delive ry system

Active Moiety concentration, particulate location and distribution, molecular weight

(M.W), (physiochemical properties like solubility, pKa, LogP), drug-
carrier interaction
Carrier Nature/concentration of polymers/excipients, surface morphology
(shape, charge, size, density etc.)
Physiological Environment pH, polarity, ionic strength, surface tension, viscosity, temperature,
enzyme, electric field, redox potential

Physiological barrie rs for the drug targeting

Drug molecules undergo systemic circulation and are prone rapid distribution throughout the body
thereby reach the non-specific target areas in the body. Further, these molecules are frequently
metabolized by the liver and rapidly excreted by the kidneys. The partitioning of the drug carrier varies
from the discrete drug particles across the endothelium and exhibit different biodistribution profiles.
Larger macromolecules are cleared from the body through mononuclear phagocytic system (MPS) and
opsonization. Various other physiological barriers which exist in the body such as mucous barrier (e.g.
Lungs, Nose and cancer cells), Blood brain barrier (BBB), Size exclusion membrane barrier (size
barrier to different membranes), Subcellular barriers, other physico-chemical barriers (disease specific
ligands, pH, charge, redox potential) also affect the targeted drug delivery to great extent (Figure 6).

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 Figure 6: Schematic representation of physiological barrie rs affecting the targeted drug delive ry

Pros of the targeting

The some of the significant contribution of TDDS to the drug delivery science has been summarized as
below:

 Simplification of drug administration

 Reduction in therapeutic dose, decrease in adverse effects and low cost of the overall therapy.
 Uniform effect with lower fluctuation in circulating drug levels due to reduction in the frequency of
dose.
 Control of drug delivery (bio-distribution) to the particular site or vicinity with a predetermined release
and kinetics.
 Increase specific localization with better therapeutic efficacy
 Avoidance of liver first pass effect.
 Improved patient compliance
Cons/Challenges in the development of TDDS

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 TDDS are the complex systems and have not been extensively characterized in a clinical setting i.e.,
pharmacokinetics, biodistribution, and toxicity.
 The screening methodologies for determining optimal characteristics of nanocarriers are still poorly
understood.
 The formulation concerns such as product stability, particle size uniformity, control of drug release rate
and large scale manufacture of sterile preparations.
 High cost/benefit ratio and the development process is time consuming due to its unique requirements.
 Rapid clearance of TDDS via clearance systems (RES).
 Immune reactions against intravenous administered carrier systems.
 Insufficient localization of targeted systems into tumor cells.
 Diffusion and redistribution of released drugs.
 The relevance of in-vitro tests of activity, selectivity, uptake, and toxicity of targeted systems to the
animal or human is still an area of research and great amount of work is needed before clinical
application of such systems.
 It has to be understood that the concepts of magic bullet are merely a hypothetical theory. Eve n with a
system that is highly specific to a target disease, not all cells in a tumor will be affected. Probably only a
limited fraction of the cells could be influenced.
 Practically, the feasibility of active targeted systems would be more applicable to liquid cancers in
comparison to solid tumors.
 Ligand-targeted systems are more complex and expensive to manufacture, and more difficult to
manufacture in a reproducible manner in particular. Moreover, the cost to benefit ratio is too high.
 Although ligand targeting is conceptually beautiful, yet it is quite impractical in wider number of
cases/situations.
 Nanotherapies without ligand targeting maximally increased tolerated dose size, altered biodistribution
and reduced toxicity profiles. They showed improved clinical outcomes by expanding survival time
period in several weeks or several months. It is not truly clear whether the improved outcome is from
the effects of nano-sized carriers in a target site or merely from increased doses with reduced toxicity.

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 Targeted drug delivery systems involves complex technology, for developing a system in terms of proof
of concept, wider research is warranted to bring the optimized solution from lab to clinic setup.
 In order to target and cure every single tumor in the body, more sophisticated an robust designs should
be developed in order to address issues of predictable extent of extravasation, intratumoral distribution
at a cellular level and tumor heterogeneity (multidrug resistance, cancer stem- like cells, genetic and
epigenetic diversity).
CARRIERS FOR TARGETING

Carriers are the specially designed molecules or cargo systems which are exploited for carrying the drug
payload to their predetermined sites (or targets). These are engineered vectors, which retain drug inside
or onto them either via encapsulation and/ or via spacer moiety and transport or deliver it into vicinity of
target cell. The carriers can be categorized into various classes such as: colloidal carriers, polymeric
carriers, supramolecular, cellular/subcellular and macromolecular etc.

Some of the ideal characters which the carriers should possess are as following:

 Biodegradability, biocompatibility, non-toxicity and non-immunogenicity of the

polymeric/macromolecular component.
 Acceptable size range for a nanomedicine is <100 nm (or 10-100nm). The lower size range of
nanocarriers is assessed by an interaction with renal filtration in the kidney whereas the upper size
range is appraised by an interaction with RES (immune system) in the spleen and liver. For drug
accumulation inside the tumor cell, the size should be ~400 nm (upper limit for extravasation).
 Appropriate shape of the carrier system to permit passage through capillaries. (particles larger than
200 nm must compensate by deformability)
 Minimum leakage of drug component before reaching the target site.
 Controlled release at the targeted site.
 Specific recognition of carrier by the targeted cells with effective homing and capacity to reach and
deliver the drug in the targeted region.
 Stability of the drug within in the carrier system.

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  Designed with optimal biophysicochemical properties for superior drug loading, circulation half-
life, and sustained drug release across infrequent administration times
 Cost-effective and scale up for commercialization
The adaptation and amalgamation of these abilities in one nanocarrier is the ‘Holy Grail’ of
nanomedicine. However, some the major issues concerning the colloidal carriers are due their inherent
properties by which they are greatly eaten up by the mononuclear phagocyte system (MPS) through
opsonization. Such issues have been addressed by surface engineering like PEGylation (PEG chains
forming stealth systems) of the carriers which reduce the RES uptake and increase the EPR effect,
thereby assist in high circulation half- life in the blood.

Mechanisms of Drug Release/Uptake or transport through Carrie r:

Figures 7 and 8 illustrate the various mechanisms of drug transport during the drug targeting. Further
the mechanism of drug release by the polymeric targeted system at the targeted site has also been shown
in Figure. 9.

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 Figure 7: Major mechanis ms responsible for the cellular uptake and drug trans port through the
cell.

Drug release from a targeted polyme ric system: In order to achieve a controlled drug release from a
polymeric system, the mechanism of the drug could be via a) diffusion from the matrix, b) surface
erosion or degradation of matrix and c) biodegrading of the polymeric matrix (enzymatic, pH based,
hydrolytic etc.). Figure 8 illustrates the different mechanism of drug behavior from the polymer based
systems.

Figure 8: Drug release mechanis ms from the targeted polyme ric systems (Reprinted with
permission from Kamaly et al., Chem. Soc. Rev., 2012, 41, 2971–3010.6; Copyright in 2012 by
Royal Society of Chemistry)
Classification of carriers

Drug targeting can be achieved through any mode i.e. either active or passive, however, the efficiency
of targeting of the molecule depends on the distribution of the carrier at the targeted site. Two
significant factors which affect the drug targeting are: a) Mononuclear phagocyte system (MPS system)
and b) EPR effect
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 Thus, in order to achieve site specific targeting, carrier systems can be categorized into different classes
(as shown in Figure 9).

1. Colloidal carrier systems (including vesicular and particulate systems)

2. Polymer based carriers (pH based, mucoadhesive, prodrug based approaches, polymer conjugates)
3. Supramolecular based carriers (micelles, lipoproteins, liquid crystals etc.)
4. Cellular/Subcellular based carriers (Resealed erythrocytes, exosomes, antibodies etc.)
5. Macromolecular targeted carriers: Hydrophilic carriers (polypeptides, glycoproteins,
immunological fragments, antibody, lectins and polysaccharides etc.)

Figure 9: Flow diagram of various carrier systems exploited for targeting

ORDER OF TARGETING

Drug targeting can be broadly classified into three levels of targeting:-

a) First order targeting: In a case, if the drug moiety is being targeted or distributed to the capillary
bed of a tissue or an organ, then it is referred to as first order targeting or organ- level targeting. e.g.
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 drug-eluting stents that deliver drug to the blocked artery or catheter-based delivery to annihilate
cancer tissue, other examples include lymphatic’s, peritoneal cavity, plural cavity, cerebral
ventricles, etc.
b) Second order targeting: In a case, if a drug is targeted to a specific cell (like tumor cells or kupffer
cells in liver), then it is referred as second order targeting. Most of the modern nanoparticulate drug
delivery systems are of second order targeted systems (i.e. designed to target specific cells).
c) Third order targeting: In a case, if a drug is targeted at sub-cellular/organelle level i.e. nucleus,
mitochondria, it is known as intracellular or third order targeting. In this level of targeting,
intracellular localization of carrier bearing drug is carried out via endocytosis or receptor based
ligand interaction, where lysosomal degradation of drug complex causes release of drug or gene
delivery to nucleolus.
Note: Fourth order targeting: If a drug is targeted to a macromolecule like DNA, protein, then it is
called fourth order targeting.

SUMMARY
The purpose of any delivery system is to enhance or facilitate the action of therapeutic compounds. It
should now be apparent that conventional drug delivery systems are associated with a number of
limitations which can reduce drug efficacy (Hillary Am et al., 2005). However, whether the TDDS are
the fool-proof concept and could replace the conventional systems in the near future is still million
dollar question. Currently, the prime focus of magic bullet technology is to combine the existing
approaches to provide a few percent of the total administered dose reaching the intended target. Hence,
it is clearly a wrong notion or a myth, that all administered nanoparticles goes to the intended target site
after prolonged circulation in the systemic circulation.
There is a big misconception that nanoparticles go straight to the tumor cells like a magic bullet.
Thus, there is an imperative requisite to understand Paul Ehrlich's “magic bullet” concept in a rational
manner. The magic bullet concept actually refers to the drug which interacts with its target in an
exclusive, highly specific manner. The real fact is: ‘Drugs never go straight to their intended targets’
All the drugs reaching the systemic circulation are distributed throughout the body and end up in
various organs, causing severe adverse effects.
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 Another misconception is ‘all the drugs specifically attach to only a single target’ However, the fact is
all the drugs interact with more than one target, resulting in side effects. Actually, drugs reach their
targets as a result of properties that affect their stability in the systemic circulation, extravasation and
intratumoral distribution.

CONCLUSION

Presently, in drug delivery science, the “magic bullet” is a system that delivers the majority, if not all, of
a drug payload to the intended target without resulting in significant effects on non-target tissues. So,
we are still far away from the actual goal of magic bullet based on the literature study. In the light of
these facts, it is concluded that there is mammoth sum of literature reporting near cures of tumors in
preclinical studies however, the translation of these studies into clinical studies is very poor. Further, the
reproducibility of the academic technologies to the pilot scape to cater the needs of patient vis a vis
industry poses a huge challenge for the researchers in the years to come.

REFERENCES

 Drews, J. and Ryser, S. The role of innovation in drug development. Nature Biotechnol. 15, 1318–1319,
(1997).
 Imming P, Sinning C, Meyer A. Drugs, their targets and the nature and number of drug targets. Nature
Reviews (Drug Discovery), 5, 2006, pp.821.
 Park K. Biomaterials for Cancer Therapeutics: Diagnosis, Prevention and Therapy, In Biomaterials,
Woodhead Publishing, USA 2014.
 Bae YH, Park K. Perspective Targeted drug delivery to tumors: Myths, reality and possibility. J
Controlled Rel. 153, (2011) 198–205.
 Hillery AM, Lloyd AW, Swarbrick J. Drug delivery and targeting for pharmacists and pharmaceutical
scientists Taylor & Francis Inc, 29 West 35th Street, New York, NY 10001 ISBN 0-203-30276-1.

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  Gregoriadis G., Poste G. Targeting of drugs: Anatomical and Physiological Considerations. NATO ASI
Series Series A: Life Sciences, Vol. 55, Proceedings of a NATO Advanced Study Institute on targeting
of drugs: Anatomical and Physiological Considerations, 1987, Cape Sounion Beach, Greece.
 Targeted and Controlled Drug Delivery: Novel Carrier Systems S.P. Vyas, R.K, Khar, CBS Publishers,
New Delhi, 2002, ISBN 81-239-0799-0.

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