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R E V I E W Targeted Drug Delivery -From Magic Bullet to Nanomedicine:

Principles, Challenges, and Future Perspectives

Article in Journal of Multidisciplinary Healthcare · July 2021

DOI: 10.2147/JMDH.S313968

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Open Access Full Text Article

REVIEW

Targeted Drug Delivery — From Magic Bullet to

Nanomedicine: Principles, Challenges, and Future
Perspectives

1
Ashagrachew Tewabe Abstract: Nanomedicine is an advanced version of Paul Ehrlich’s “magic bullet” concept.
Atlaw Abate 2 Targeted drug delivery is a system of specifying the drug moiety directly into its targeted
Manaye Tamrie 3 body area (organ, cellular, and subcellular level of specific tissue) to overcome the aspecific
Abyou Seyfu 3 toxic effect of conventional drug delivery, thereby reducing the amount of drug required for
1 therapeutic efficacy. To achieve this objective, the magic bullet concept was developed and
Ebrahim Abdela Siraj
pushed scientists to investigate for more than a century, leading to the envisioning of
1
Department of Pharmacy, College of different nanometer-sized devices — today’s nanomedicine. Different carrier systems are
Medicine and Health Sciences, Bahir Dar
University, Bahir Dar, Ethiopia; 2Ethiopian being used and investigated, which include colloidal (vesicular and multiparticulate) carriers,
Food and Drug Authority (EFDA), polymers, and cellular/subcellular systems. This review addresses the need for and advan­
Federal Ministry of Health (FMoH), Addis
tages of targeting, with its basic principles, strategies, and carrier systems. Recent advances,
Ababa, Ethiopia; 3Department of
Pharmaceutics and Social Pharmacy, challenges, and future perspectives are also highlighted.
School of Pharmacy, College of Health Keywords: targeting, polymers, nanoparticles, carriers, nanosomes
Sciences, Mizan-Tepi University, Mizan-
Aman, Ethiopia

Introduction
Drug delivery (DD) refers to the methods, formulations, technologies, and pro­
cesses involved in transporting a pharmaceutical substance in the body to achieve
the desired therapeutic effect.1 It encompasses the approaches of administering
medicinal compounds in humans and animals to attain therapeutic effectiveness.
Recent developments in drug delivery systems (DDSs) are primarily been focused
on smart DD, which focuses on drug administration at the appropriate time,
dosage, and location with maximum safety and efficacy.2 The advancement of
novel DDSs (NDDSs) has attracted pronounced attention in recent years. These
systems enhance the therapeutic effectiveness of new and existing drugs with
targeted, managed, and sustained delivery while meeting real and appropriate
drug demand.1 DD is a growing field in pharmaceutical science. There are five
generations of DDSs, and targeted delivery belongs to the fourth generation.3
Figure 1 illustrates the generations of DDSs. Over the last few decades, develop­
ing sustained or controlled DDSs has been a focus, with the objective of control­
ling and/or sustaining drug release, reducing dose frequency, or increasing drug
Correspondence: Ashagrachew Tewabe efficacy compared to conventional delivery. Bilayer tablets are one example of an
Department of Pharmacy, College of
Medicine and Health Sciences, Bahir Dar NDDS, used with modification of conventional drug-preparation and -delivery
University, PO Box 79, Bahir Dar, Ethiopia approaches. They are composed of two of the same drug or different drugs fixed
Tel +251 91-296-0525
Email [email protected] in a single dose for sequential release of the combined drugs or sustained and

Journal of Multidisciplinary Healthcare 2021:14 1711–1724 1711

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 Tewabe et al Dovepress

Figure 1 Generation of drug-delivery systems.

immediate release of the same drug, one as a loading dose The Concept of the Magic Bullet
and other as a maintenance dose.4 Such modifications in The concept of targeting of drugs to their site of action dates
all forms of traditional DD can represent promising back to the postulation of the “magic bullet” concept.9
advancements, but there are still types of DDSs that A century ago, Paul Ehrlich envisioned the concept of
need to be refined, such as delivery of poorly soluble selectively targeting a pathogen without harming the host
drug formulations, protein delivery, self-regulated insulin organism using “magic bullets.” Analysts in cancer treat­
delivery, and targeted DDSs (TDDSs). Targeted delivery ment were particularly inspired by the idea.10 Ehrlich
to tumors is another potential advance that can be approached his magic bullet concept in two consecutive
achieved with nanotechnology-based DSs.5 Nanoparticle steps: screening for toxic drugs, followed by modifying
(NP)-based DD brings an opportunity for controlled toxic drugs to be more specific and less toxic.11 He strongly
release of drugs, allowing sufficient time for drugs to pictured that achieving a cure would be very stress-free with
act with enhanced therapeutic action and respond to spe­ substances that had exclusive affinity toward the causative
cific stimuli, such as pH, light, heat, or enzymes.6 bacteria alone, with no affinity for the host. This would
TDDSs are where a drug is delivered to a specific finally result in the least harmful effect on the human body
location, rather than the whole body or organ, and combine by exerting an exclusive lethal action on the parasite within
diverse fields of science, such as polymer science, phar­ the organism, hence the term “magic bullet.”12 Ehrlich
macology, bioconjugate chemistry, and molecular biology. anticipated site-specific therapies to acquiring knowledge
TDD is aimed at managing and controlling the pharmaco­ on how to cast magic bullets, as the magic bullets of
kinetics, pharmacodynamics, aspecific toxicity, immuno­ a gunman hit the enemies exclusively. This fascinating
genicity, and biorecognition of therapeutic agents.7 The idea pressed scientists to investigate further for more than
end goal is improving treatment effectiveness while redu­ a century, and led to the discovery of different nanometer-
cing side effects. TDDSs differ from conventional or tra­ scale devices, called “nanomedicines” nowadays.13 The suc­
ditional DDSs in that they acquire site-specific release of cess of this concept is a good indicator of its appeal, but
drugs from a dosage form, while the former depends on implementing the magic bullet in the clinic remains
drug absorption through biological membranes.8 a challenge. This is due to difficulties in finding the right

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target for a specific disease state, the medication that effi­ methods is not only important to enhance therapeutic effec­
ciently cures the disease, and the way to deliver the drug in tiveness but also to reduce the toxicity associated with a small
a stable form to specific sites while preventing immunogenic therapeutic index and high doses.15 Targeting is needed to
and aspecific interactions. NPs are potentially useful as achieve solutions to these constraints and innate disadvantages
carriers of active drugs, and when coupled with targeting of conventionalDDSs. Parenteral delivery is highly invasive,
ligands, may fulfill many attributes of a magic bullet.9 oral administration cannot be used for protein- or peptide-
According to the magic bullet philosophy of Ehrlich, drugs derived drugs, and topical creams and ointments are limited
should go straight to their anticipated targets in the body and to local effects. Furthermore, the effectiveness of drug–target
only interact with the target molecule. However, drugs pass interactions is compromised unless the drug is delivered to its
complex pathways and contacts during their transport to site of action at a dosage and rate that produces minimal side
reach their targets and possibly interactwith multiple targets, effects while maximizing therapeutic effects.8 In addition,
resulting in side effects. Unfortunately, there has never been simpler drug-administration procedures, decreased drug quan­
a drug or aDDS that has directly reached the bodily target tity, which reduces therapeutic costs, and the potential to
without these pathway interactions. This interference with sharply increase drug concentration in target compartments
several targets makes the drug a “magic shotgun,” rather without adverse effects on nontarget compartments are pro­
than a magic bullet. To meet the magic bullet target, we still mising benefits of TDD. Generally, drug targeting results in
have a long way to go.14 increased efficacy, modulated pharmacokinetics, controlled
biodistribution, increased specificity of localization, decreased
toxicity, reduced dose, and improved patient compliance.8,16
The Need for Targeted Drug Delivery
The need for TDD over conventional DSs is fourfold: unsa­
tisfied peformance of drugs in terms of pharmacodynamic, Basic Principles and Applications of
pharmacokinetic, pharmaceutical, and pharmacotherapeutic Targeted Drug-Delivery Systems
features with conventional delivery, as shown in Figure 2. The basic principle behind drug targeting is delivering a high
Targeting of drugs to a particular area through optimized DD concentration of drug to the targeted site while minimizing its

Figure 2 The need for targeted drug delivery.

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concentration to the nontargeted region. This principle aids in and physicochemically stable in vivo and in vitro. It should
optimizing the drug’s therapeutic effects while decreasing the also have a predictable and controllable pattern of drug
side effects due to multitarget interactions, higher doses, and release, reasonably simple, reproducible, and cost-effective
nontarget concentrations.17 Targeting also ameliorates preparation, be easily and readily eliminated from the body,
unwanted interactions of the drug with bioenvironmental and minimal drug leakage during transit.16,20
factors that affect drug access to targeted sites in the body, In order to assure the fulfillment of these ideal char­
as shown in Figure 3.18 Drug targeting comprises coordi­ acteristics, targeted drug products should be prepared
nated drug behavior, targeting site, and pharmaceutical car­ while considering the specific properties of target cells
rier. The target is the specific organ, a cell, or group of cells in and the nature of transport carriers or vehicles that convey
chronic or acute condition demanding treatment with which the drug to specific receptors. These considerable para­
the drug is going to interact. The carrier is a specially engi­ meters include drug concentration, particulate location
neered molecule or system essential for effective transporta­ and distribution, molecular weight, physicochemical prop­
tion of the loaded drug toward preselected sites.19 Ideally, erties, enzymes, electric fields, physiological environment,
a drug-targeting complex is expected to be atoxic, nonimmu­ nature/concentration of polymers/excipients, and surface
nogenic, biochemically inert, biodegradable, biocompatible, morphology (shape, charge, size, and density) of the

Figure 3 Principles of drug targeting.

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carrier system.16 Physiological variables, such as blood Types of Targeted Drug-Delivery

flow for intravenous administration of drugs and tissue
Systems
architecture, along with physicochemical parameters, Various approaches are used to help target specific body
including carrier geometry, avidity, composition, and func­ sites, as depicted in Figure 4.
tionalization, should be controlled for effective targeting
of desired cells or tissue.21 In addition, the clinical
Active and Passive Targeting
enhanced permeability and retention (EPR) effect, extra­
Passive targeting is DD that targets systemic circulation. In
vasation, intratumoral distribution, tumor heterogeneity, this technique, drug targeting occurs because of the body’s
and overexpression characteristics are important factors natural response to physicochemical characteristics of the
in effective tumor-targeted treatment.14 If the ideal proper­ drug or drug-carrier system. This is based on the accumula­
ties are well met and formulation factors well considered, tion of drug(s) at areas targeting the site of interest, such as
TDD can be applied effectively in innovative nanomedi­ in the case of tumor tissue.3 NPs are used as carriers in
cine and therapeutics. Though TDD can be used to treat passive targeting, and they are directed to enter blood ves­
many chronic and infectious diseases, its most important sels more at the disease site, which provides the opportunity
application is in treating cancerous tumors, due to its better for significant drug accumulation at the target. This process
microphage penetration and enhanced concentration at the is aided by slow lymphatic drainage — the EPR effect.6 On
infection site.3 Promising applications and purposes of the other hand, active targeting is a particular ligand recep­
TDD include cancer therapy, vaccine adjuvant, ocular tor–type interaction that occurs after blood circulation and
and brain delivery, DNA and oligonucleotide delivery, extravasation.15 It mainly relies on the biological interface
intracellular and systemic targeting, oral and transdermal between target cells and the ligands attached to NPs.
delivery, enzyme immunoassays, and radioimaging. Various types of ligands have been employed for this pur­
Generally, outcomes reported with these applications pose, including proteins, polysaccharides, nucleic acids,
include reduced toxicity, enhanced uptake, prolonged sys­ peptides, and small molecules.6,8 Figure 5 illustrates the
temic circulation with enhanced bioavailability and drug differences between the two targeting approaches.
effect, enhanced immunoresponse, improved drug absorp­ Tumors are characterized by highly defective vessel
tion and permeation, and improved drug retention or architecture and poor lymphatic drainage, in accordance
reduced washout.20 with the EPR effect. Small nanocarriers with those tumor

Figure 4 Various categories of drug targeting.

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Figure 5 Active vs passive targeting.

properties are believed to be suited for passive targeting of targeted NPs from the bloodstream into the tumor micro­
anticancer drugs, at relatively smaller dimensions than environment than more passive transport mechanisms like
abnormal blood-vessel gaps, and can easily reach and the EPR effect.23 Though the development of NPs for
selectively localize tumors.22 However, recent studies targeting brings many promising advantages, the efficacy
have demonstrated that interendothelial gaps on tumors of current nanodrugs is not significantly better than the
are not responsible for NP transport and accumulation original drug treatments, especially in cancer chemother­
into solid tumors. One study found that active processes apy. This is because of poor and incomplete nanodrug
take place for up to 97% of NP transport into tumors penetration into tumor tissue, due to the complex features
through endothelial cells. These investigations suggest associated with nanodrug size and tumor pathology.
the EPR effect in clinical cases in oncology patients has Remodeling the microenvironment of tumor tissues, car­
not yet been proven. On the other hand, active transport rier charge inversion, dimensional change, and surface
mechanisms are predicted to be better for uptake of modification are among the demonstrated strategies for

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promoting tumor penetration of nanodrugs. Even with agents to target areas through the use of antibodies (Abs),
promising penetration-enhancing strategies, effective peptides, proteins, or other biomolecules that have affinity
application of targeting of tumors is far from complete, with receptors, sites, or other biological targets in
and cancer chemotherapy still has many difficulties and a specific manner. Gene expression can also be localized
challenges. As such, DD and targeting systems of a more to target areas through the use of cells, tissue, or other
bioresponsive nature, reduced side effects, and better treat­ specific promoters in vector systems.25
ment efficacy are required.24
Local and Systemic Targeting
First-, Second-, Third-, and Fourth-Order Locally targeted systems are noninvasive targeting strate­
Targeting gies with the pricipal goal of delivering the drug to the
Drug targeting can further be classified into three (or four) local site for the management of local pathologies. With
different orders of targeting. In first-order targeting, there systemic targeting, delivery of such therapeutic systems
is limited distribution of the drug-carrier system to the occurs through an invasive route, such as intravenous
capillary bed of the target site. Second-order targeting administration of nanotechnological systems. Such sys­
refers to the selective provision of drugs to specific cell tems deliver the drug via systemic circulation after distri­
types, such as tumor cells. Third-order targeting indicates bution in the body. The major limitations of such systems
targeting intracellular sites specifically, and fourth-order arise from the adverse effects of the drugs in aspecific
targeting is sometimes nominated for drugs targeting tissue.26
macromolecules, such as DNA and proteins.15

Location-Based and Disease-Based

Inverse, Dual, Double, and Combination
Targeting
Targeting TDD with specific location-based strategies is a targeted
If the normal activity of reticuloendothelial system is delivery to specific cells, organs, and organelles.
inhibited by a blank colloidal carrier to minimize its pas­ Intracellular targeting, gastrointestinal tract (GIT) target­
sive drug uptake, the system will be saturated with sup­ ing, brain targeting, and targeting the respiratory tract are
pression of its defense mechanisms, an approach known as some examples of location-based targeting. Intracellular
inverse targeting. Dual targeting is the delivery of carrier delivery of pharmaceutical agents like proteins, Abs, and
molecule with its own therapeutic activity and thus drug-loaded nanocarriers ensures that the therapeutic
increasing the (synergistic) therapeutic effect of the drug. action is specifically introduced to the nucleus or specific
In double targeting, temporal and spatial methodologies organelles. Floating DD is a model for this type of target­
are combined, ie, spatial placement to specific sites and ing in which antiviral, antifungal, and antibiotic agents are
temporal delivery at a controlled rate. Combination target­ absorbed from very specific regions of the GIT. Various
ing is a way of targeted delivery equipped with carriers, site-specific oral controlled-release systems have been
polymers, and homing devices of molecular specificity that developed to target the stomach/duodenum, small intes­
provide a direct approach to a target.3,20 tine, lymph nodes, and colon. Polymer-based DDSs like
dopamine–liposome conjugates show effective brain tar­
Physical, Chemical, and Biological geting with reduced degradation during circulation,
Targeting whereas disease-based targeted delivery is a site-specific
Physical targeting describes systems that localize agents to therapy targeting tumors and other targetable infectious
target areas because of their size, composition, or other diseases. Tackling infections using nano-DDSs could pro­
characteristics that are not specifically designed toward vide a practical alternative to antibiotic therapy. Designing
a biological receptor. Chemical targeting involves the loca­ nanovaccines to achieve advanced targeting and improved
lization of agents to targeted areas through the use of site- cellular responses is a new prospect. Specific and specia­
specific prodrugs. Agents can also be directed to areas lized approaches of targeting some important pathogens
through the use of enzymatic or chemical reactions that for persistence inside the cell are being developed. These
lead to the targeting of a vehicle or the controlled release include functionalization of NPs with antimicrobial
or action of the agent. Biological targeting allows localized agents.2,17,19,26

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Vehicle/Carrier Systems for Colloidal Carrier Systems

Targeted DD Colloidal DDSs are nanoscaled targeting vesicles of parti­
Drug carriers, sometimes called drug vectors, are the most culate or vesicular dosage form. They include liposomes,
important entity required for successful transportof the loaded niosomes, nanospheres, multiple emulsions, and ceramics.
drug for to intended targeted. They transport, retain, and These type of drug vectors sequester, transport, and retain
deliver the drug within or at the localion of the target. They the active drug en route, while they elute or deliver it
are capable of performing such specific functions by slight within or in the vicinity of the target, with the ability to
virtue of structural modification. Currently, DD technology modify the distribution profile. They are commonly cate­
has become refined by the consideration of several factors gorized as vesicular and microparticulate systems.32
such as bioavailability, pharmacokinetic processes, and timing
for optimal DD.17,27 Depending on the type of targeting Vesicular Carrier Systems
mechanism, TDDSs require specific carrier systems. TDD Novel vesicular DDSs have the objective of delivering the
carriers/vehicles are purposely engineered vectors capable of drug at a rate- and site-controlled manner as per treatment
retaining the drug inside or on them via encapsulation and/or needs. Recently, these types of carriers have been emer­
via bonding with the help of a spacer moiety. These DD ging with various routes of administration for targeted and
vehicles are used for polymeric carriers like micelles, lipo­ controlled DD.33 Vesicular DDSs are used to improve the
somes, lipoprotein-based carriers, and NP-based carriers.28,29 therapeutic index, solubility, stability, and rapid degrada­
Ideally, carriers for TDD must be atoxic, stable, non­ tion of drug molecules.34 Nanosomes are the best-known
immunogenic, biocompatible, and biodegradable, readily advance in vesicular carrier systems. They are small, vesi­
eliminated from the body, and unrecognizable by the cular carrier structures for the delivery of drugs to the
host’s defense mechanisms. In addition, they should suc­ target area. They are available in different forms, eg,
cessfully transport the drug to the target site, cross barriers liposomes, niosomes, transferosomes, and ethosomes. All
and tumor vasculatures as needed, be of acceptable size these vesicular carriers are nanosome generations with
and shape (for nanocarriers), and have optimum release modifications of one from the other in their vesicular
properties at the target site, but no or minimum drug characteristics and composition during preparation, condi­
leakage before that target site. Carriers should also have tions of preparation and storage, and intended therapeutic
reasonably simple, reproductive, and cost-effective pre­ applications.35,36 These structural and compositional dif­
paration processes.28,29 The DDS should have optimal ferences are summarized in Table 1.
target selectivity and specificity, which can be achieved Liposomes are simple, microscopic, nanoscaled lipoi­
by controlling the biodistribution profiles of the drug and dal vesicles that have a lipid-bilayer structure. These
carrier material. The physicochemical and biochemical bilayers consist of an aqueous core entirely enclosed by
properties of both parties are used to determine the biodis­ a membrane that is composed of lipid molecules in such
tribution profile.30 Similarly, drug release and polymer a way that both hydrophilic and lipophilic drugs can be
biodegradation are important factors in developing successfully entrapped. The bilayer membrane captures
a successful nanoparticulate system. In sum, solubility, lipophilic drugs, whereas hydrophilic drugs will be
diffusion, and biodegradation of the matrix materials are entrapped in the central aqueous core.37 Liposomes are
important for the release process.31 synthesized for use in targeted oral, topical, and pulmon­
ary DD.38 Liposomes are composed of many internal and
external constituents and layers. Generally, liposome
Commonly Used Carriers for Targeted composition includes natural and/or synthetic phospholi­
Drug Delivery pids, cholesterol, hydrophilic polymer-conjugated lipids,
There are different types of drug carriers, such as colloi­ and water. In most cases, cholesterol is used to improve
dals, polymers, monoclonal Abs, NPs, and cell. The nature membrane fluidity and bilayer stability while reducing
of the drug, the target, and the disease state determine the the permeability of water-soluble molecules through the
selection of the carrier to be used. Abs, proteins, lipopro­ membrane. Liposomes have a special advantage due to
teins, hormones, charged molecules, and polysaccharides the use of physiological lipids to form the lipid mem­
are used with carriers as targeting moieties.16 brane, which decreases the risk of toxicity.39,40 They can

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Table 1 Differences in nanosomal vesicular carriers

Nanosome Main component Uses Special properties

Niosomes Cholesterol, charge-inducing substances, Carrier of lipophilic and amphiphilic drugs Stable, no need for special
nonionic surfactants storage or preparation

Liposomes Phospholipids dispersed in aqueous solution Used in targeted oral, topical, and Unstable, needs special storage
pulmonary DD and preparation

Transferosomes Surfactants, a little alcohol, dye, Penetrate deeper epidermis layers, used Ultraflexible and deformable
phosphatadylcholine in buffer solution for transdermal delivery vesicles

Ethosomes High concentration of alcohol, phospholipid, Controlled transdermal delivery Soft and novel vesicles
water, cholesterol, dye

be formulated in liquid dosage forms (suspension), solid Transferosomes are specially optimized, ultradeform­
forms (dry powder), or semisolid preparations (gel, able (ultraflexible) lipid supramolecular aggregates that are
cream). They can also be administered parenterally or able to penetrate mammalian skin intact. They are com­
topically.39 After systemic (usually intravenous) admin­ posed of an inner aqueous compartment and a surrounding
istration, liposomes accumulate inside the body simply lipid bilayer incorporated with edge-activator surfactants
due to their prolonged circulation and small size, like sodium cholate, Span 80, and Tween 80. They act as
enabling them to extravasate. Topical applications of penetration enhancers, disrupting the highly organized
liposomes are based on the similarity between lipid- intercellular lipids from the stratum corneum and facilitat­
vesicle bilayers and natural membranes, including the ing drug penetration in and across the stratum corneum.44
ability of lipid vesicles to alter cell-membrane fluidity Therapeutically, they are used as carriers for proteins and
and to fuse with them. In the dermatological field, lipo­ peptides like insulin, bovine serum albumin, and vaccines.
somes were initially used because of their moisturizing They improve site specificity, upgrade overall drug safety,
and restoring action.41 and lower doses of drugs for skin diseases. Because of
Niosomes are nanometric NDDSs in which the med­ their good penetration and flexibility, they are used for
ication is encapsulated in vesicles composed of a bilayer effective delivery of nonsteroidal anti-inflammatory drugs
of nonionic active surface agents, hence the name. They like ibuprofen and diclofenac.43 Ethosomes are other
are promising vehicles for DD, and being nonionic, they forms of vesicular carriers that are used for delivery of
are less toxic and improve the therapeutic index of the drugs. They have low penetration through biological mem­
drug by restricting its action to target cells. Niosomes brane, mainly skin, bute relatively higher skin penetration
and liposomes are similar in physicochemical properties, than liposomes. They contain phospholipids, alcohol (etha­
with some differences depending on bilayer composition nol and isopropyl alcohol), and water, and are used mainly
and preparation methods. While liposomes are composed for transdermal DD. Ethosomes are used as
of phospholipids, niosomes have a major component of replacements of liposomes, mainly for the transdermal
surfactants. Niosomes need no special conditions of pre­ route of DD, and can be used for transdermal delivery of
paration or storage, since they have very good stability, hydrophilic and impermeable drugs.44
as opposed to liposomes. This can reduce production
costs.42 However, their poor skin permeability, breaking Microparticulate Systems
of vesicles, leakage of drug, aggregation, and fusion of Microparticles are DDSs on the micrometer–millimeter
vesicles limits the suitability of liposomes and niosomes scale. This microencapsulation technology allows protec­
for transdermal delivery. Transferosomes, which are tion of the drug from the environment, stabilization of
recently introduced carrier systems, overcome these sensitive drug substances, elimination of incompatibilities,
challenges and become capable of effectively delivering and masking unpleasant taste. As such, they play an impor­
low– and high–molecular weight drugs through the tant role as DDSs, aiming at improved bioavailability of
transdermal route.43 conventional drugs and minimizing side effects.

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Microparticulate systems includes microparticles, NPs, and Polymeric micelles are composed of a hydrophobic
magnetic microspheres.45 internal core and hydrophilic external surface in which
physical entrapment of drug molecules occurs in the
hydrophobic core, escaping the need for encapsulation-
Polymeric Carriers for TDDSs
functional groups. Loading can be boosted by chemically
Polymers are the backbone of pharmaceutical DDSs. They
conjugating the micelles with amphiphilic polymers,
have been found extensive applications in DD because
which prevents early drug release. The hydrophobic core
they offer unique properties that have not been attained
enhances transportof low or no aqueous solubility, which
by any other material. Advances in polymers have led to
can improve the therapeutic window of lipophilic drugs.
the development of several NDDSs, with proper consid­
This further prevents the formation of embolisms of intra­
eration of surface and bulk properties contributing to make
venously administered hydrophobic drugs. Micelles are
medical treatment more efficient, effective, and safe.
also characterized by decreased chances of rapid drug
Polymers play an important role in advanced DDSs, as
clearance and prolonged circulation in vivo that
they can used to assist delivery and as excipients, and they
encourages drug accumulation at tumor cells. These char­
allow controlled and targeted drug release.46 Micro- and
acteristics make polymeric micelles an important new-
nanospheres fabricated from a biodegradable polymer
generation nanomedicine with advanced diagnostic and
enable controlled drug release at desired sites. Polymeric
therapeutic clinical applications.49,50
nanocarriers, such as poly(D,L-lactide-co-glycolide) have
Dendrimers are the other types of polymeric carriers
shown promising pharmacokinetics at both the whole-
for drug targeting. They are monodispersed macromole­
body and cellular levels.47 Generally, polymer-based drug cules with well-articulated and structurally multibranched
nanocarriers can significantly increase the solubility of globular units. Dendrimers consist of three main parts
hydrophobic drugs, reduce their cytotoxicity toward nor­ with particular functions: focal point, interior branching
mal tissue, prolong the circulation time of drugs in blood, units, and exterior surfaces with functional groups (their
facilitate the entry of NPs, and improve utilization effi­ function is described in Table 2). Both polar and apolar
ciency. Though natural polymers, such as chitosan and drugs are trapped into dendrimers by electrostatic interac­
dextran, have been well investigated in the last few dec­ tion and hydrophobic fragmentation, respectively. Drug
ades, research on using synthetic polymers, such as polye­ molecules can either be attached to dendrimers’ interior
sters, polyamides, and polypeptides, has been more cavity noncovalently with physical interaction or cova­
prevalent in the field of DD.48 lently linked to the exterior groups. Gene plasmids and
Amphiphilic polymers that contain both hydrophilic and nucleic acids are examples that can be linked through
hydrophobic blocks have been extensively studied for use electrostatic interaction. The covalent linkage offers
in DD as polymeric carriers, such as micelles, nanomicelles, a more stable formulation for DD. Drug release is deter­
and dendrimers. By controlling the hydrophilic–hydropho­ mined by the nature of the linkage.49 For a successful
bic balance, various nanostructures, such as spherical dendrimer DDS, the critical nanoscale design para­
micelles, cylindrical micelles, and vesicles, can be formed meters — particle size, shape, surface, flexibility/rigidity,
from amphiphilic polymers. Both polymeric micelles and architecture, and elemental composition — should be well
vesicles are the commonest and stablest morphological considered.51
structures of amphiphiles in water. Polymeric micelles are
nanostructures with a hydrophobic core and a hydrophilic Monoclonal Antibodies and Fragments
shell, where hydrophilic drugs are encapsulated in the core. Monoclonal Abs (mAbs) are getting attention as therapeu­
Meanwhile, polymeric nanovesicles possess bilayer struc­ tic agents in targeting for the treatment of various chronic
tures with an aqueous interior core, isolating the core from conditions, such as cancer and infectious diseases. They
the external medium, where hydrophilic drugs can be can be conjugated with chemotherapeutic drugs, radioiso­
encapsulated within the aqueous interior, integrating the topes, bacterial toxins, cytokines, and enzymes for target­
hydrophobic molecules within the membrane. Therefore, ing of tumors in order to potentiate their cytotoxic effects.
polymeric vesicles have the capability to deliver hydrophi­ Nowadays, human mAbs are being formulated as antitu­
lic and hydrophobic drugs, such as anticancer drugs, genes, mor agents. For example, adalimumab is the first human
and proteins.48 mAb officially approved for clinical use.3

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Table 2 Structural components of dendrimers

Structural Components Description/Function

Focal point (core) The center of the dendrimer can be a small molecule, nanoparticle, or polymeric material.

Free (void) spaces These are empty spaces between the core and interior branchings to be used as room for drug encapsulation or
carrying.

Interior branching Multibranched globular units with internal functional groups that have a covalent framework that connect the
dendrimer core with the outer-surface groups.

Exterior groups These are the outer hydrophilic or hydrophobic surface groups that construct the cover of the dendrimer–drug
complex.

Dendrimer–drug linkage Covalent or noncovalent bond between the dendrimer and the drug.

Recent Advances, Challenges, and ligands with drug/carrier, and release characterization of
drug from ligands (selection of a linker). Carrier-based
Future Perspectives
challenges consist of carrier selection and physicochemical
In recent years, microsponges, solid-lipid NPs, and nanos­
and pharmacokinetic characterization of carriers.53
tructured lipid carriers have been used and further investi­
gated as carrier systems/vesicles for DDSs. Microsponges
are synthetic, biologically porous, inert polymers that can Misconceptions
carry up to their own weight in drugs. They have the There are uncomfortable facts concerning TDD that are
overlooked and misconceived. First, targeting is not pre­
ability to protect the drug from the external environment
cise, but implies simply random distribution. Second, the
and to provide controlled release. Nanotechnology has
theory of receptor overexpression has not yet fully corre­
been implemented in several fields of nanomedicine,
lated with targeted delivery. Third, there is improved
such as drug/gene delivery, imaging, and diagnostics.
delivery from the EPR effect, but not as exact as with
Ab–drug conjugates or immunoconjugates are being inves­
targeted delivery. Fourth, there may be drug release before
tigated as alternative recombinant Abs by covalently bind­
the target site, and reaching the tumor tissue does not
ing through a linker to a drug to target potent drugs to
necessarily mean achieving improved delivery.5
specific sites using the specificity of mAbs, thus avoiding
nontargeted-organ toxicity. There are also other advances,
such as micro- and nanoemulsions, nanocapsules, smart
Complex Manufacturing Processes
There is a need for additional steps in chemical synthesis
capsules, cyclodextrins, microspheres, nanotubes, nano­
and purification for targeted drug formulation. There are
shells, quantum dots, hydrogels, metal and magnetic
also associated challenges like more quality control and
NPs, and natural and synthetic polymeric NPsthat are
regulatory steps, increased cost, and longer time lines.
being investigated for local and systemic targeting.2,52
Scalability, sensitivity, biocompatibility, and toxicity are
Though there have been promising recent advances, there
all associated design challenges for nanocarriers.6,54
are also associated challenges in their application. The fol­
lowing sections outline some of the critical challenges.
Tumor Heterogeneity
Additional complexity exists in the immense heterogeneity
Challenges Specific to Receptors, Ligands, within and between tumors. There is also the existence of
and Carriers tumor- and metastasis-associated stroma, eg, tumor-
Difficulties with identification of receptors, variable associated macrophages and fibroblasts.54
expression characteristics, receptor accessibility in terms
of reachability and availability, and shedding of receptors Barely Predictable Practical Outcomes
are among the challenges specific to receptors. Ligand- There is still substantial debate on the practical outcome of
specific challenges include appropriate selection of drug-targeting strategies. Lack of clinically translatable
a ligand, developing conjugation strategies of targeting models and completely specific targets, along with

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selection of targets with spatial and temporal expression Advanced Models, Good Laboratory
well aligned to interventional requirements, make the suc­ Practice, and Standardization
cess of these approaches hardly predictable.55 The development of targeting strategies should be subjected
to continuous evaluation in the light of advances in the
Barriers in Clinical Translation understanding of numerous processes occurring after
Unproven EPR effect in clinical cases in human oncology, administration.16 Developing better and more predictive pre­
lower-than-expected NP accumulation within tumors with clinical animal models, adoption of good laboratory practice
active targeting mechanisms, and factors that should be and standardization guidelines, better understanding of
considered, modified, and controlled during the prepara­ tumor biology, and identification of actual biomarkers will
tion and delivery of nanomedicines have posed intensify the accomplishment rate of clinical translation.54
a significant barrier to clinical translation of nanomedi­
cines into human medicine.23 Precision Medicine (Engineering Precision
NP-based targeting depends on certain physicochem­ NPs)
ical factors, such as particle size, surface charge, surface Precision medicine is an optimized drug design and DS for
modification, and hydrophobicity. There is still limited individual patients that has changed the setting of cancer
knowledge on NP toxicity and still many problems related chemotherapy remarkably. In precision medicine, a drug’s
to selective binding and targeted delivery that need to be pharmacological and pharmacokinetic parameters are modu­
overcome. Consideration of these problems now and with lated without compromising the anticipated effect at the
future NP advances may lead to a new, more prosperous molecular targets. Precisely, a drug’s absorption characteris­
paradigm of therapeutics and research.56 tics, its behavior upon exposure to target and nontarget tissue,
There are growing and interesting future perspectives and its administration in synergistic drug combinations can
on responding to these challenges and extracting maxi­ be modified.57 Interpersonal and interdisease differences in
mum benefit from targeted delivery. Some are briefly biological barriers against effective DD can be addressed by
lipid- based, polymeric and inorganic NPs that are engi­
stated in the following sections.
neered and optimized in increasingly specified ways. These
optimized and engineered NPs are entering the era of preci­
Advances in Clinical Extrapolation sion medicine to overcome the heterogeneous biological
Bursting clinical extrapolation of TDDSs is yet to be profi­ barriers found across patient populations and diseases.
cient. This can be attained only through advanced strategies Immunoactivation or -suppression, genome engineering,
and reproducible methods of carrier preparations, as well as and intracellular targeting are some of the promising applica­
extensive and elaborative preclinical evaluations.53 tions of NPs in precision medicine.58

Cell-Specific Delivery From Nanoparticles to Nanorobots

Receptor-targeted delivery has a very positive future in Pharmacytes, nanorobotic DDSs, are self-powered, compu­
areas of identifying newer targets for therapeutics, ter-controlled systems capable of digitally precise transport,
advanced biological products, and development of various timing, and targeted delivery within the human body. They
need not always be endocytosed: nanorobots may use trans­
NDDSs for cell-specific delivery.53
membrane mechanical nanoinjectors to avoid having to
enter a target cell. The design, fabrication, and therapeutic
Theranostic Strategy deployment of pharmacytes will be a promising advance
The future of nanomedicine will combine diagnosis and with the application of nanomedicine in the future engineer­
targeted therapy into a single, centralized system of treat­ ing discipline of medical nanorobotics.59
ment. This novel theranostic strategy brings the potential
of a highly selective, effective, and relatively sensitive Conclusion
treatment of cancer and other chronic diseases which Nanomedicine is the advanced version of Paul Ehrlich’s magic
further results in personalized chemotherapy with bullet concept. A large variety of NPs can be used to prepare
improved patient outcomes.10 targeted-delivery nanomedicines. TDD is advancing as one of

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