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Targeted Drug Delivery: Principles and Strategies 59
3.4 Liposomes
3.5 Solid Lipid Nanoparticles
Liposomes are tiny spheres composed of multiple overlapping
bilayers of lipid consisting of phospholipids and cholesterol and
are partitioned by aqueous compartments (Fig. 4) [36]. They
were first used as transporter for drug transportation in the 1970
37]. These liposomes are extensively utilized for delivering both
[
polar and non-polar drugs, which are situated within their respective compartments of aqueous and lipid bilayers [38]. Liposomes
are classified into three distinct categories based on their dimension
and surrounded numbers of layers: size >500 nm, multilamellar
vesicles; size >100 nm, bigger unilamellar vesicles; and a mean
diameter of 20–100 nm, smaller unilamellar vesicles [
32]. Encapsu-
lating drugs in liposomes shields the active substances from enzymatic breakdown and can mitigate their toxicity [39]. Additionally,
liposomes are pliable, compatible with biological milieus, degradable on their own, and unlikely to trigger immune responses. They
can efficiently transport significant quantities of drugs which are
lipophilic in nature and can be altered to regulate their physical and
chemical properties, thereby influencing their interactions within
the body [
39]. Liposomes are currently being employed as excipi-
ents for developing commercial preparation of a number of lipophilic, low water-soluble drugs, like amphotericin B, that are more
effectively absorbed [
40].
Solid lipid nanoparticles (SLNs) first came up in the year 1990 as a
way to transport non-water-soluble pharmaceuticals at room temperature inside a solid lipid matrix [
41]. Solid lipids such as partial
glycerides, triglycerides, steroids, fatty acids, or waxes make up the
composition of the nanoparticles (Fig. 5) [42]. These fatty acids are
anchored with compatible emulsifiers such as phospholipids, bile
salts, polysorbates, polyoxyethylene ethers, or polyvinyl alcohols
42]. SLN technology could be explored to enable site-specific
[
delivery of medicines, especially for peptides and merely soluble
protein molecules [43]. SLNs are thought to possess significant
Fig. 4 Structure of liposomes (drug molecule—green color)
60 Meemansha Sharma et al.
Fig. 5 Structure of solid lipid nanoparticles
biocompatibility because of use of well-tolerated emulsifiers. Similar to other nanosystems, they have possessed capacity to shield
pharmaceuticals and prevent from degradation by various enzyme
or chemicals [
regulated delivery of medications and may be readily manufactured
on an enormous scale without utilizing organic solutions. Pandita
and coworkers [
where they have shown an increased bioavailability of orally given
paclitaxel in comparison with the control group in their in vivo
experiment. Additionally, the other research showed that effective
inclusion of weakly soluble medications such as fenofibrate, camptothecin, and vinpocetine into SLNs enhanced their dissolving rate
and bioavailability [
44]. Additionally, these lipid tiny carriers can facilitate
45] have made a SLN preparation for paclitaxel
25].
3.6 Co-crystal Preparation
3.7 Dendrimers
The issue of poor solubility of pharmaceutical in water may also be
resolved by utilization of co-crystal methodology. Co-crystals are
novel crystals that are created when more than two distinct compounds are arranged [
46]. They have better qualities than each of
the independent molecules. Co-crystal synthesis can occur via sublimation, or ball mill grinding of more than two solid co-crystal
formers [
31]. The co-crystals’ tendency to dissolve drugs are
mainly due to their decreased lattice force and increased solvent
adhesion properties [47]. Over the past ten years, pharmaceutical
co-crystal nano-methodology has proven highly effective in administering medications that were previously insoluble, thus making a
substantial impact. Co-crystal methodology has been employed to
increase the soluble nature of numerous drugs, including itraconazole, carbamazepine, gabapentin, caffeine, modafinil, piroxicam,
and various others [
31].
Dendrimers are three-dimensional, nanoscale biomolecules with a
clearly defined spherical structure (Fig.
6). Due to their multivalent
and host-guest trapping characteristics, they are frequently
Targeted Drug Delivery: Principles and Strategies 61
Fig. 6 Structure of dendrimers
employed in different applications, including drugs and genes targeting delivery [
48]. Dendrimers are believed to be the newest
tools for encapsulating and delivering of bioactive molecules at
the nanoscale [48]. They have demonstrated enormous promise
as a medication delivery vehicle due to their ability to pass across
both transcellular and paracellular membranes [49]. Dendrimers
are worked in two ways to distribute the drugs where they can be
employed in the formulation & nanoconstruct [
noncovalent interactions are used to entrap
49]. Normally,
the drugs, whereas in
nanoconstruct preparation, dendrimers are covalently bound. Various dendrimers like PAMAM (polyamidoamine), polypropylene,
polylysine, and triazene have been employed in TDDs applications.
It was discovered that dendrimers were used as drug-transporting
agents to treat various illnesses including herpes simplex and HIV
infection, anti-inflammatory agents, antidotes, anti-Alz
anticoagulants, and tumor-killing agents [
50].
heimer’s,
4 Strategies Related to Tissue-Specific Targeted Drug Delivery
Tissue-specific targeted drug delivery is a promising approach in
medicine, aiming to enhance the efficacy of drugs while minimizing
their side effects. Here are some strategies used in tissue-specific
7).
51]. Focusing on the chemical
52]. Small-sized molecule ligands
The most used small-sized
53].
4.1 Small-Sized Molecule-Based Targeting Strategies
targeted drug delivery (Fig.
In targeted drug delivery, small sized molecules are are defined
as substances with a molecular weight below 1kDa or a StokesEinstein radius of around 1 nm, enabling efficient transport and
interaction at the cellular level [
nature of small molecule based targeting structures, previous studies have explored the potential of small molecule targeting ligands
for improved drug delivery. [
often bind weakly to their targets; consequently, to achieve excellent target engagement, these ligands must act together with receptors that have deep topographies [
molecule targeted agent is folic acid (FA). All cells utilize this
vitamin to synthesize nucleotides. Different cells have receptors
62 Meemansha Sharma et al.
Fig. 7 Various strategies for targeting tissue-specific drug delivery
for folic acid, those can be addressed specifically. After FR-mediated
endocytosis, FA facilitates effective intracellular distribution as well,
assuming the linker has endosomal escape potential [
efficient family of small-sized molecule-based targeting ligands is
monosaccharides, which include galactose, mannose, glucose, etc.
For example, glucose targets the overexpressed GLUT1 receptor at
blood–brain barrier. Viable cells use glucose as a main energy fuel.
A chemotherapeutic drug glufosfamide targets cells that undergo
aerobic glycolysis by means of Warburg effect, altered by D-glucose
[
. Likewise, the mannose-6-phosphate receptor is a glycopro-
55]
tein
present
ing the brain, lung, and cells of immune system. Receptors for
proteins that respond to carbohydrates are called lectin-like receptors, and mannose-6-phosphate receptor represents one of them.
Use of urea derivatives to target prostate-specific membrane antigen (PSMAg) has been examined [
urea has been included in single photon emission computed
tomography (SPECT) imaging to diagnose PSMA markers
[
57]. Other small-sized molecules also found functional to target
certain
58], the competence of bisphosphonates as targets for bone [59],
[
and chances of biotin-associated preparation delivery for application involving the biotin receptor that target tumors [60]. It’s
possible to target firm tumors that express carbonic anhydrase
using derivatives of sulfonamide [61]. Phenyl boronic acid selectively targets sialic acid components, whereas benzamides, such as
anisamide, can target sigma-1 receptors [
proteins, a
For example, thalidomides, a peptide-based PROTAC, have been
recently utilized to exhibit knockdown effectiveness in non-human
primate replica [
targeting strategy product to receive FDA clearance [
54]. Another
on transmembrane found in numerous organs, includ-
56]. Additionally, glutamate-
tissues likewise hyaluronic acid’s affinity for CD44 receptors
7]. For destabilization of
potent technique, proteolysis, targeting chimera is used.
62]. Givlaari is the only small-sized molecule-based
63].
Targeted Drug Delivery: Principles and Strategies 63
4.2 Nucleic Acid Fragment-Based Targeting Strategies
4.3 Peptide- and Antibody-Based Targeting Strategies
Another targeting mechanism involves aptamers, which are molecules ranging in size from 5–15 kDa are known for their high
specificity in binding to target molecules. Aptamers are oligonucleotides consisting only one strand that can identify certain binding regions on receptors. Dissimilar to small sized molecules, which
often need profound topography to enable interactions, aptamers
have a good binding capacity for the targeting interest and, because
to their distinctive three-dimensional geometries, can act together
with several flatter receptor surfaces [
64]. Preclinical experiments
are being conducted on most aptamers to arrange to assess their
potential to target delivery of drug [
65]. Many chemotherapeutic
medications and nanocarriers can be conjoined to aptamers, which
are generally flexible, multifaceted, three-dimensional configuration that help in efficient delivery of these substances deeply into
the targeted cells and tissues [
66]. Their tissue-specific drug libera-
tion is major possibility because of these features and their minimal
immunogenicity. Aptamers, in instance, bind more favorably with
highly glycosylated receptors like MUC1. One aptamer beside
VEGF that the FDA licensed for application in age-linked macular
degeneration is among the numerous aptamers that have independently progressed to the clinic [
67].
In various drug delivery stages, biomacromolecules, mainly antibodies (Abs), are frequently utilized. In the sub-nanomolar range,
recombinant monoclonal Abs exhibit significant binding coefficient
kD and high specificity when interacting with their har monizing
antigens (Ags). Therefore, monoclonal Abs have been employed to
create immunoconjugates known as Abs drug conjugate (ADC)
[
68].
The majority of IgG antibodies have lengthy circulation
periods, lasting from several days to many weeks. Their reprocessing by cells of endothelial origin, which is facilitated by receptors
present on surfaces, gives them very long half-lives, and they also
enable substantial tissue exposure for related therapies. Nevertheless, antibodies’ distinct mechanism is only seen in their natural
state. For example, Abs-modified nanoparticles, for instance, get
FDA approved
eli
minated
far more rapidly than free Abs [
69].
ADC including gemtuzumab ozogamicin, brentuximab vedotin,
ado-trastazumab emtansine, etc., for solid and hematological
tumors [
70]. ADC are also being extensively researched as antiviral
and antibiotic in both preclinical and experimental situations
71]. Strategies to target tissue involved peptides and Abs:
[
(A) Abs-mediated targeting techniques—it rely on selecting appropriate antibody-antigen pairs that ensure precise interaction with
target site antigens while minimizing or avoiding effects on normal,
healthy tissues; (B) peptide-mediated targeting techniques—biomimetic peptides can be facilitated using bioinformatics and/or
biomolecular methods like phage display. Therefore, peptides lead
64 Meemansha Sharma et al.
to supramolecular self-assembly; nanocarriers, and peptide-drug
conjugate [
71].
4.4 Cell-Based Targeting Strategies
Even though this technology is quite recent, cell-based targeting
has benefits over conventional tactics, such as excellent specificity
and/or adaptability. Depending on characteristics and intended
uses, drugs can sum up within cells or linked to surfaces of cell.
Numerous cell types are involved in transportation of small or large
molecules and even nanoparticles to particular tissues, including
RBCs, stem cells, leukocytes, T cells, platelets, dendritic cells, and
bacteria [
71]. Disguised immune recognition and inherent tissue
tropism are the two biological cornerstones upon which cell-based
targeting techniques primarily rely [72]. When it comes to tissuespecific targeting, RBCs have been reviewed the most. In humans,
RBC has several self-markers, including CD47, on surfaces that
keep them from being removed by macrophages, which give them
an extremely long circulation (120 days) period [
73]. Owing to
these benefits, RBCs are primarily utilized to target blood tissue,
allowing for the prolonged release or retention of medications in
Several medicines, from tiny to big particle,
the bloodstream [
74].
have been loaded onto or attached to RBC for treating a number of
situations, including inflammatory conditions, cancer, and disorders lacking in certain enzymes. For example, dexamethasone
encapsulated in RBC produced a prolonged release of drug in
75].
people for as long as one month following dosage [
The leukocytes which have been most studied to target tissues includes
monocytes or macrophages. Since monocytes/macrophages are
capable to phagocytes, they preferentially absorb pathogens that
are nano- or micro-sized, which presents prospect to use this characteristic to provide treatments as a nanoparticle. Macrophages may
cross the blood–brain barrier, and they are employed as a targeted
method to deliver nanoparticles to the brain. Further, the capacity
of monocytes and macrophages to target tumors for both remedial
and analytical purposes had been examined by Christie & coworkers [
T cells and neutrophils are investigated as potential
76].
targets. Neutrophil-based approaches are operated to target lung
inflammations and neuroinflammation beside tumor microenvironments [
77]. Targeting techniques based on monocyte/macro-
phages and neutrophils are still limited to preclinical
investigations and not yet used in clinical applications [78]. Clinicians have evaluated >200 T cell-based treatments for malignancies and viral infections [79]. Based on innate or obtained tropism
of stem cells to certain diseased/pathological areas, stem cells also
have been further studied as targeted specific delivery techniques
80]. Stem cells can migrate to wounds, inflammation, and tumors
[
because they possess chemokine receptors. So, stem cells, particularly mesenchymal stem cells, are being used to nearly every organ
as a targeted technique for tumors or injuries [
81]. The most well-
5 Conclusion
Targeted Drug Delivery: Principles and Strategies 65
known function of platelets is blood clotting and thrombosis. The
investigation of utilizing platelets as an avenue to target vessels
damage and thrombosis areas was prompted by the platelets
biological function [
1]. Additionally, platelets have a natural affinity
for surgical wounds, and research has recently focused on using
them to target and treat residual malignancies after surgery [82].
Targeted-delivery nanomedicines could be made with a wide range
of nanoparticles. TDDs is an emerging field in medicine for the
identification and management of fatal illnesses. Conjugated polymeric micelles, nanoparticles, dendrimers, and liposomes exhibit
distinct structural characteristics that enable effective drug binding,
enhancing site-specific delivery. Further, evaluating current developments in hydrophobic compounds and their transportation at
specific target site can lead to more effective medicinal uses and
increased compliance among patients. Devices used for delivering
insoluble drug compounds are increasingly being utilized for commercial benefits, with a focus on developing improved formulations. Continued progress in these devices and their evaluation for
novel drug applications hold significant promise for the future
development. Apart from above-mentioned points, we have
included various strategies employing molecules or ligands that
target particular cells or tissues involved in the pathogenesis of
specific diseases. Various body cells possess distinct capabilities for
tissue-specific targeting as a result of either their physiological
functions or chemotaxis responding to signals. Moreover, targeting
molecules were categorized on the basis of range of targeting
interactions, which included interactions at the cellular level, with
small molecules and antibodies. We underscored the distinctiveness
of receptor-ligand biology and efforts in translating ligand-targeted
systems into clinical applications.
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