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354 Herbal Pharmacopeia
Phytosomes make use of the power of liposomes and hence enhances the absorption & bioavailability of herbal drugs. Phytosome technology is applicable to help facilitate the delivery of different
herbal drugs for various diseases. The pharmacokinetic and pharmacodynamic parameters can be
improved via the use of phytosomes (Mahadev B. Khanzole, 2020).
Phytosomes enhances the bioavailability of phytoconstituents, especially hydrophilic groups
containing herbal drugs, and hence increases drug efcacy. Phytosomes have been tested by different research groups for comparing the bioavailability of the herbal compounds alone as well as in
phytosome form. Here are a few phytosome based herbal drugs available on the market. Ginkgo
biloba extract, olive oil compounds, silymarin, ginsenosides, green tea catechins, anthocyanins and
other avonoids, curcumin, and visnadine (Prasad, S. B 2016).
16.2.7 dnA nAnoCArriers for tArgeted drug delivery
DNA nanostructures, also called DNA origami, make use of the basic building blocks, i.e. nucleotides. The nucleotides work as basic building material that self- assembles to form special kinds of
nano- scale structures (see Figure 16.1g). The resulting DNA nanostructure may be 1D, 2D, or 3D
molecular structures with controlled shapes and sizes. The Watson- Crick base pairing is the logic
behind the design of the DNA origami structure. DNA origami is designed in software such as cadnano and the nano structure is made up of a large Scaffold (M13 phage genome) and short staple
strands (Castro et al., 2011).
A number of webservers have been introduced over the past few years to facilitate the origami
design. Desired structure and shape and size can be designed in the software, depending upon the
requirements. The most notable servers which contributed to this eld of science are cadnano and
OxDNA. Once a desired structure is designed, it is large enough to carry drugs to the target site.
Keeping in view that the basic structure is solely made up of nucleotides, its nonimmunogenic. DNA
nanostructures has vast applications in the pharmaceutical and biomedical elds. DNA origami can
be designed with spaces or voids in its structure that can excellently hold the drug cargo without any
external disturbance or effect. Thus, DNA nanostructures serves as a good delivery vehicle for many
types of drug molecules (Shishparenok et al., 2023).
DNA nanostructures serve as a versatile platform for a large number of application like drug
delivery, biomaging, and theranostics. The main features of DNA origami include:
1. Improved drug effectiveness through effective solubility, circulation in body uids, and
cellular uptake.
2. Customizable size, shape, and chemical properties because DNA origami can be merged
with different chemistries and surface modications such as antibodies, proteins, nucleic
acid aptamers, drugs, and other functional groups. This makes DNA nanostructures a versatile platform.
3. Controlled drug release mechanisms at target site with low off- targeting.
4. Size- dependent organ distribution of cargo and effective tumor targeting.
These features make DNA nanostructures/origami a promising tool for targeted drug delivery and
other therapeutic applications (Kumar et al., 2023).
Cancer therapy, targeted gene therapy, vaccine delivery, and bioimaging are among the major
areas where DNA nanotechnology is currently being applied at the research scale. Personalized
medicines is another promising area where DNA nanocarriers offer the solution to the challenges
posed by conventional drug delivery systems (Zheng et al., 2022).
Since DNA nanotechnology is still in its initial stages of development, it has a long way to go.
Keeping in view the potential of DNA nanotechnology, the eld of herbal drug delivery will benet
from it.
Targeted Delivery Systems for Herbal Drugs 355
16.2.8 AptAmers for drug tArgeting
Aptamers are short stretches of single- stranded DNA or RNA. Previously, had been thought that
nucleic acids only perform genetic roles. A few decades ago, however, scientist reconsidered this
theory and stated that nucleic acids can also perform other functions. It was at this point that the term
functional nucleic acids was introduced. The binding of nucleic acids to ligands laid the foundation
of this eld of science (Nimjee et al., 2017).
These are now termed aptamers and they can perform functions such as ligand binding. At present, the discovered aptamers can bind with a vast range of targets, starting from small organic molecules, inorganic groups to complex protein, and even entire cells.
Since aptamers can bind with the receptors on the cell membrane and facilitate themselves or
conjugated nanostructures to enter the cells. Hence, aptamers can be used as excellent targeting
ligands for novel drug delivery systems (He et al., 2018).
Aptamers can precisely deliver functional nucleic acids to target cells. They bind specically to
cell surface proteins, ensuring accurate delivery (Xie et al., 2023). Aptamers can improve the effectiveness of natural compounds in targeted drug delivery. They have many advantages like stability
and simple synthesis and a wide range of targets. Combining natural products with aptamer- based
delivery systems offers potential for broader applications in medicine (Joana Gamboa, 2024).
16.2.9 miCrospHeres And miCropellets
Microspheres are tiny spherical particles, with sizes ranging from 1 to 50 μm. It offers a promising approach to herbal drug delivery. These special microparticulates enhances drug concentration
at the target site while minimizing the unwanted effects. Microspheres enhance the efcacy of the
drug and hence patient compliance by prolonging the drug action as well as keeping plasma concentrations steady. It potentially reduces the overall herbal drug dosage and minimize side effects by
lowering off- targeting (Elkordy et al., 2021).
To date, different herbal ingredients have been successfully formulated into microspheres.
Rutin, camptothecin, and quercetin are the prominent examples of this application. Recent studies
have made use of the variable microsphere, the immune and the magnetic microspheres. Immune
microspheres incorporate the coating of antigen or antibody on the polymer surface (Sarangi and
Padhi, 2018).
16.3 TARGETING STRATEGIES AND MECHANISMS
Nature has equipped plants with a huge array of secondary metabolites which serve two major roles:
defense against predators and signaling within plant body. Generally speaking, these secondary
metabolites demonstrate a huge number of biological and pharmacological properties. The early
civilizations started using plant extracts and exploiting specic plant products and extracts for treating a number of ailments. Secondary metabolites exhibit two kind of bioactivities: a) specic and
b) nonspecic.
Specic Bioactivities The secondary metabolites which interact with the specic targets within
or on the surface of cells, such as membranes, proteins or nucleic acid molecules. For example,
alkaloids on receptors of neurotransmitters.
Nonspecic Bioactivities Secondary metabolites like phenolics and terpenoids are less specic
in their actions and attack large number of proteins by building different bonds like hydrogen, ionic
bonds and hydrophobic bonds, which in turn change the 3D structures of proteins and, as a result,
modulate their bioactivities (Wink, 2015).
Due to these variations and diversities, herbal drugs follow different mechanisms for targeting
and hence their mode of actions differ.
356 Herbal Pharmacopeia
16.3.1 ligAnd- reCeptor mediAted tArgeting
There is a difculty in getting drugs into the brain because of a protective layer called the blood–
brain barrier. A special type of chemistry, called receptor- ligand chemistry, is used to help drugs cross
this barrier and reach the brain. This could be useful for treating brain diseases like Alzheimer's,
Parkinson's and Lou Gehrig's disease (Anthony et al., 2021).
The development of multi- target directed ligands is a promising approach for the treatment of
complex diseases. It focuses on multi- protein- coupled receptors as key targets for multi- target
directed ligands due to their involvement in various human diseases (Huang, et al., 2021).
Ligand- decorated nanoparticles are used for targeted drug delivery in cancer therapy as they can
selectively target cancer cells without harming healthy tissues (Bandyopadhyay et al. 2023). By
incorporating specic ligands onto the polymeric nanomicelles (PNMs), they can bind to receptors
on the surface of target cells, facilitating their uptake and improving therapeutic efcacy. This
receptor- mediated targeting approach can help overcome the limitations of passive targeting and
enhance the delivery of drugs to specic tissues and organs (Agwa et al., 2023).
16.3.2 Antibody drug ConjugAtes
Antibody drug conjugates have made signicant advancements over the past decade. They are a type
of chemotherapy that combines a cytotoxic agent with a monoclonal antibody through a spacer arm.
While only one antibody drug conjugate had been approved by 2009, there are now nine approved
ADCs and over 80 in clinical trials (Gogia et al., 2023).
Antibody- drug conjugates (ADCs) are a promising cancer treatment that combines a monoclonal
antibody with a cytotoxic payload (Lu et al., 2023).
ADCs have evolved from broadly targeting cancer cells to precisely targeting them and bolstering
the immune system to combat drug resistance. ADCs were initially developed in preclinical trials in
20th century & the second generation addressed the issue through innovative antibody modication
techniques. At present, a third generation of ADCs is in development (Song et al. 2023a, 2023b).
ADCs have revolutionized targeted cancer therapy. Despite challenges, recent advancements
have led to increased development and approvals. Novel conjugation and linker technologies are
expanding the scope of antibody drug conjugates (ADCs) (Bulger et al., 2023).
16.3.3 AptAmers for A tArgeted delivery system for HerbAl drugs
Aptamers are single- stranded nucleic acids or short peptides, ranging in size from 15 to 80 nucleotides (ssDNA and ssRNA, XNA or peptide aptamers). Aptamers were discovered in the 1990s
and selected or evolved through a process called Systemic Evolution of Ligands with Exponential
Enrichment (SELEX). Aptamers can bind selectively and specically to proteins, DNA, RNA, small
molecules, carbohydrates, vitamins, metabolites, drugs, and any other ligand. Aptamer can even
bind whole cells or target a specic organelle inside cells or surfaces of bacteria and other microorganisms (Gold et al., 2012). Aptamers are comparable to antibodies in their binding behavior. But
antibodies are more costly to produce at industrial scale where aptamers are cost- effective. However,
despite all the research and development in the promising domain of aptamers, they have still a long
way to go to enter into real competition with the antibodies in the global market (Liu et al., 2022).
Aptamers have a vast number of applications:
a. It can act as a binder against ligands (Gold et al., 2012).
b. It can work as direct biologic therapeutics (Wang et al., 2023a)
c. It can be used as an imaging molecule in diagnostics (which can be detected based on chro-
mogenic material like uorescence labelling attached to aptamer bound to specic target
site in a sample) (Liu et al., 2022).
Targeted Delivery Systems for Herbal Drugs 357
d. It plays a role in drug delivery mechanisms, as a cargo carrier molecule.
e. Aptamers can also work as binding to nanomaterials to make complex systems for drug
delivery (Liu et al., 2022).
Based on these signicant applications, aptamers open a window on research in drug designing,
drug delivery, drug targeting, the diagnosis and prognosis of diseases and a lot more is yet to come
(Wang et al., 2023b).
Keeping in view the challenges of herbal medicines, e.g. efcacy, targeting and retention, aptamers can be effectively utilized for addressing the aforementioned issues the potential of aptamers has
the answer. Recently, many groups have conducted studies in this regard, by merging the power of
aptamers to counter the challenges of plant- based therapeutics. One study, conducted by Gamboa
etal. (2024), recently offered a thorough account of the use of aptamers in drug delivery for plant
herbal medicines. The study analyzed published literature on the above said topic from January 1,
2018 to December 31, 2023. Their analysis concluded 43 such studies, which made use of aptamers
for herbal drugs delivery. In the same study it was demonstrated that natural compounds extracted
from plants, with known therapeutic potential but with low expression in clinical practice, were
more signicantly used for aptamer- related studies (Gamboa et al., 2024).
In these studies, herbal compounds were logically loaded into different kind of nanoparticles
and the complexes were modied with different aptamers (see Figure 16.2). This approach was
FIGURE 16.2 Aptamer-based therapeutics and the variety of nanomaterials utilized for drug delivery.
358 Herbal Pharmacopeia
promising to overcome herbal drugs’ generic issues and problems, like bioavailability, solubility, and
stability and tissue permeation with extended retention time (Liu et al., 2022). This slightly unexplored area can be explored further with the addition of more innovative technologies like combining
herbal drugs, aptamers, and nanobiotechnology for more effective and novel drug delivery systems.
16.3.4 stimuli- responsive delivery systems
Different targeting strategies and mechanisms are useful for drug delivery systems. The nanomaterials
(e.g polymers, liposomes, micelles, etc.) encapsulate drugs and then external stimuli, such as temperature, pH and so on trigger drug release. One excellent method for targeting cancer cells is stimuliresponsive medication delivery, which makes use of particular characteristics and triggers. Choosing
nanomaterials with efcient drug encapsulation and taking into account the stimuli that would cause
drug release at the tumor location are essential. With this strategy, side effects could be reduced and
therapeutic efcacy could be increased through the possibility of precise and targeted therapy.
Nanomaterials encapsulate drugs and then target specic sites. Biological ligands facilitate active
targeting and uptake. Thus, it is also another effective mechanism. The strategies that can be adopted
are the following: Optimize nanoparticle properties, use biological ligands & prioritize in vivo studies (Yijie Wu, 2019); Stimuli- responsive drug delivery systems to release drugs only in tumor environments, maximizing effectiveness in cancer treatment (Sun and Davis, 2021). Ligand- based active
therapy is a promising approach for treating various cancers and it also improves targeting.
16.4 APPLICATIONS OF TARGETED DRUG DELIVERY SYSTEMS
FOR HERBAL DRUGS
16.4.1 HerbAl drugs for CommuniCAble diseAses
Communicable diseases, those transmissible from person to person, pose a persistent global health
challenge. Viruses, in particular, have demonstrated an alarming capacity to mutate and evade
immune responses, necessitating a continuous search for effective countermeasures.
Polyphenols, a vast class of naturally occurring compounds, are a promising strategy to combat
these infectious diseases. Polyphenols, which number more than 10,000, are ubiquitous in the plant
kingdom. Viral infections, such as COVID- 19, SARS, and MERS, are all communicable diseases
and spread from person to person. Thus, polyphenols which are derived from plants are used as
herbal medicines to treat the communicable diseases.
Herbal drugs, with their rich phytochemical prole, offer a promising avenue for exploring the
therapeutic potential of polyphenols. These plant- based remedies have been used for centuries in
traditional medicine systems to cure communicable diseases. For example, thyme, oregano, mint, and
basil have been employed for centuries to alleviate and combat contagious diseases (Garcia, 2020).
Many plants contain natural substances that work together to ght viruses and bacteria that cause
communicable diseases. We can cure E. coli infections and skin infections through the use of herbal
medicines.
16.4.2 HerbAl drugs for CommuniCAble And non- CommuniCAble diseAses
Non- communicable diseases are those which cannot be transmitted from person to person.
Natural medicine has ancient roots, with records dating back to 2600 BCE in Mesopotamia. Key
historical documents showcase the widespread use of plant- based remedies:
1. Mesopotamian records(2400 BCE): ~1000 plant- derived compounds
2. Egyptian Ebers Papyrus (1500 BCE): >700 natural drugs
Targeted Delivery Systems for Herbal Drugs 359
3. Chinese Materia Medica (1100 BCE): 52 medicinal preparations
4. Indian Ayurvedic texts (1000 BCE): >800 natural extracts
Notably, Hippocrates incorporated herbal healing (phytotherapy) into his medical practice, demonstrating the enduring inuence of natural remedies across diverse ancient cultures and medical
traditions (Shaito et al., 2020).
The World Health Organization's Traditional Medicine Centers identied 122 key medicinal
compounds derived from just 94 plant species. These compounds are used similarly across different
countries for traditional treatments. For example:
a. Galegine, extracted from Galega ofcinalis L. (goat's rue), led to the development of met-
formin and other antidiabetic drugs.
b. Papaverine, from Papaver somniferum (the opium poppy), inspired the creation of vera-
pamil, a medication for high blood pressure.
Despite a shift towards synthetic drug development in the late 1980s, natural products have regained
prominence in drug discovery due to facts such as advances in scientic research demonstrating
their efcacy in disease prevention and treatment. Economic accessibility among communities and
perceived safety by general public, especially in developing countries. There is unparalleled biological activity and structural diversity compared to synthetic libraries, and huge potential for optimization with minor structural changes.
However, challenges remain such as the need for interdisciplinary approaches in natural productbased drug development for communicable diseases. There are concerns about herb–drug interactions and safety proles in living systems. There is a need for more focus on structural modications
to improve potency and pharmacokinetics for herbal drugs. African herbs that interact with the
cytochrome P450 (CYP) enzyme system & P- glycoprotein (P- gp), which are crucial for drug metabolism and transport, can also affect the efcacy of drugs used for the prevention of non- communicable
diseases such as kidney and liver diseases, heart diseases, and inammatory processes and neurological diseases (Ondieki et al., 2017).
Overall, natural products remain a rich, largely untapped source for drug leads, offering ‘privileged scaffolds’ for drug design, despite only a fraction of nature’s biodiversity being tested for
biological activity.
Antioxidants are also crucial in the prevention of non- communicable diseases, such as aging,
kidney and liver disease, heart diseases, inammatory processes and neurological diseases.
16.5 CONCLUSION AND FUTURE PERSPECTIVE
In the era of AI, there have been advancements in research in the domains of drug discovery,
drug delivery, natural products, drug repurposing, the identication of new herbal compounds,
the discovery of new drug targets within human bodies, nanobiotechnology, metabolomics and
bioinformatics. Scientists from these multidisciplinary areas of research are joining hands together
and nding new avenues and possibilities to bring more herbal drugs to the market. The limitations
associated with herbal compounds and drugs such as poor pharmacokinetics, lower specicity
and side effects like potential toxicity can be effectively encountered through the strategic use of
precise combinations of nanomaterials, targeting molecules like antibodies and aptamers. In the
years to come, we expect to see more studies on herbal drugs delivery in which more complex
chemistries will be utilized for the delivery of herbal drugs to target sites with lower side effects
and off- targeting.
Given the pace of developments and the way in which AI is being integrated into daily lives, AI
will obviously play a future role as a catalyst in herbal drug discovery and drug delivery.
360 Herbal Pharmacopeia
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