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Biomarkers as Targeted Herbal Drug Discovery
the cardiac functions against isoproterenol-induced AMI and arrhythmia
along with the involvement of SERCA2 and RyR2 receptors. During the
study, it also revealed its potential in cardiac remodeling attenuation. In
the case of cardiac fibrosis, rosmarinic acid meticulously targeted Cf’s
and through AMPK activation and Smad3 inhibition cardiac fibrosis was
inhibited. The results point out a bigger role that rosmarinic acid can play
in modifying CVDs.
We express our sincere thanks to the DST-INSPIRE fellowship program,
DST-SERB, UGC-UPE II, and AICTE-RPS schemes of Govt. of India for
providing financial support which was utilized for the present study.
• acute myocardial infarction
• aortic banding
• arrhythmia
• caffeic acid
• cardiovascular
• rosmarinic acid
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Biomarkers as Targeted Herbal Drug Discovery
CHAPTER 11
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Long-Term Toxicity and Regulations for
Bioactive-Loaded Nanomedicines
IQBAL AHMAD,
S. M. KAWISH,
1
1,2
SOBIYA ZAFAR,2 SHAKEEB AHMAD,2 SUMA SAAD,
2
SANJAY AGARWAL,1 and FARHAN JALEES AHMAD
2
2
2
Nanomedicine Research Lab., Department of Pharmacy,
School of Pharmaceutical Education and Research, Jamia Hamdard,
New Delhi – 110025, India
ABSTRACT
Incorporation of natural bioactive into nanomedicines, their applications,
and evaluation have aggressively been put forward during the last couple
of decades. The enormous ability of nanocarriers in enhancing the bioavailability, targeting, and efficacy of natural molecules have been well documented. Many findings also demonstrate the application of nanosystems in
toxicity reduction and lessening of possible side effects of drugs effective
targeting and thereby decrease the dose required. However, it should be
noted that the conversion of molecules from natural to the nanoscale can
display entirely new or significantly altered physicochemical as well as
biological properties and may impose some newer risks to the patient. For
instance, some drugs that are not crossing biological barriers may surpass
them when transformed into nanoparticles, opening up new dimensions to
therapeutic strategies specifically for brain delivery. In addition, they may
also get into other cellular compartments and undesirably cause a cascade of
adverse reactions including genotoxicity. This chapter outlines the suitability
of various bioactive loaded nanocarriers in therapeutics, their toxicity, and
regulatory considerations.
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Biomarkers as Targeted Herbal Drug Discovery
Natural products have continued to be the major driver of primary healthcare
throughout human history with about 80% prevalence found in developing
countries and up to 30% in developed countries. This equates to approximately
5.1 billion world population depends on natural products for medicinal applications (Picking, 2017). Bioactive, obtained from natural products, including
antioxidants, probiotics, polyunsaturated fatty acids (PUFAs), and proteins
have demonstrated great potential as therapeutic agents for the treatment of
several medical conditions including cancer, central nervous system-related
disorders, arthritis, inflammation, infections, and several others. However,
the stability, solubility, and hence the bioavailability severely limits the
successful clinical translation of the herbal bioactive for therapeutic applications. Although most of the natural compounds exhibit low toxicity, highdose-induced side effects are a major reason limiting patient compliance
(Watkins et al., 2015). Nanocarrier based delivery of bioactive has been a
major advancement in the efforts to increase the therapeutic effectiveness of
herbal bioactive.
Nanotechnology is the science and technology of manipulating matter of
size <100 nm to produce devices with new molecular properties, organizations, and functions, that cannot be achieved at large scales. Nanotechnology
is a rapidly evolving eld and can be considered as the start of a new technological revolution with immense potential in healthcare, environment,
smarter electronics, and advanced agriculture and energy (Hoet et al., 2009).
Nanotechnology in the food sector is focused on the production of nanofood
ingredients and additives developing delivery systems for the bioactive
molecules and food packaging. The major applications of nanotechnology
in the area of food and additives include-improving nutraceuticals stability,
augmenting bioavailability of poorly soluble functional food ingredients,
enhancing shelf life, and modifying the avor and texture of food products
(Chaudhry et al., 2008).
Nanomedicine is a branch of nanotechnology that encompasses specic
medical intervention through which the human biological system can be
monitored and controlled at the molecular level. Nanomaterials (NMs) such
as metallic nanoparticles, ceramic, or carbon-based nanoparticles can be
developed using simple molecules or they can be organized structures such
as liposomes and nanoemulsion, or as dendrimers and polymers (Satalkar
et al., 2016). Numerous benets offered by nanomedicines include but
not limited to, enhanced solubility of poorly soluble bioactive and thereby
improved bioavailability, protection from degradation of bioactive, reduc-
https://t.me/medicina_free
tion in toxicity, decreased drug’s immunogenicity and selective targetability
(Sastry et al., 2010; Viacava et al., 2017). The United States-Food and Drug
Administration (US-FDA) and the European Medicines Agency (EMA) have
approved several nanomedicine-based products for therapeutic applications.
Functionalization of nanoparticles with specic ligands, antigen, aptamer,
peptide, etc., enhances the accumulation of nanoparticles in ischemic tissue,
tumor, and organ inamed area. Stimuli sensitiveness to pH, temperature, light, enzymes can mediate triggered drug release to the target site.
Nanoparticles can also bypass biological barriers including cell membranes
and blood-brain barrier bringing about increased drug concentrations to the
diseased site (Smolkova et al., 2017).
NMs have different physicochemical and biological properties as
compared to their larger counterparts. These characteristics confer double
identity to the nanoparticles as their utilization implies novel medical and/
or industrial applications as well as the possible hazardous outcome for
both human and environmental health. The physicochemical characteristics
of the nanoparticles, including, particle size, shape, and surface chemistry
inuences the cellular uptake, biodistribution patterns, and clearance
mechanisms (Hoet et al., 2009). Any modication to any of these features
induces new functions and potential toxicity. Challenges in the optimization procedure, characterization, and screening methods, instability under
biological environments, robust, and reproducible manufacturing and scaleup, batch-to-batch consistency and regulatory barriers further impedes the
successful clinical translation of a range of nanoparticles (Agrahari and
Hiremath, 2017). Bioactive targeting is still a major challenge. Nanoparticles
can enter the cells via endocytosis and can potentially cause the systemic
toxicity if their bio-distribution is not controlled or if they form toxic
metabolites. Non-biodegradable nanoparticle accumulation in the body over
time could further lead to unwanted toxicity and cell death. For the product
to be commercially successful, the two primary and essential qualications
are the high therapeutic efcacy and safety. Majority of the nanomedicines,
however, fail to accomplish these requirements which impede their successful
commercialization. Furthermore, the safety concerns with the nanoparticles
stem from their translocation potential to the tissues attributed to their small
size and higher-than-physiologically-normal concentrations of the delivered
bioactive in the tissues. Oxidative stress is the major mechanism underlying
NMs induced toxicity which further mediates inammatory cell responses,
immunotoxicity, and genotoxicity. Epigenetic alteration is another issue of
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Biomarkers as Targeted Herbal Drug Discovery
NMs induced toxicity to be taken into consideration (Smolkova et al., 2017;
Stoccoro et al., 2013).
The long-term toxicity of nanoparticles is crucial to determine, especially
if these systems are to be used for the treatment of chronic human diseases.
When setting up a long-term toxicity (or safety) test for a nanomaterial,
the route of administration and the vehicle used should correspond to the
expected usage in humans. Species selection is another important consideration and the immune responses to the biological molecules should be
comparable to that in humans. The test design and test outcomes necessitate
supervision with great caution (Hoet et al., 2009).
Facilitating human safety is the prime concern with any delivery system.
Nanotechnology is revolutionizing the eld of medicine and drug delivery,
but the unpredictable nature and the underlying nanotoxicity has the potential for harm. This necessitates the development of a regulation plan for
nanotechnology that will serve the dual purpose of fostering innovation and
keeping the public safe. Fiedler and Reynolds have correctly stated, “the law
of unintended consequences operates with a vengeance where technology is
concerned” (Fiedler and Reynolds, 1993).
Consuming plants for potential health benefits for the prevention and treatment of several disorders has been a common practice since ancient times.
Developments in phytochemical and pharmacological sciences have successfully enabled to interpret the composition as well as biological effectiveness
of natural bioactive (Kamboj, 2000). The past few decades have witnessed the
exponential increase in the use of phytochemical based dietary supplements
and herbal remedies. The sudden surge in the use of dietary supplements has
been particularly observed in cancer patients who consume these in conjunction
with traditional cancer treatment, without informing their physicians. Epidemiological studies indicate that the phytochemicals are considered safe and
might be a more natural alternative to conventional medication, however, only
limited data are available for the safety and efficacy of most phytochemicals
for disease interventions (Bode and Dong, 2015). Flavonoids are the constituents of fruits, vegetables, plant-derived beverages and are also present in a
huge number of herbal-containing dietary supplements. They have shown to
be potent antioxidants, however, a dark side still remains. Dietary phenolics act
as prooxidants in systems containing redox-active metals. Series of chemical
253 Long-Term Toxicity and Regulations for Bioactive-Loaded Nanomedicines
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reactions are involved to mediate the prooxidant effects of the dietary phenolics.
Transition metals such as copper (Cu) and iron (Fe) catalyze the redox cycling
of phenolic compounds, in the presence of O
, resulting in the formation of
2
reactive oxygen species (ROS) and phenoxyl radicals which cause damage
to DNA, lipids, and other biological molecules. Epigallocatechin gallate
(EGCG), a green tea catechin, induce hydrogen peroxide (H
) generation in
2O2
the presence of transition metal ions, subsequently causing oxidative damage
to isolated and cellular DNA. The in vitro studies have further demonstrated
the DNA oxidation induction ability of EGCG in promyeloblast cell line,
HL60 cells, for acute promyelocytic leukemia. EGCG induced DNA oxidation was more pronounced in glutathione (GSH) depleted cells while no such
activity was observed in H
catalase (CAT) activity than HL-60 cells. This implies that the H
-resistant HP100 cells that have 18 times higher
2O2
generation
2O2
by EGCG is involved in DNA oxidation. This also relates to the prooxidant
activity of EGCG on enhancing the dimethylhydrazine or nitrosamine colon
carcinogenesis in rats. Another phenolic component of green tea, Pyrogallol
produced significant hepatic damage in rats when administered at a dose of
100 mg/kg, intraperitoneally (I.P.). The increased level of serum enzymes
aspartate aminotransferase (AST) and alanine aminotransferase (ALT) along
with the increased level of malondialdehyde (MDA) suggests the formation
of free radical and pro-oxidant effects as the key mediator of hepatic damage.
Tea flavonoids, EGCG, propyl gallate and gallic acid (GAE) at a dose of 120
mg/kg, 170 mg/kg and 500 mg/kg, respectively, caused a 4-fold increase in
plasma ALT levels, on the administration to the CD-1 mice indicating significant hepatic damage in rodent models (Galati and O’brien, 2004; Furukawa
et al., 2003; Hirose et al., 2001). The catechol B ring containing flavonoids,
such as quercetin, upon oxidation by peroxidase, forms semiquinone-and
quinone-type metabolites that may act as electrophiles which bind to cellular
macromolecules producing ROS through redox cycling. Peroxidase-mediated
oxidation of phenol B ring containing flavonoids such as, apigenin (API),
naringenin, resulted in the formation of phenoxyl radicals which catalyzed
GSH or NADH co-oxidation and generated ROS. Another toxicity concern
with flavonoid is the cytochrome P (CYPs)-flavonoid interaction. The CYP
enzymes inhibiting or inducing the ability of flavonoids depends upon their
structures, concentrations, or the experimental conditions. CYP activity is inhibited with flavonoids possessing hydroxyl groups while those lacking hydroxyl
groups may induce the enzyme. Flavonoid-drug interactions may occur with
the simultaneous administration of flavonoids and therapeutic agents. This
can modulate the pharmacokinetics (PKs) of the active molecule with either
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