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Nanotechnology
combines the knowledge of pharmaceutical, medicinal, material science,
engineering and information technology and has made accurate, precise and rapid
diagnosis creating a major development in the field of medicine. The
nanoparticle size lies between 1 nm to 100 nm. The main important factor is the
size itself. It mainly helps to enter the cell cavity of any small sized microorganisms
including bacteria, fungi and even virus. This small size helps nanoparticles
to travel through blood stream and ultimately reach the target centers in the
human body. Their shape and high surface area to volume ratio make
nanoparticles to use in medicine effectively. Nanotechnology aims for the
effective drug delivery, better ways of organ regeneration and development of
Nano drugs. Techniques used in Nanotechnology include, delivery of Drugs into
targeted cells by using Nano particulate carriers. Unfortunately, excess use of
Nano drugs has led to toxicity or poisoning due to the Nano medicine carriers.
In this paper we would like to highlight the important facts about the toxic
side of using Nano drugs in modern medicine. This paper explores the potential
and versatile applications of nanoparticles in the field of medicine.
Keywords: Nanotoxicity, Nanomedicines (NMs), PEGylated (Polyethylene
glycolated) Nano liposome (SPI-077TM), Respiratory syncytial virus (RSV),
Transcriptome analysis console (TAC) software, Targeted drug delivery
INTRODUCTION
Nanomedicine is a relatively new and rapidly
evolving field combining nanotechnology with the biomedical and pharmaceutical
sciences [1-4]. Nanotechnology has wide applications in medicine in the form of
diagnostic imaging, treatment and prevention [5]. Global investment in
nanotechnology has been increasing steadily; a significant increase in
researches addresses the benefits of nanomedicines over free drugs and presents
new opportunities and challenges in all branches of medicine [6]. These
medicines are used mainly to overpower diseases like cancer which has proved
quite effective, when used in low or trace amounts. Along with such revolutionary
advantages, problems and issues like toxic effects of drugs, tissue injury,
selective organ toxicity and its carcinogenic effects are to be accounted.
Nanomedicine (NM) is the application of
nanotechnology (the engineering of tiny machines) to the prevention and
treatment of disease in the human body [7]. This evolving discipline has the
potential to dramatically change medical science. The most common application
of nanomedicine involves employing nanoparticles to enhance the action of drugs
in treatment. NM has potential advantage and less toxic but still one should be
very careful while subjecting these interventions in human being. It is
important to have a thorough understanding of NMs and their specific
properties. Immunotoxic effects, such as complement activation-related pseudo
allergy, myelosuppression and hypersensitivity, are not readily detected by
using current testing guidelines [8,9].
Cisplatin
encapsulated pegylated nanoliposome
Nano particulate carriers deliver
nanoparticles without undergoing the normal absorption process and many a times
are responsible for toxicity and can also accumulate in organs. Cisplatin
encapsulated PEGylated nanoliposome or SPI-077TM, a nanodrug that was
experimented to study its effect on tumor growth in mice [10]. Anti-tumor
activity and accumulation of cisplatin was observed inside tumor tissues
Accumulation of non-biodegradable
nanoparticles
Site targeting is a best way to
cure diseases, but nonspecific targeting and the accumulation of Nano medicine
in the liver, spleen and kidney are unsolved problems [6]. Accumulation of Non-biodegradable
nanoparticles can cause cell damage and inflammation, if taken up by
macrophages as it would cause free radical release. Similarly if taken up by
lysosomes they accumulate and cause toxicity. This is caused due to the absence
of a degradation enzyme which results in accumulation of materials in lysosome.
The other affected organs due to this accumulation include liver, which is most
likely and brain which is the least likely to be affected. These
problems can be overcome by coating biodegradable materials on nanomedicines
which avoid the accumulation of such particles.
Drug-induced muscle
injury
Drug-induced
muscle injury is due to exposure of tissue to the slowly releasing drug. ‘Application-specific
design’ methodology requires the accurate identification of the disease, its
subtype and target and also needs an in-depth comprehension of the nature and
pathogenesis of the disease. Particle-encapsulated cytotoxic drugs are broken
down by liver cells and this leads to drug-induced hepatic injury. Increased
drug induced toxicity after encapsulation has also been observed recently.
Unfavorable effects on the central nervous
system and the immune system
Zinc
oxide (ZnO) is termed as a multi-purpose item and is used for manufacturing
porcelain, ceramic items etc. ZnO containing creams are used to treat sunburn,
insect bites and other skin irritations. Studies prove that these nanomaterials
have unfavorable effects on the central nervous system and the immune system.
The path for entry and the target organ of the nanoparticles are the lungs.
Immunotoxicity and
genotoxicity
Oxidative
stress is also caused due to NM-induced toxicity and other problems include
immunotoxicity and genotoxicity [14]. Genotoxicity testing is important, as it
causes mutagenicity and carcinogenicity. Lungs are affected mainly due to
burning caused by oxidative stress. Antioxidants reduce the bad effects of
oxidative stress. ZnO nano medicines are widely used and show toxic nature on
human pulmonary alveolar epithelium and lungs. In order to overcome the
problem, studies were conducted on a combination of RSV + ZnO NP. It resulted
in showing positive results, cytotoxic and genotoxic toxicity decreased
compared to their levels when ZnO was used alone. The reason was that RSV,
being a natural antioxidant, avoided genotoxic and cytotoxic damage induced by
ZnO nanoparticles on the epithelial cells. They also cause changes in genetic
matter that plays a role in the pathogenesis of various diseases. The
epigenetic toxicity of NMs is based on in
vitro. It is not a simple task to find the impact of NMs on genetic
material as large number layers of epigenetic control mechanisms and vast
variations in individual susceptibility [15].
Different
experiments of RSV and ZnO nanoparticles are carried out on the epithelial
cells and results are observed using TAC analysis. It was observed that there
was decrease in TAC value, on adding ZnO nanoparticles. While increasing
amounts of RSV increased TAC on the cells. Thus it was concluded use of
antioxidants were beneficial in overcoming oxidative stress problems [15].
Severe combined
immunodeficiency disease (SCID)
Targeting
of current Nano drugs is based on permeability and retention effect. As a
result of binding with many items, increases their chances of accumulation in
organs and other tissues. A controlled release of drugs can be brought about by
pH, enzymes and temperature. There are several negative effects caused by Nano
drugs, given below are some more examples. Severe combined immunodeficiency
disease (SCID) was caused by Adagen which was used to improve circulation time
and reduce immunogenicity injected Intravenous in 1990 [16]. Mircera, Neulasta
and Oncospar causes Anemia, Fibrile neutropenia and leukemia respectively and
all these drugs were used to improve stability of proteins. The above include
protein based Nano particles. Similarly lipid based Nano particles including
DepoCyt and Marqibo cause lymphomatous meningitis and acute lymphoblastoic
leukemia, both drugs are used for increased delivery to tumor site through
intravenous injection.
Liposomal encapsulated doxorubicin
Generally
liposomes are designed to lower their toxicity to healthy tissues as well as to
increase their efficacy. A liposomal encapsulation of doxorubicin with
surface-bound methoxypolyethylene glycol is known to be less cardiotoxic and
nephrotoxic than unbound doxorubicin; however, it produces more dermal lesions
primarily on the feet and legs [17]. A liposome-encapsulated
doxorubicin–citrate complex shows less cardiotoxicity than unbound doxorubicin;
however, it induces increased bone marrow suppression [18].
DNA methylation, acetylation of histones and
mRNAs
Production
of reactive nitrogen species causes inflammation. NMs cause changes in DNA
methylation, acetylation of histones and mRNAs expression also NMs showed that
they impair the expression of genes. Nanoparticles coated by gold cause
hypermethylation. Gold (Au) nanoparticles are used widely because they are
inert and biocompatible. Chiral Au nanoparticles capped with gold components
decrease the catalytic activities of TET proteins. Silver (Ag) nanoparticles
induce a reduction in hemoglobin levels in mice erythroleukemia cells.
Similarly, titanium dioxide (TiO2) in nano-form is a substance that
causes cancer through inhalation.
Effectiveness and
toxicity
Effectiveness
and toxicity are two important parameters viewed for medicine development. Free
drugs and nanodrugs are compared, effectiveness (E)/toxicity (T) ratios for
nanomedicine, (E/T) nanomedicine and a free drug, (E/T) free drug is done as
first approach. While the ratio of the toxicity or efficacy of nanomedicine (N)
to that of the free drug (F), (N/F) effectiveness and (N/F) toxicity is done as
second approach. The E/T ratio for Nano medicines decreases and approaches a
ratio value closer to that of the free drug when concentration is increased,
suggesting a lowered benefit with an increase in concentration in the first
case. While the N/F ratio does not show overall benefit between nanomedicines
and free drugs, but it does provide an idea regarding the magnitude of the
difference in efficacy or toxicity between a Nano medicine and a free drug [6].
CONCLUSION
Nanomedicines
have wide applications and merits in the field of modern medicine, but they
have toxic effect also. Cisplatin is a versatile nanomedicine it will collect
in the active target tissues and blood resulting less toxic effect. But its
effect in human beings is not commendable and it causes nephrotoxicity.
Non-biodegradable nanomedicines will lead cell apoptosis and infection inside
the body. Particle-encapsulated nanomedicines can cause drug-induced hepatic
injury. Versatile nanomedicines like zinc oxide will lead bad impacts on the
central nervous system and the immune system. Oxidative stress, immunotoxicity
and genotoxicity are the other bad impacts of NM-induced toxicity. Certain
nanomedicines cause severe combined immunodeficiency disease and DNA
methylation. Using antioxidants and liposomal encapsulation are certain ways of
reducing the nanotoxicity. Nanomedicine with lower concentration reduces the
toxicity compared to free drug with similar concentration.
Depending on particulate characteristics of their formulations, the toxicokinetic profile or toxicodynamic effects can be stratified. The differences in absorption, distribution, metabolism, excretion, interactions with other chemicals may affect the side effect or toxicity. This may result in altered availability of NM within different tissues leading to toxicity.
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