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Advances in Clinical Toxicology Research Article 12 min read

Perspectives of Toxicity Associated with Nanocarrier Systems

Bhatia R*, Singh A, Rathor S and Narang RK
* Corresponding author
ISSN: 2577-4328  10.23880/act-16000222  Received: August 17, 2021  Published: September 03, 2021
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Keywords
Nanocarrier Toxicity ROS Biomarker Carbon Nanotubes Liposomes
Abstract

The utility and diversified applications of various nanocarrier systems have led to the development of a wide variety of formulations with smart properties. Although these formulations offer several advantages over traditional delivery systems such as site-specific, time-dependent and controlled delivery of the medicaments but unfortunately the toxicological behavior of these has remained unexplored. There are several reports in the literature that have described the significant toxicity in major organs of animals. This toxicity has majorly associated with the formation of reactive oxygen species (ROS), elevation/ reduction in biomarker levels, induction of apoptosis and several other molecular changes. In this short compilation, we have summarized some toxicity reports which have been based on pre-clinical evidences and attributed to multiple organs of animals. These include the kidney, heart, lungs, liver and GIT prominently. Also, we have made an attempt to highlight the mechanism of the reported toxicity along with the toxic dose. This compilation may be helpful to drug developers and researchers to understand these issues and to design newer strategies during formulation to bypass these complications.

Introduction

In the past decade, nanocarrier systems have been extensively explored for their divine drug delivery potentials and had been widely utilized in the development of targeted drug delivery systems, research and technology. Nanocarrier based drug delivery systems have been proven as blockbusters for site-specific delivery in the therapy of life-threatening ailments. In other words, we can coin these systems as smart nanocarriers because of their smart functionality and application in the development of smart drug delivery systems (SDDs). These delivery systems have bypassed the disadvantages of non-specific distribution and uncontrollable drug delivery patterns of traditional delivery systems. Smart nanocarrier systems include micelles, liposomes, dendrimers, carbon nanotubes (CNTs), multi-walled carbon nanotubes (MWCNTs), single-walled carbon nanotubes (SWCNTs) nanorods, nanoemulsions, phytosomes, magnetic nanoparticles, nanospheres, quantum dots and mesoporous silica nanoparticles (MSNs). Many nanocarrier-based formulations are already available in the market and some are in clinical trial phases. Despite several extraordinary advantages of these smart nanocarriers, there is a continuously emerging issue of toxicity of these systems. As a matter of great concern, continuous research is in progress specially focussing on toxicity and biocompatibility of nanocarriers. In general, nanoparticles are able to induce toxicity based upon their internalization site and composition. It is also revealed that nanoparticles can cause inflammation, oxidative stress and DNA damage [1]. Table 1 highlights some significant reports describing the potent toxicities exhibited by nanocarrier systems on different organs/parts of the body. Major consequences involved in nanocarrier toxicity in terms of targets, molecular involvement, genotoxicity, routes and physicochemical factors have been outlined in Figure 1.

Figure 1: Consequences of nanocarrier toxicity.
Click to enlarge
Figure 1: Consequences of nanocarrier toxicity.
CarrierOrganEffectsAnimal
used /cell
line		Mechanism of toxicityToxic DoseRefer
ence
CNTsLungsAlteration in mitochondrial
membrane potential		Rat alveolar
macrophage
cell line
(NR8383)		Metal catalysed induction of
reactive oxygen species (ROS)		50 µg/mL[2]
MWCNTsLungsDNA damageFemale micePulmonary inflammation
induced by neutrophil influx in
broncho-alveolar lavage (BAL))
and genotoxicity leading to DNA
damage		6-54 µg/
mL		[3]
SWCNTsLungsDeath due to blockage of
airway		Male ratsAlveolar macrophage
accumulation and lung tissue
thickening		5mg/Kg[4]
MWCNTsLungsPulmonary lesion and
collagen rich granuloma in
the mice exposed		Guinea pigs
(males)		Perivascular, peribronchial
and interstitial permeation of
inflammatory cells associated
with central and peripheral
atelectasis, emphysema and
alveolar exudation		1-5mg/Kg[5]
SWCNTsHeartProgression of
atherosclerosis		MiceAortic DNA damage10-40µg[6]
CNTsFoetusThe fetal and
developmental
abnormalities		Male and
female mice		Increased resorptions during
organogenesis, induction of
oxidative stress due to ROS		10mg/Kg[7]
IONPs
(Iron oxide
nanoparticles)		LiverLiver inflammation and
necrosis		Adult male
Wistar rats		Enhancement of free radicals
and reduction of GSH in lung
tissues		>2.2mg/Kg[8]
Curcumin
capped IONPs		Liver
and
kidney		Abnormal liver and kidney
performance		MiceChanges in the levels of
biomarkers of liver and kidney		>5mg/Kg[9]
Dendrimer
coated IONPs		LiverEdema and losing
cytoplasm in the liver cells		MiceIncrease in blood urea nitrogen,
bilirubin and histopathological
abnormalities		10mg/Kg[10]
Platinum
nanoparticles		HeartDecrease in the heart rate,
prolonged P-R intervals
and finally complete A-V
conduction block		MiceDecrease in current densities
of ion channels, conduction
block and increased lactate
dehydrogenase leak		3-10mg/kg[11]
CuO NPs
(Copper oxide
nanoparticles)		Liver
and
spleen.		Liver and kidney
dysfunction		Female miceIncreased production of ROS
leading to lymphocyte apoptosis		100-
1000µg/Kg		[12]
CuO NPsG.I.T.G.I.T. Toxicity, an imbalance
in antioxidant levels.		Artemia
salina		Generation of oxidative stress
and disturbances in antioxidant
defence pathway		12.2mg/L[13]
TiO NPs
2		Heart
and
liver		Heart injury and liver
injury		RatElevated reduced glutathione
(GSH)/oxidized glutathione
ratios due to increased plasma
levels of glucose and GSH		50-200mg/
Kg		[14]
TiO NPs
2		LiverLiver injury markers and
a reduction in certain
hematological parameters.		Female miceElevated levels of alanine
aminotransferase, alkaline
phosphatase, aspartate
aminotransferase, lactate
dehydrogenase and
cholinesterase, total protein and
the reduction total bilirubin,
triglycerides, and the total
cholesterol levels		125-
250mg/Kg		[15]
TiO NPs
2		FoetusFetal toxicity in pregnant
mice		MiceElevated dopamine levels
in the prefrontal cortex and
neostriatum, abnormal fetal liver
development		0.25–1.00
mg/mL		[16]
Mesoporous
Silica NPs		KidneyHemorrhage, vascular
congestion, and renal
tubular necrosis		Male miceRenal tubular necrosis, vascular
congestion in renal interstitium		40mg/Kg[17]
ZnO NPsFetusToxicity during gestation
period		RatsMultifocal mixed cell
permeation, thrombosis in lung,
tubular dilation in kidneys		10-20mg/
Kg		[18]
LiposomesLiver,
Lung,
Breast		CytotoxicityL 1210,
HepG2,
A549 cell
lines		DNA damage due to the cationic
surface charge		0.25 µM P/
ml		[19]
MicellsLung,
Liver,
Kidney		Polymeric micelle-based
drug carriers trigger
transient immunogenicity		Female MiceIncreased ROS production,
Increase in cell volume		Dose
dependent		[20]
DendrimersLung,
Liver,
Kidney		Dendrimers, such as
PPI, PAMAM, and PLL,
exert significant in vitro
cytotoxicity due to their
surface catatonic groups		Mammalian
Cells		High charge and strong
interaction with the negatively
charged cell membranes leading
to destabilization and leakage
and lysis of cytoplasmic proteins		Dose
dependent		[21]

Table 1: Reported toxicity of nanocarrier systems on various organs.

Possible Mechanisms of Toxicity

The various pre-clinical studies of nanocarrier systems have been carried out by several research groups including the toxicity along with its underlying mechanisms. A few significant mechanisms of toxicity revealed by various nanoparticles (NPs) have been described in the following sections.

Generation of Reactive Oxygen Species (ROS)

The physiological activity of nanocarriers leads to the generation of reactive oxygen species which include hydroxyl radicals, superoxide radicals as a result of activation of oxidative enzymes which ultimately is the prominent cause of oxidative stress (Figure 2) [22, 23, 24]. It is worth notable that the extent of this kind of stress has been reported majorly in nanocarriers systems possessing metals or impurities of transition metals [25, 26]. Deposition of nanoparticles in multiple organs leads to ROS generation and initiation of inflammation. This mechanism is not fully understood but it has been evidenced that oxidative stress affects intracellular calcium contents, transcription variables and induction of cytokines [27]. Elevated ROS adversely affect mitochondrial respiratory mechanisms and induces changes in protein structures in the endoplasmic reticulum and induce stress. These events lead to more production of ROS, severe DNA damage, induction of signals, more inflammatory events, cell death due to apoptosis and necrosis [28, 29].

The redox process may occur in the solution as well as on the nanoparticle surface leading to changes in the crystalline structure. Some nanocarrier preparations such as fullerenes, carbon dots, SWNTs and quantum dots produce ROS upon exposure to ultraviolet radiations or transition metals [30]. Exposure of a mother to titanium dioxide can cause changes in apoptotic genes and oxidative stress in the newborn offspring [31]. Nanoparticles possess a large surface area which can produce prominent ROS and leads to cytotoxicity. The CNS is highly sensitive towards oxidative stress due to abundant lipids, proteins, high oxygen consumption and weak antioxidant properties [32]. Therefore ROS causes maximum damage in CNS leading to neurodegenerative disorders and diseases. It has also been reported that nanoparticles are also capable of damaging dopaminergic neurons as a result of high production of ROS due to microglial stimulation [33].

Figure 2: Consequences of oxidative stress induced by nanoparticles in animals.
Click to enlarge
Figure 2: Consequences of oxidative stress induced by nanoparticles in animals.

Cellular uptake Mechanisms

The structural organization, chemistry and size of nanoparticles greatly influence the cellular entry, uptake and distribution of these systems. The cell membranes give entry to nanoparticles by the endocytosis process which is influenced by the nature, size and shape of the nanoparticles [34]. The size directly affects various cellular processes like target identification, circulatory residence time, concentration, uptake pathway and clearance. Smaller particles enter and exit with great ease; spherical particles get internalized inside the cells and negatively charged particles exhibit a low rate of endocytosis as compared to positively charged ones. Pinocytosis is the type of endocytosis that is meant for the intake of fluid or smaller solute particles whereas phagocytosis intakes the heavy and solid materials. Phagocytosis takes place through macrophages, neutrophils, monocytes and dendritic cells. Opposing to this, pinocytosis involves van der Waals, electrostatic, steric interactions and the formation of vesicles leading to free movement of nanoparticles between cells and multiple organelles [35, 36].

Followed by pinocytosis, the nanoparticles got located in various compartments of cells such as cell membrane, cytoplasm, mitochondria, lipid vesicles, nuclear membrane, nucleus and exert significant toxicity by causing organelle/ DNA damage leading to cell death [37, 38, 39]. Complications produced by nanoparticles upon localizing in particular organelles have been depicted in Figure 3. The shape of nanoparticles also affects the cellular uptake and has been reported highest in the case of nanorods in human cervical cancer cells followed by nanospheres, cylindrical and cubical shapes [40, 41]. Lysosomes are also a significant target for nanoparticle localization and toxicity due to endocytosis. NPs exert their toxicity in lysosomes due to cytoskeleton destruction, alkalization or overload [42].

Figure 3: The shape of nanoparticles also affects the cellular uptake and has been reported highest in the case of nanorods in human cervical cancer cells followed by nanospheres, cylindrical and cubical shapes [40,41]. Lysosomes are also a significant target for nanoparticle localization and toxicity due to endocytosis. NPs exert their toxicity in lysosomes due to cytoskeleton destruction, alkalization or overload [42].
Click to enlarge
Figure 3: The shape of nanoparticles also affects the cellular uptake and has been reported highest in the case of nanorods in human cervical cancer cells followed by nanospheres, cylindrical and cubical shapes [40,41]. Lysosomes are also a significant target for nanoparticle localization and toxicity due to endocytosis. NPs exert their toxicity in lysosomes due to cytoskeleton destruction, alkalization or overload [42].

Genotoxicity and Inflammation

The activation of microglia by nanoparticles leads to the initiation of inflammatory responses by secreting pro- inflammatory factors and ultimately causes cell dysfunction, death and cytotoxicity [43]. Nps have been also regarded as autophagy inducers with the potentials of inducing ROS- dependent and lysosome-dependent autophagy. Titanium, silicon, polymeric, oleic-acid coated nanoparticles are responsible for brain autophagy whereas zinc oxide NPs cause oxidative stress in macrophages leading to autophagy and apoptosis [44]. Nanoparticles of varying sizes accumulate in mitochondria and lead to abnormal electron transport chain mechanisms [45]. This oxidative stress ultimately leads to genotoxicity due to DNA modifications and cell injuries [46]. Epigenetic effects are also prominent in chromatin due to acetylation/methylation of histones, mutagenic DNA damage and abolition of DNA repair pathways which is the prominent cause of Ni-nanoparticles induced carcinomas [47, 48, 49, 50].

Conclusion

It is evident from the above reports that along with therapeutic efficacy the nanocarrier systems exhibit a significant amount of toxicity. This toxicity has been attributed to several factors like ROS generation, inflammation, endocytosis, nanoparticle size, shape and localization, etc. This is a matter of immense concern and researchers/drug developers should work in this direction so as to reduce the induced toxicity. Although there are a few approaches that have been successfully utilized for reducing the toxicity such as modification in size, shape, shell, surface charge and route of administration; still a keen work towards this direction is the demand of the hour.

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@article{bhatia2021,
  title   = {Perspectives of Toxicity Associated with Nanocarrier Systems},
  author  = {Bhatia R, Singh A, Rathor S and Narang RK},
  journal = {Advances in Clinical Toxicology},
  year    = {2021},
  volume  = {6},
  number  = {3},
  doi     = {10.23880/act-16000222}
}
Bhatia R, Singh A, Rathor S and Narang RK (2021). Perspectives of Toxicity Associated with Nanocarrier Systems. Advances in Clinical Toxicology, 6(3). https://doi.org/10.23880/act-16000222
TY  - JOUR
TI  - Perspectives of Toxicity Associated with Nanocarrier Systems
AU  - Bhatia R, Singh A, Rathor S and Narang RK
JO  - Advances in Clinical Toxicology
PY  - 2021
VL  - 6
IS  - 3
DO  - 10.23880/act-16000222
ER  -