the nanoparticles as well as the choice of the material used, its biocompatibility,
biodegradation [144], etc.
The potential toxicity of nanomaterials is influenced considerably by its
biodistribution, phagocytosis, opsonization, and endocytosis, all of which are
critically impacted by the nanoparticle size and surface characteristics [145].
Protein opsonization of nanoparticles eventually leads to their clearance, mainly
through uptake via the reticulo-endothelial system, resulting in its accumulation.
The particles taken up by dendritic cells after opsonization are shown to activate
NALP3 inflammasome, which enhances the effects of both innate and antigenspecific cellular immunity. Apart from this, interaction with the vascular
components of the blood can also result in local inflammation, which is caused
by nanoparticle-mediated oxidative stress. The interaction of nanoparticles with
highly oxidatively active mitochondria can lead to an increased release of free
radicals as reactive oxygen species (ROS), which depletes the natural defensive
antioxidants such as glutathione. The resultant oxidative stress generates a wide
variety of cellular events such as cell cycle arrest, apoptosis, inflammation, induction of signaling pathways, etc. Generation of specific antibodies against BSA was
observed on administration of BSA-carbon nanotube conjugates [146]. Because the
protein nanocarrier is essentially a non-self peptide fragment, generation of
antibodies and immune activation is not surprising. Instead of activating the
immune system, protein nanoparticles are sometimes also reported to cause
downregulation of the immune system. Abraxane, the paclitaxel albumin conjugate
drug, resulted in a lower incidence of grade 4 neutropenia (a form of myelosuppression that leads to a decreased number of neutrophils) than the first generation of
paclitaxel formulations [147].
For biodegradable polymers such as carbohydrates and proteins, the toxicity
associated with their tissue accumulation and metabolism is considerably less.
However, upon interaction with blood and its constituents, nanoparticles can
induce cyto- or hemotoxicity, inflammation, and oxidative stress. Anionic
polymers with sizes greater than 60 nm have been reported to be biocompatible
in terms of hemolysis, coagulation, thrombocyte and granulocyte activation, and
membrane integrity, as compared to cationic particles with smaller size [148]. In
general, cationic carbohydrates such as cellulose and chitosan can cause cytotoxicity by inducing apoptosis and, when in direct contact with blood, can
activate the blood coagulation pathway, resulting in clot formation. Even though
acute systemic toxicity studies in mice did not show any significant toxicity,
chitosan solution even at very low concentrations caused hemeagglutination and
platelet aggregation and activation [149–151]. This property of cationic polymers
necessitates surface modification or engineering with different molecules such as
PEG, dextran, mannose, lactose, galactose etc., with ensuing reduction in toxicity
and improvement in the nanoparticle hemocompatibility [103, 151–155]. Figure 6
demonstrates how glycosylation of nanocarriers would be an ideal approach for
evading nanoparticle toxicity. Additionally, the unreacted components used in
the formulation (crosslinkers, stabilizers, and solvents) can also impart cyto- or
hemotoxicity and, hence, complete removal of these components has to be
ensured for better performance.
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D. Narayanan et al.
biodegradation [144], etc.
The potential toxicity of nanomaterials is influenced considerably by its
biodistribution, phagocytosis, opsonization, and endocytosis, all of which are
critically impacted by the nanoparticle size and surface characteristics [145].
Protein opsonization of nanoparticles eventually leads to their clearance, mainly
through uptake via the reticulo-endothelial system, resulting in its accumulation.
The particles taken up by dendritic cells after opsonization are shown to activate
NALP3 inflammasome, which enhances the effects of both innate and antigenspecific cellular immunity. Apart from this, interaction with the vascular
components of the blood can also result in local inflammation, which is caused
by nanoparticle-mediated oxidative stress. The interaction of nanoparticles with
highly oxidatively active mitochondria can lead to an increased release of free
radicals as reactive oxygen species (ROS), which depletes the natural defensive
antioxidants such as glutathione. The resultant oxidative stress generates a wide
variety of cellular events such as cell cycle arrest, apoptosis, inflammation, induction of signaling pathways, etc. Generation of specific antibodies against BSA was
observed on administration of BSA-carbon nanotube conjugates [146]. Because the
protein nanocarrier is essentially a non-self peptide fragment, generation of
antibodies and immune activation is not surprising. Instead of activating the
immune system, protein nanoparticles are sometimes also reported to cause
downregulation of the immune system. Abraxane, the paclitaxel albumin conjugate
drug, resulted in a lower incidence of grade 4 neutropenia (a form of myelosuppression that leads to a decreased number of neutrophils) than the first generation of
paclitaxel formulations [147].
For biodegradable polymers such as carbohydrates and proteins, the toxicity
associated with their tissue accumulation and metabolism is considerably less.
However, upon interaction with blood and its constituents, nanoparticles can
induce cyto- or hemotoxicity, inflammation, and oxidative stress. Anionic
polymers with sizes greater than 60 nm have been reported to be biocompatible
in terms of hemolysis, coagulation, thrombocyte and granulocyte activation, and
membrane integrity, as compared to cationic particles with smaller size [148]. In
general, cationic carbohydrates such as cellulose and chitosan can cause cytotoxicity by inducing apoptosis and, when in direct contact with blood, can
activate the blood coagulation pathway, resulting in clot formation. Even though
acute systemic toxicity studies in mice did not show any significant toxicity,
chitosan solution even at very low concentrations caused hemeagglutination and
platelet aggregation and activation [149–151]. This property of cationic polymers
necessitates surface modification or engineering with different molecules such as
PEG, dextran, mannose, lactose, galactose etc., with ensuing reduction in toxicity
and improvement in the nanoparticle hemocompatibility [103, 151–155]. Figure 6
demonstrates how glycosylation of nanocarriers would be an ideal approach for
evading nanoparticle toxicity. Additionally, the unreacted components used in
the formulation (crosslinkers, stabilizers, and solvents) can also impart cyto- or
hemotoxicity and, hence, complete removal of these components has to be
ensured for better performance.
262
D. Narayanan et al.