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3 In Vitro and In Vivo Tests to Assess Oral Nanocarriers Toxicity

3 In Vitro and In Vivo Tests to Assess Oral Nanocarriers Toxicity

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7 Toxicity of Nanodrug Delivery Systems


Table 7.2 In vitro and in vivo parameters to assess oral nanocarriers toxicity




Cell models


In vivo

assessment of





In vitro tests based on cell culture techniques, though with various

restrictions as models for the behavior of cells in an organism, are

very functional in the screening of NPs and in mechanistic assays;

they are comparatively economical and can have a highthroughput

There are enormous assortments of well-known cell lines derived

from different human tissues that keep some of the original

characteristics. A number of them even show the possibility of

differentiation, by means of specific cell culture conditions, to

better exhibit the characteristics of the organ. Additionally, 3D

cell cultures or co-cultures have also been developed in effort to

mimic the target organ

Various in vitro assays, with diverse toxicological endpoints, have

been projected to evaluate the adverse effect that NPs may

provoke on organs of the human body. Viability assays detect

whether cells are dead or alive, generally by evaluating the cells’

capability to multiply or to form clones. Cytotoxicity assays

examine the consequence of the NPs at different levels within the

cell such as membrane integrity (e.g. lactate dehydrogenase

(LDH) leakage, or oxidative status (e.g. 2070-dichlorofluorescein

diacetate (DCFA) assay to detect reactive oxygen species), trypan

blue uptake), metabolic activity (e.g. 3-(4,5-dimethylthia

zol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay,

adenosine triphosphate (ATP) detection assay)

Currently, in vitro models, though giving very value data, are

inadequate to predict potential hazards to humans and to

rationalize transition through clinical trials to the market. In vitro

approaches yield incomplete information and they do not

symbolize a realistic model of how NPs will interact with a

specific organ of the body. For an instance, if the toxic effects of

NPs are connected to inflammation, simple in vitro assays may

not be sufficient for examining the toxic potential. Hence

currently information, obtained for in vitro studies involve

verification from in vivo experiments to precisely evaluate





[7, 9,



Toxicity of Nanocarriers for Oral Delivery

In contrast to the fact that polymeric nanocarriers may offer a number of distinct

advantages over microdevices or macroscopic drug delivery systems, including the

capability to reach some specific areas or improve the intracellular delivery of macromolecular drugs, they can also produce toxicological issues. In fact, the same

physicochemical parameters determining their fate and efficacy would be involved

in the possibility to induce toxicological effects. However, the main problem is that

most investigations are concentrated on the efficacy of NPs and toxicity aspects, if

studied, are usually restricted to a screening of their cytotoxicity. In this way very

little information is known about the genotoxicity and immunogenic potential of


Toxicity of Nanocarriers for Oral Delivery


Table 7.3 Toxicity considerations of nanocarriers for oral delivery

Toxicity consideration


properties of polymeric

NPs affecting their

toxicological profile


Size and shape

Surface properties



Physicochemical parameters of polymeric NPs such as size,

material, shape, surface properties, or the presence of ligands may

result in different “kinetic” properties when administered orally

Various polymers, macromolecules and lipids, both synthetic and

natural, have been employed in formulating biodegradable

nanocarriers. Usually most of these compounds are utilized as

excipients for other pharmaceutical applications or they have the

consideration of “Generally Recognized as Safe” (GRAS) when

administered by the oral route. Nevertheless, as mentioned before,

their conversion into nanoparticulate devices opens the door to

toxicological concerns

Particle size has obvious effect on the toxicity of nanomaterials. An

inverse relation between size and potential toxic effects is usually

established; small NPs offer a higher surface area and as a result a

higher number of potentially reactive molecules in comparison with

larger ones (given equal mass) [20]. Decreasing the size of NPs

triggers the potential reactivity of these materials in an exponential

way [21]

For an instance CS-derived NPs as a model of negatively and

positively charged nanocarriers were investigated in their ability to

be taken up by phagocytic cells [22]. Macrophage uptake enhanced

as the surface charge (either positive or negative) increased. This

outcome would be linked to the concern of electrostatic interactions

between particles and phagocytic cells that would allow their

internalization [23]. Nevertheless, when the absolute values of zeta

potential were alike, positively charged NPs offered a higher

phagocytic uptake in contrast to negatively charged ones,

irrespective of their composition [22]

Theoretically nanocarriers capable of “disappearing” in the

body conditions and/or of being “inert” when in contact with a

living system or tissue would have a lower hazardous effect

[23–26]. Nevertheless, the biodegradability of NPs may produce

biodegradation products with a different toxicological profile

from that of the nanocarrier. In addition, the biodegradation

process, which would occur during the interaction of

nanocarriers with the biological medium, can alter the

physicochemical properties of nanocarriers (e.g. size, shape and

surface properties) and therefore the toxicological performance

may also be influences throughout this process. In contrast,

non-biodegradable materials should present a high toxicity risk

linked with their accumulation in the body

nanocarriers capable of translocating and entering into the circulation after their

administration by the oral route. Similarly, the study of in vivo toxicity has been

pursued only with a small number of polymeric nanocarriers. Various toxicity considerations of nanocarriers for oral delivery is mentioned in Table 7.3.


7 Toxicity of Nanodrug Delivery Systems


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