3.2.3. Surface Modification

NP-cell interactions and solubility depend on the nature of the NP surface [61]. NP surface coating alteration can modify their magnetic, electrical, chemical, and optical properties, which a ffects their cytotoxic properties by influencing pharmacokinetics, distribution, accumulation, and toxicity [62].

Surface charges determine the response of the organism to changes in NP shape and size in the form of cellular accumulation, called colloidal behavior [63]. The e ffect of surface chemistry on NPs affects absorption [64], colloidal behavior, plasma protein binding [65], and crossing the blood-brain barrier [66]. The NP cytotoxicity increased with an increase in surface charge [67]. This suggests that higher positive charges ge<sup>t</sup> greater cell electrostatic interactions and, consequently, greater endocytic uptake. However, the uptake of positively charged NPs may produce higher toxicity than negatively charged [68]. NPs with a positively charged surface tended to accumulate more in tumors than negatively charged ones most likely because positively charged density can be more easily separated in the interstitial space and, therefore, internalized by tumor cells [56].

Surface chemical modification is an important strategy utilized in biomedical applications to decreases toxicity, increase stability, and to control and modulate cellular internalization [69]. Surface functionalization is predominantly comprised by polyethylene glycol (PEG), the negative carboxyl group, and neutral groups like hydroxyl group, and amine groups [67]. For example, the NP surface can be functionalized by proper polymers such as PEG to reduce non-specific binding and to ge<sup>t</sup> specific binding to cell receptors [70].

Hydrophobicity is another key factor that also a ffects pharmacokinetics and bio-distribution [70]. NPs with a 2more hydrophobic surface tend to absorb plasma proteins, which reduces the time spent in the bloodstream [71]. A computer molecular simulation study revealed that the surface membrane uptake of hydrophobic C60 agglomerates is thermodynamically favored than semi-hydrophilic ones because of the interior membrane hydrophobicity space in cells [72].
