In vitro evaluation of the internalization and toxicological profile of silica nanoparticles and submicroparticles for the design of dermal drug delivery strategies

Abstract

The use of colloidal silica nanoparticles and sub-microparticles (SiPs) have been considered a very interesting strategy for drug delivery applications. In the present study, we have focused our attention on the suitability of these nanomaterials as potential carriers for dermal drug delivery, thus studying their toxicological profile in vitro, cellular uptake and intracellular localization in both human keratinocytes (K17) and human dermal fibroblasts (HDF) as a function of their particle size (SiPs of 20, 70, 200 and 500 nm). Full characterization of these aspects enabled us to observe a strong cell-type dependency in terms of cytotoxicity and cell internalization, whereas particle size was only relevant for ultra-small SiPs (20 nm), being the most toxic SiPs. For 70, 200 and 500 nm SiPs, the differences in uptake and intracellular trafficking determined the different toxicological profiles in K17 and HDF. In addition, these characteristics can further define different drug delivery strategies. Hence, phagocytosis has been identified as the main internalization mechanism for K17, and caveolae-mediated endocytosis for HDF. This relevant information led us to conclude that fibroblasts would be optimal targets for delivering delicate therapeutic molecules such as proteins or genetic material using SiPs while maintaining a low toxicity profile, whereas keratinocytes could enable accelerated drug release therapies based on SiPs.

In Vitro and In Vivo Short-Term Pulmonary Toxicity of Differently Sized Colloidal Amorphous SiO2

“…Section 3.2 ), and hence the manner in which they come into contact with the cultured cells [ 80 ]. However, the cellular uptake of colloidal SiO 2 nanoparticles also appears to depend on the type of cultured cells [ 81 ], and noninternalized particles can also damage the cell membrane, and hence induce cellular effects, by diffusion contact [ 74 , 82 ].…”

<p>The Size-dependent Cytotoxicity of Amorphous Silica Nanoparticles: A Systematic Review of in vitro Studies</p>

“…Tokgun et al 23 demonstrated that among 6, 15, and 30 nm sizes of aSiNPs, 6 nm-sized nanoparticles had strongest cytotoxic effects on A549 cells, and this cytotoxicity came from dead receptor-mediated induction of apoptosis. Liu et al 24 examined the cell viability of A549 cells after exposing to SiO 2 particles at various concentrations (5,10,20,30,40,60,80, and 100 μg/mL). Results of CCK-8 assay showed that exposures of 10-20 nm aSiNPs resulted in significantly decreased viability of A549 cells, while 5 μm SiO 2 particles did not affect the cell viability obviously.…”

“…Li et al 28,29 investigated the possible cytotoxicity of three sizes of aSiNPs (40,60, and 200 nm) in human bronchial epithelial BEAS-2B cells. These particles inhibited the cell viability in a size-dependent manner, the smaller aSiNPs produced higher toxic effect.…”

“…Results of LDH and MTT assay showed dose-and size-dependent cytotoxicity of 30 and 48 nm nanoparticles, while larger sizes of aSiNPs (118 and 535 nm) exhibited less toxicity compared with smaller nanoparticles. Vicente et al 60 investigated the toxicological profile of aSiNPs (20,70,200, and 500 nm) in human keratinocytes (K17) and human dermal fibroblasts (HDF), and described that the ultra-small particles (20 nm) was the most toxic aSiNPs, whereas particles larger than 70 nm demonstrated to be nontoxic for both dermal cells in a wide range of concentrations.…”

“…88 Thus, it could be proposed that different synthetic methods varied the surface properties of aSiNPs, which would eventually lead to diverse biological reactivity. 89 However, Napierska et al 26 used two types of silica nanoparticles produced by either Stöber process or Lys-Sil process, with four different diameters (2,16,60, and 104 nm), and found the cytotoxicity was related to the particle size directly, which indicated that compared with the synthetic method, the higher surface area of smaller particles played a pivotal role in the enhancement of surface reactivity. Similar results were obtained in the study of Napierska et al, 2 in which little difference in toxicity was found between Ludox silica nanoparticles (diameters of 14 and 15 nm) and Stöber silica nanoparticles (16 nm).…”