Mesoporous Silica Nanoparticles in Targeted Cancer Therapy

Safety & Toxicity of MSNs

The number of studies regarding safety and toxicity of MSNs has increased rapidly during the last years. In a recently published study MSNs showed significantly less cytotoxicity and apoptotic cell death and lower expression of proinflammatory cytokines than colloidal silica nanoparticles in vitro, and MSNs neither induced contact hypersensitivity nor acted as immunogenic sensitizer in vivo, which was shown with local lymph node assay.^[48] Depending on the type of MSNs studied to date, quite different conclusions have been drawn. On a very general level, surface functionalized MSNs seem to reduce the observed harmful effects as compared with pristine mesoporous silica.^[16] Porosity, particle size, and postsynthetic treatment (calcination/solvent extraction) may be other significant contributors. The porosity effect is mainly connected to the increase or decrease in available surface area and postsynthetic treatment giving rise to different degrees of condensation and consequently biodegradation rate, possible residual template surfactants, as well as surface density of silanol groups. The latter has been especially brought forward in terms of hemocompatibility,^[49–51] whereby the silanol groups have been found to interact specifically with surface phospholipids on the red blood cell membranes. This effect was moreover enhanced by either a higher density of surface silanols on nonporous silica surfaces as compared with corresponding porous surfaces, giving rise to a higher accessible external surface area,^[51] ultimately leading to hemolysis. Blocking the access to the silanol groups by functionalization with organic groups, however, diminished the observed hemolysis. Remarkably enough, primary amine groups were also very (and almost equally as PEG) effective in preventing hemolysis in a dose-dependent manner,^[51] even though the common conception is that positively charged groups would enhance the interaction with the negatively charged cell membrane. The favorable effect of surface functionalization on biocompatibility also seems to be reflected in some of the existing biocompatibility studies, whereby the disadvantageous observations especially in vivo have pronouncedly been recorded for nonfunctionalized silicas.^[52,53] Whereas 240 mg/kg nonmodified MSNs resulted in immediate death when injected iv. into mice, the lethal dose (LD50) value for mesoporous hollow silica nanoparticles was found to be greater than 1000 mg/kg.^[54] These discrepancies have also been observed for the same type of materials when either solvent-extracted or calcined, whereby the extracted materials were found to inhibit cellular respiration,^[55] whereas the calcined counterparts were later shown to be reasonably biocompatible in terms of interference on bioenergetics when incubated at high concentrations (200µg/ml) with murine tissues.^[56] One main contributing factor was also thought to be the surface density of silanol groups, as well as differences in accessible surface area between the studied materials possessing different pore sizes (~3 and ~7 nm, respectively). Similar findings have also been appointed for nonmesoporous silicas (^[56] as well as references therein). A disadvantage for the calcined MSNs could be the consequently lower hydrophilicity, arising from the lower density of silanols, potentially leading to poorer dispersability under physiological conditions. Once dispersable MSNs have been successfully produced, however, surface functionalization can facilitate the dispersability of the nanoparticulatate carriers in the physiological environment. Another concern that has to be solved, originated from metabolic changes caused by MSNs, resulting in melanoma promotion. It was suggested that the effect induced by MSNs was due to the decrease of endogenous reactive oxygen species in cells and upregulation of antiapoptotic molecules. These results show that tumor growth can be regulated by nanocarriers themselves in a reactive oxygen species-dependent manner, and this important finding highlights the need for more tests aiming at a clearer understanding of metabolic deviations in MSN-targeted cells.^[57]

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