Engineering Sub-Cellular Targeting Strategies to Enhance Safe Cytosolic Silica Particle Dissolution in Cells

Abstract

Mesoporous silica particles (MSP) are major candidates for drug delivery systems due to their versatile, safe, and controllable nature. Understanding their intracellular route and biodegradation process is a challenge, especially when considering their use in neuronal repair. Here, we characterize the spatiotemporal intracellular destination and degradation pathways of MSP upon endocytosis by HeLa cells and NSC-34 motor neurons using confocal and electron microscopy imaging together with inductively-coupled plasma optical emission spectroscopy analysis. We demonstrate how MSP are captured by receptor-mediated endocytosis and are temporarily stored in endo-lysosomes before being finally exocytosed. We also illustrate how particles are often re-endocytosed after undergoing surface erosion extracellularly. On the other hand, silica particles engineered to target the cytosol with a carbon nanotube coating, are safely dissolved intracellularly in a time scale of hours. These studies provide fundamental clues for programming the sub-cellular fate of MSP and reveal critical aspects to improve delivery strategies and to favor MSP safe elimination. We also demonstrate how the cytosol is significantly more corrosive than lysosomes for MSP and show how their biodegradation is fully biocompatible, thus, validating their use as nanocarriers for nervous system cells, including motor neurons.

Design of Polymeric and Biocompatible Delivery Systems by Dissolving Mesoporous Silica Templates

“…Previous literature and studies [ 23 , 26 , 32 , 36 , 37 ] support the conclusion that MSPs are dissolved in these media. Indeed, silica disappearance is concomitant with the progressive detection of Si species in the media [ 32 ]. Hence, we believe these experiments reveal that isotonic solutions (ca.…”

“…In the other example, MSPs were coated with oxidized multi-walled carbon nanotubes (CNTs). These were pre-treated with acetone and ethanol to remove organic materials, subsequently, they were oxidized in a mixture of H 2 SO 4 /HNO 3 (3:1); a stable dispersion (1.54 mg/mL) of oxidized CNTs holding a negative surface charge was obtained, as previously described [ 32 ]. The CNTs were attached to previously sealed MSPs coated with a positively charged PEE following the procedure previously described [ 59 ].…”

“…It was observed that silica dissolution rates are higher in lung fluid, followed by body fluid (similar to phosphate-buffered saline (PBS)), although they were more stable in gastric juice [ 31 ]. Similarly, at the subcellular level, MSPs are rapidly dissolved in the culture media or intracellularly, compared with the lysosome [ 32 ]. In general, silica particles dissolve faster in media of physiological pH containing amino-rich compounds such as cell culture medium, although serum seems to reduce degradation [ 22 , 30 ].…”

Microtubule cytoskeleton-disrupting activity of MWCNTs: applications in cancer treatment

“…attached to particles (500 nm diameter). No biomechanical impedance, microtubule cytoskeletal reorganization, cytotoxicity, or apoptosis is observed [ 60 , 61 ], results that reinforce the hypothesis that to interact with tubulin, CNTs must be dispersed.…”

Receptor-targeted nanoparticles modulate cannabinoid anticancer activity through delayed cell internalization

“…However, in our previous studies 11 , the NPs suspension was replaced by culture media at the end of each incubation period, in order to treat and analyze the living cells at the end of the study. Exocytosis of nanoparticles from culture cells has been reported in several studies 51 , 57 , especially when the nanoparticles are removed from the incubation media and hence the concentration gradient is reversed 56 , 58 . Therefore, and regardless of the experimental specifics of each case, the maintenance of cells in NP-free media after incubation with the formulations could be overall considered a factor inducing decreased value of total uptake, due to nanoparticle exocytosis.…”