Nanoparticle-mediated Targeting of senescent cells

This project involves the synthesis of mesoporous silica nanoparticles that can selectively deliver senolytic to senescent cells.

Project Background: Literature shows senescence to be one of the key drivers of numerous age-related diseases through the senescence-associated secretory phenotype (SASP) that can induce inflammatory states throughout the body. It is characterized by an increased lysosomal beta-galactosidase expression (Senescence-associated beta-galactosidase). Senolytic drugs can target and cause apoptosis of SCs that accumulate with age and at sites of numerous chronic conditions. Nanoparticle-mediated drug delivery enables controlled release, higher target concentrations, first-pass metabolism bypass, and lower off-site interactions of the target drug. In particular, Flavonol senolytics like Quercetin and Fisetin have poor oral bioavailabilities given their low aqueous solubility. Mesoporous silica nanoparticles (MSNs) have been shown to be efficient drug carriers due to their porosity and drug-loading capacities. The surface functionalization of MSNs enables the gating of these pores as well as selective targeting and drug release in cells of interest. I use this principle to load senolytic drugs into MSNs and gate the particles to halt drug release. Project importance: The method of nanoparticle-mediated delivery for senolytics can be utilized for the clinical use of these drugs, especially since senolytics are being clinically tested for numerous conditions. Not only does this strategy promote higher therapeutic efficiency, but it also offsets adverse side effects and provides an easy medium for testing newer senolytics that have poor bioavailability. Skills learned:

  • Mesoporous silica(mcm-41) synthesis- sol-gel processing with liquid-crystal templating
  • Amine functionalization of mesoporous silica- Grafting amine groups over MCM-41 or co-condensation MCM-41 and amine groups.
  • Characterization of nanoparticles- Field emission scanning electron microscopy, Spectroscopy(UV-visible, Fourier transform infrared), Nitrogen absorption-desorption isotherm(Brunauer–Emmett–Teller) analysis for pore size and surface area analysis, Thermogravimetric analysis for amine group characterization.
  • Cell Culture- Handling, passage, revival
Mouse fibroblasts(NIH/3T3) were stained to observe Beta Galactosidase expression imaged through inverted microscopy. Left- NIH/3T3 cells Right- NIH/3T3 cells treated with H2O2 to induce Stress-induced premature senescence. Blue stained cells indicate positive Senescence associated beta-galactosidase expression.
Mesoporous silica nanoparticles are viewed through Field emission scanning electron microscopy (FESEM).