Nanoparticles containing high loads of paclitaxel silicate prodrugs: Formulation, drug release, and anti-cancer efficacy

Han, J.; Michel, A. R.; Lee, H. S.; Kalscheuer, S.; Wohl, A.; Hoye, T. R.; McCormick, A. V.; Panyam, J.; Macosko, C. W. Mol. Pharmaceutics 201512, 4329–4335.

"We have investigated particle size, interior structure, drug release kinetics, and anticancer efficacy of PEG-b-PLGA-based nanoparticles loaded with a series of paclitaxel (PTX)-silicate prodrugs [PTX-Si(OR)3]. Silicate derivatization enabled us to adjust the hydrophobicity and hydrolytic lability of the prodrugs by the choice of the alkyl group (R) in the silicate derivatives. The greater hydrophobicity of these prodrugs allows for the preparation of nanoparticles that are stable in aqueous dispersion even when loaded with up to ca. 75 wt % of the prodrug. The hydrolytic lability of silicates allows for facile conversion of prodrugs back to the parent drug, PTX. A suite of eight PTX-silicate prodrugs was investigated; nanoparticles were made by flash nanoprecipitation (FNP) using a confined impingement jet mixer with a dilution step (CIJ-D). The resulting nanoparticles were 80–150 nm in size with a loading level of 47–74 wt % (wt %) of a PTX-silicate, which corresponds to 36–59 effective wt % of free PTX. Cryogenic transmission electron microscopy images show that particles are typically spherical with a core–shell structure. Prodrug/drug release profiles were measured. Release tended to be slower for prodrugs having greater hydrophobicity and slower hydrolysis rate. Nanoparticles loaded with PTX-silicate prodrugs that hydrolyze most rapidly showed in vitro cytotoxicity similar to that of the parent PTX. Nanoparticles loaded with more labile silicates also tended to show greater in vivo efficacy."