Temperature and pH-Responsive Nanocarrier for Paclitaxel Controlled Release Based on P(NIPAM-<i>co</i>-HEMA)-Modified Silica Microgel

Paclitaxel is an important chemotherapeutic drug, but it is not well tolerated and has serious adverse drug effects. In the past decades, many nanoparticle-based drug delivery systems, including liposomes, polymeric micelles, dendrimers, and inorganic nanoparticles, have been developed to improve drug efficacy, transport, and release. In this sense, chemotherapeutic nanomedicines have been successfully applied to cancer therapy; however, the antitumor effect of these nanoformulations has been found to be no significant improvement when compared with common treatments. Here, we report on the design and synthesis of a smart hybrid core–shell nanocarrier (NC) for the loading, transport, and specific release of Paclitaxel under well-defined pH and temperature conditions. The NC was prepared by a sequential method that produced an integrated nanosystem composed of a silica core surrounded by a Poly(N-isopropylacrylamide-co-2-hydroxyethyl methacrylate) biocompatible microgel, P(NIPAM-co-HEMA). We demonstrate by DLS studies that these core–shell NC present a transduction from both stimuli to a mechanical shrinkage of the polymeric shell, which changes the size or aggregation behavior triggered by temperature and pH alterations. This dual stimulus response can be synthetically tuned by controlling the molar ratio between monomers. Besides, the NC was designed to host and carry the hydrophobic drug Paclitaxel. Specific pH and temperature changes lead to the shrinkage of the external microgel polymer layer of the NC, and consequently, Paclitaxel can be released by external control. Overall, these results demonstrate that Paclitaxel-loaded NC is a promising platform to build externally controlled drug delivery systems for environment-triggered therapy. We successfully extended this concept to in vitro studies using B16–F10 cells. Paclitaxel-loaded NC induced tumor cell death, and our findings revealed the “intelligence” of the developed NC in carrying and releasing the cargo in the context of a tumoral microenvironment. This proof-of-principle opens the path to hybrid nanocarrier technologies that could significantly reduce various side effects caused by naked drug molecules in patients who are receiving regular chemotherapy.