ADAM9-Responsive Mesoporous Silica Nanoparticles for Targeted Drug Delivery in Pancreatic Cancer

Simple Summary The clinical efficacy of systemic chemotherapy is limited in pancreatic cancer (PDAC) due to toxicity-dependent dose-limitations often leading to premature cessation of therapy. Targeted delivery of chemotherapeutic drugs to cancer cells, without affecting healthy nontumor cells, will largely reduce collateral toxicity. Reductions in collateral toxicity will allow increased drug concentrations to be used, thereby increasing the efficacy of chemotherapy. In the current study, we designed and validated a PDAC-specific protease-dependent drug release system. More specifically, we generated capped mesoporous silica nanoparticles that only release their cargo after proteolytic removal of the cap by PDAC-expressed proteases. We demonstrated the feasibility of protease-mediated targeted drug delivery in PDAC through the release of paclitaxel, resulting in cytotoxicity in cultured PDAC cells. Pancreatic ductal adenocarcinoma (PDAC) has the worst survival rate of all cancers. This poor prognosis results from the lack of efficient systemic treatment regimens, demanding high-dose chemotherapy that causes severe side effects. To overcome dose-dependent toxicities, we explored the efficacy of targeted drug delivery using a protease-dependent drug-release system. To this end, we developed a PDAC-specific drug delivery system based on mesoporous silica nanoparticles (MSN) functionalized with an avidin-biotin gatekeeper system containing a protease linker that is specifically cleaved by tumor cells. Bioinformatic analysis identified ADAM9 as a PDAC-enriched protease, and PDAC cell-derived conditioned medium efficiently cleaved protease linkers containing ADAM9 substrates. Cleavage was PDAC specific as conditioned medium from leukocytes was unable to cleave the ADAM9 substrate. Protease linker-functionalized MSNs were efficiently capped with avidin, and cap removal was confirmed to occur in the presence of PDAC cell-derived ADAM9. Subsequent treatment of PDAC cells in vitro with paclitaxel-loaded MSNs indeed showed high cytotoxicity, whereas no cell death was observed in white blood cell-derived cell lines, confirming efficacy of the nanoparticle-mediated drug delivery system. Taken together, this research introduces a novel ADAM9-responsive, protease-dependent, drug delivery system for PDAC as a promising tool to reduce the cytotoxicity of systemic chemotherapy.