Mechanistic study of the covalent loading of paclitaxel via disulfide linkers for controlled drug release.

A novel controlled drug-delivery system (CDDS) based on fluorescent mesoporous silica nanoparticles (FMSN) covalently linked with paclitaxel (PTX) via a disulfide linker was designed and characterized. A PTX prodrug based on a disulfide linker was synthesized, and its drug-delivery mechanism was determined through HPLC characterization. Utilizing the carboxyl group of the prodrug, PTX was covalently conjugated to the surface of amino-functionalized FMSN, with a disulfide linker as a spacer to bridge between PTX and FMSN, and the loading content of PTX reached as high as 13% by weight. The most important feature of this nanoscale CDDS is that the PTX prodrug modules conjugated with FMSN can be activated to its cytotoxic form inside the tumor cells upon internalization and in situ drug release. To prove the efficacy of this CDDS, glutathione-mediated intracellular drug delivery was investigated against the HeLa cell line, and the results indicated that our CDDS showed higher cellular proliferation inhibition against glutathione monoester pretreated cells than against untreated cells and the cytotoxicity increased with increasing intracellular glutathione concentration. The result indicates that CDDS can release PTX molecules to kill cancer cells and the release behavior is GSH-dependent. Furthermore, the in vitro evaluation revealed that the FMSN-PTX conjugate could be effectively taken up by HeLa cells. All of these results suggest that this redox-responsive CDDS is potentially useful as a drug-delivery system that can reduce the toxic and side effects of anticancer drugs.