Sustained Codelivery of Cisplatin and Paclitaxel via an Injectable Prodrug Hydrogel for Ovarian Cancer Treatment.

The sustained release of both the hydrophilic drug and hydrophobic drug from one delivery system remains challenging in pharmaceutics and biomaterials science. The combination of hydrophilic cisplatin and hydrophobic paclitaxel (PTX) exhibits a clinical survival advantage compared with the individual drug therapy against various tumors such as ovarian cancer. In this study, a localized, long-term codelivery system of cisplatin and PTX was developed using an injectable and thermosensitive polymer-platinum(IV) conjugate hydrogel as the carrier. The thermosensitive Bi(mPEG-PLGA)-Pt(IV) (PtGel) conjugate was synthesized via covalently linking two mPEG-PLGA copolymers onto a Pt(IV) prodrug, and its concentrated aqueous solution exhibited a reversible sol-gel transition upon heating. Meanwhile, the core-corona micelles formed by the amphiphilic conjugates in water could serve as a reservoir for the solubilization of PTX, and thus an injectable binary drug-loaded hydrogel formulation was obtained. We also found that the introduction of PTX into the conjugate hydrogel decreased its sol-gel transition temperature and improved its gel strength. In vitro release experiments showed that both of the loaded drugs were released in a sustained manner for as long as 2.5 months, which was the longest combination delivery of these two drugs ever reported. In vitro cellular assays revealed that the dual-drug system exhibited a synergistic anticancer effect against ovarian cancer cells. Finally, using the SKOV-3 ovarian cancer xenograft mouse model, we demonstrated that a single injection of the PTX-loaded conjugate hydrogel system resulted in enhanced anticancer efficacy and significantly reduced the side effects, when compared with the multiple injections of the free drug combination.