PCL-PEtOx-based Crystalline-core Micelles for the Targeted Delivery of Paclitaxel and Trabectedin in Ovarian Cancer Therapy.

Ovarian cancer (OC), which primarily metastasizes through ascites, is both invasive and fatal. Despite its toxicity and drug resistance, the platinum-based chemotherapy Taxol®+Carboplatin has been the first-line standard treatment for decades. Trabectedin (TBD) is a recently developed, highly effective antitumor drug that is also capable of regulating tumor-associated macrophages (TAMs), however, its severe side-effects hinder further clinical application. Here, we developed safe and efficient pH-responsive crystalline-core micelles for the combined treatment of OCs, exploiting parallel delivery of paclitaxel (PTX) and TBD. PCL-PEtOx-COOH was selected as the optimal carrier to encapsulate PTX or TBD, which self-assemble into micelles with internal crystalline cores. The carboxyl group exposed on the surface of the micelles was utilized to react with the amines of Herceptin and hyaluronic acid cross-linked polymer (Herceptin-HA) to form PTX(Target). Similarly, TBD(Target) was formed by reaction with the CD206-targeted peptide mUNO. The low critical micelle concentrations of PTX(Target) and TBD(Target) stabilize the micelles in the bloodstream and normal tissues to prevent drug release. In an acidic microenvironment, the tertiary amide group on PEtOx chain of micelles ionizes, causing disassembly and pH-responsive release. Compared with Taxol®+Carboplatin, the combination therapy displayed dramatically improved safety and efficacy, as evidenced by the elimination of peritoneal tumor spheroids and reduced expression of NOX4, a gene that is overexpressed in most OC tissues. Furthermore, in human tissues, the ROS-response gene NOX4 is linked to the development of M2-type TAMs. Collectively, this study provides a safe and effective non-platinum-based chemotherapy for OC, offering an alternative to traditional Taxol®+Carboplatin. STATEMENT OF SIGNIFICANCE: (1) Significance: This work reports a new approach for ovarian cancer (OC) treatment. We utilized trabectedin (TBD) which a recently developed, highly effective antitumor drug that is also capable of regulating tumor associated macrophages (TAMs) combined with paclitaxel (PTX) to replace platinum-based chemotherapy Taxol®+Carboplatin (TC regimen). Compared to the clinical formulations, Yondelis® and Taxol®, pH-responsive PCL-PEtOx-based crystalline-core micelles were utilized for targeted independent delivery of TBD and PTX to TAMs and tumor cells, which maintained safe and efficient transport, overcoming the challenges posed by TAMs and carboplatin resistance. The system capabilities have also been confirmed in organoid and PDX models. (2) This is the first report demonstrating that this approach simultaneously overcomes the abdominal metastasis and carboplatin resistance of OC.