Polymer micelles with cross-linked ionic cores for delivery of platinum anticancer agents

Platinum complexes remain the mainstay of a number of chemotherapy strategies, however, there clinical use is associated with a number of limitations. Majority of patients treated with platinum drugs experience only partial anti-tumor response with numerous systemic toxicities severely limiting the patient quality of life. Carrier based delivery of platinum complexes represents an approach with the potential for improving platinum drug efficacy and reducing unwanted side-effects.;Polymer micelles derived from block ionomers complexes are one such class of macromolecular carriers, which offer several key benefits over other colloidal systems. We demonstrate that polymer micelles with cross-linked ionic cores can efficiently and reversibly incorporate platinum anticancer drugs cisplatin and DACH-platinum where core cross-linking prevents complex disassembly and provides stability against dilution. The platinum drug-loaded micelles exhibited distinct physicochemical, biochemical, and pharmacological characteristics. An increased drug bioavailability at the tumor target, improved antitumor activity and prolonged survival are shown in a mouse model of ovarian cancer treated with these formulations. Detailed toxicological evaluation in healthy mice additionally demonstrated a significantly reduced systemic toxicity with these formulations. The overall therapeutic performance of the polymer micelle-platinum drug delivery system was further improved by conjugating folic acid as the targeting ligand on the carrier surface. Folic acid conjugated micelles demonstrated specific interaction with folic acid receptor overexpressed on cancer cell surface and resulted in improved platinum drug performance in cell culture experiments and in mouse model of ovarian cancer.;Altogether, we show that polymer micelles with cross-linked ionic cores can enhance the potential of platinum therapy. As demonstrated using two different platinum complexes, the approach may also allow improved delivery of other platinum complexes having a similar geometry and coordination state of the central platinum and identical leaving groups. Altogether, this study demonstrates the fundamental possibility for targeted delivery of the platinum anticancer agents using core cross-linked polymer micelles and opens a new prospect for clinical development of such nanoformulations.