| A new type of functional nanomaterials---polymer micelles with cross-linked ionic cores---was synthesized and evaluated their utility as tumor-directed carriers for delivery of doxorubicin (DOX). Though DOX has potent anti-cancer activity, severe side effects such as cardiotoxicity as well as development of drug resistance in many types of tumors are severe impediments to successful cancer chemotherapy. Therefore, it was hypothesized that incorporating DOX into cross-linked micelles could create an efficient nanomedicine with superior properties such as prolonged blood circulation and higher tumor accumulation thereby improving its therapeutic efficacy.;Nano-sized, cross-linked micelles with ionic cores were synthesized via a two step procedure that involves condensation of poly(ethylene oxide)- b-polycarboxylate anions by Ca2+ ions into core-shell block ionomer complex micelles followed by chemical cross-linking of the polyion chains in the micelle cores. The resulting materials represent nanogels and are capable of swelling in a pH-dependent manner.;DOX was successfully incorporated into ionic cores of cross-linked micelles via electrostatic interactions with high loading capacity of ca 50 % (w/w). The DOX-loaded polymer micelles exhibited noticeable pH-sensitive behavior with accelerated release of DOX in acidic environment due to the protonation of carboxylic groups in the cores of the micelles. The composition of the cross-linked micelles could be easily tuned to modulate drug loading efficiency and drug release properties. Such micelles have restricted entry in normal epithelial cells (MDCK) due to the presence of tight junctions, but enter selectively to cancer cells, which is very important to minimize the toxicity to cancer chemotherapy. Introduction of the biodegradable disulfide bonds in ionic cores potentiated the release and in vitro cytotoxic activity of incorporated DOX under intracellular redox conditions. Notably, administration of DOX-loaded micelles induced tumor growth inhibition compared to free DOX in mice bearing subcutaneous A2780 human ovarian carcinoma tumors.;In conclusion, these results suggest that the polymer micelles with cross-linked ionic cores can offer an effective platform for cancer chemotherapy with doxorubicin. |
