Electrostatically driven supramolecular drug-carrier system for targeted, efficient, safer Cancer chemotherapy

This study successfully demonstrates a new concept of complementary electrostatic interactions between drugs and nanocarriers. Water-soluble modified chitosan (Na-CMC) has negatively charged carboxylate groups on its side chains and co-assembles with the positively charged anticancer agents rhodamine 6G (R6G) or doxorubicin (DOX). This concept represents a promising facile strategy for the development of efficient, multifunctional drug delivery systems to potentially enable safer, more effective chemotherapy. Due to electrostatic interactions, Na-CMC and R6G (or DOX) can form complexes in aqueous environments and subsequently co-assemble into nanogels. The resulting Na-CMC/R6G nanogels exhibit several excellent and unique physical properties, including high R6G-loading capacity, nearly uniform co-assembled morphology and size, stable intrinsic fluorescence, outstanding structural stability in biological media, sensitive acid-responsive behavior, and controllable pH-triggered drug release. Systematic cellular studies clearly confirmed that the Na-CMC/R6G nanogels were selectively internalized by HeLa cells via stable micropinocytosis and subsequently released R6G in the mildly acidic microenvironment, and thereby induced targeted apoptosis in cancer cells. In contrast, the Na-CMC/DOX nanogels self-aggregated and induced massive levels of necrotic cell death in both normal and cancer cells. Overall, this study clearly demonstrates that the combination of appropriate anticancer agents and stable electrostatic interactions in a bio-based drug delivery system can critically enhance selective internalization and induce programmed cancer cell death.