Unraveling Mechanism and Enhancing Selectivity of a Ru-bis-bipyridyl-morphocumin Complex with RAFT-Generated Glycopolymer Exploiting Warburg Effect in Cancer.

The Warburg effect, which generates increased demand of glucose in cancer cells is a relatively underexplored phenomenon in existing commercial drugs to enhance uptake in cancer cells. Here, we present a chemotherapeutic strategy employing a Ru(II)-bis-bipyridyl-morphocumin complex (2) encapsulated in a self-assembling glucose-functionalized copolymer P(G-EMA-co-MMA) (where G=glucose; MMA=methyl methacrylate; EMA=ethyl methacrylate), designed to exploit this effect for enhanced selectivity in cancer treatment. The P(G-EMA-co-MMA) polymer, synthesized via reversible-addition fragmentation chain transfer (RAFT) polymerization, has a number average molecular weight (M) of 8000 g/mol. Complex 2, stable in aqueous media, selectively releases a cytotoxic, lysosome-targeting compound, morphocumin, in the presence of excess hydrogen peroxide (H₂O₂), a reactive oxygen species (ROS) prevalent in tumor microenvironments. Additionally, complex 2 promotes ROS accumulation, which may further enhance morphocumin release through a synergistic domino effect. Comparative studies reveal that 2 outperforms its curcumin Ru(II) complex (1) analog in solution stability, organelle specificity, and cellular mechanisms. Both 1 and 2 exhibit phototherapeutic effects under low-intensity visible light, but their chemotoxicity significantly increases with incubation time in the dark, highlighting the superior chemotherapeutic efficacy of the O,O-coordinating Ru(II) ternary polypyridyl complexes. Complex 2 induces apoptosis via the intrinsic pathway and shows a 9-fold increase in selectivity for pancreatic cancer cells (MIA PaCa-2) over non-cancerous HEK293 cells when encapsulated in the glucose-conjugated polymer (DP@2). Glucose deprivation in the culture medium further enhances drug efficacy by an additional 5-fold. This work underscores the potential of glucose-functionalized polymers and ROS-responsive Ru(II) complexes in targeted cancer therapy.