Extracellular barrier via in situ cross-linked catechol for blocking tumor mass transport and synergistic chemotherapy

Abstract

Due to the heightened nutritional consumption resulting from aberrant metabolism of tumor cells, starvation therapy, which involves blocking or depleting key nutrients in tumors, has gained popularity as an attractive approach to treating cancer. Herein, the catechol-containing polymer, P(DMA-co-MAA)-BTZ, was successfully synthesized via the copolymerizing dopamine methacrylamide (DMA) with polymethacrylic acid (MAA), followed by grafted with chemotherapy drug bortezomib (BTZ). The P(DMA-co-MAA)-BTZ exhibited pH-responsive behavior in the acidic tumor microenvironment, facilitating controlled release of BTZ for chemotherapy. Additionally, the liberated phenolic groups could form a membranal coating on the surface of tumor cells in response to overexpressed H₂O₂, thereby impeding the uptake of external nutrients and enabling starvation therapy. The efficacy of P(DMA-co-MAA)-BTZ in inhibiting glucose uptake by tumor cells has been demonstrated through both in vitro and in vivo experiments, resulting in a reduction of intracellular lactate, GSH, and ATP synthesis as well as the accumulation of reactive oxygen species as metabolic waste. This synergistic strategy of combining starvation therapy with chemotherapy yielded efficient anti-tumor effects while suppressing tumor metastasis and invasion, presenting a promising alternative approach for clinical tumor treatment.