Oxygen self-supplied enzyme nanogels for tumor targeting with amplified synergistic starvation and photodynamic therapy

Abstract

Tumor tissues need vast supply of nutrients and energy to sustain the rapid proliferation of cancer cells. Cutting off the glucose supply represents a promising cancer therapy approach. Herein, a tumor tissue-targeted enzyme nanogel (rGCP nanogel) with self-supply oxygen capability was developed. The enzyme nanogel synergistically enhanced starvation therapy and photodynamic therapy (PDT) to mitigate the rapid proliferation of cancer cells. The rGCP nanogel was fabricated by copolymerizing two monomers, porphyrin and cancer cells-targeted, Arg-Gly-Asp (RGD), onto the glucose oxidase (GOX) and catalase (CAT) surfaces. The cascade reaction within the rGCP nanogel could efficiently consume intracellular glucose catalyzed by GOX. Concurrently, CAT safely decomposed the produced H₂O₂ with systemic toxicity to promote oxygen generation and achieved low toxicity starvation therapy. The produced oxygen subsequently facilitated the glucose oxidation reaction and significantly enhanced the generation of cytotoxic singlet oxygen (¹O₂) in the presence of 660 nm light irradiation. Combining starvation therapy and PDT, the designed enzyme nanogel system presented an amplified synergic cancer therapy effect. This approach potentially paved a new way to fabricate a combinatorial therapy approach by employing cascaded catalytic nanomedicines with good tumor selectivity and efficient anti-cancer effect. STATEMENT OF SIGNIFICANCE: The performance of starvation and photodynamic therapy (PDT) is usually suppressed by intrinsic tumorous hypoxia. Herein, an oxygen self-supplied and tumor tissue-targeted enzyme nanogel was created by copolymerization of two monomers, porphyrin and cancer cell-targeted Arg-Gly-Asp (RGD), onto the surface of glucose oxidase (GOX) and catalase (CAT), which synergistically enhanced starvation therapy and PDT. Moreover, the enzyme nanogels possessed high stability and could be synthesized straightforwardly. This anti-cancer system provides an approach for constructing a combinatorial therapy approach by employing cascaded catalytic nanomedicine with good tumor selectivity and therapeutic efficacy.

Keywords: Anti-cancer; Enzyme nanogels; Oxygen self-production; Photodynamic therapy; Polymerization; Starvation therapy.