Cisplatin resistance reversal in lung cancer by tumor acidity-activable vesicular nanoreactorsviatumor oxidative stress amplification

Drug resistance of cisplatin significantly limits its therapeutic efficacy in clinical applications against different cancers. Herein, we develop a novel strategy to overcome cisplatin drug resistance through sensitizing cisplatin-resistant human lung cancer cells (A549R) under amplified oxidative stress using a vesicular nanoreactor for simultaneous cisplatin delivery and H2O2 generation. We engineer the nanoreactor by the self-assembly of the amphiphilic diblock copolymers to co-deliver glucose oxidase (GOD) and cisplatin (Cis) (Cis/GOD@Bz-V). Cis/GOD@Bz-V was rationally designed to stay impermeable during blood circulation while mild acidity (pH 6.5-6.8) can activate its molecular-weight selective membrane permeability and release cisplatin locally. Diffusion of small molecules such as oxygen and glucose across the membranes can induce the in situ generation of superfluous H2O2 to promote cellular oxidative stress and sensitize A549R cells via activation of pro-apoptotic pathways. Cis/GOD@Bz-V nanoreactors could effectively kill A549R at pH 6.8 in the presence of glucose by the combination of H2O2 generation and cisplatin release. Growth of A549R xenograft tumors can be inhibited efficiently without the obvious toxic side effects via the systemic administration of Cis/GOD@Bz-V. Accordingly, the tumor acidity-activable cisplatin-loaded nanoreactors show great potential to enhance the therapeutic efficacy against cisplatin-resistant cancers.