Abstract
Recently, combining immunotherapy and chemotherapy has become a promising strategy to treat cancer. However, this therapeutic strategy still has its limitations because of the adverse effects caused by the simultaneous administration of multiple therapeutic agents. Using nanoparticles is an effective approach to successfully combine these therapies because they can reduce side effects, increase circulation time, and ensure the delivery of cytotoxic agents to tumor tissues. In this study, dual pH-sensitive and tumor microenvironment (TME)-active targeting micelles comprising poly(propyl methacrylate-co-glucosamine/histidine/doxorubicin) (P(PAA-co-GLU/HIS/DOX) and methoxy-poly(ethylene glycol)-block-poly(l-lysine) were prepared to encapsulate an immunomodulator, imiquimod (IMQ). Because these micelles can expose glucose targeting ligands at the TME and pH-dependently release IMQ and DOX, micelles effectively inhibit the growth of 4T1 cells selectively and highly accumulate in 4T1 cells as the pH decreased to 6.5. Moreover, in RAW 264.7 cells, these micelles prevent cell death and induce M1 macrophage polarization. In 4T1 orthotopic tumor-bearing mice, micelles not only exhibited high tumor accumulation, effective tumor inhibition, and fewer adverse effects, but also dramatically increased the number of mature dendritic cells, activate cytotoxic T cells, and polarize M1-like macrophages in tumor tissues. Overall, these micelles exhibit precise pH responsiveness and ideal drug delivery capabilities for combined chemo- and immunotherapy; these results significantly contribute to the future development of nanomedicines in cancer therapy.