Combination of an autophagy inhibitor with immunoadjuvants and an anti-PD-L1 antibody in multifunctional nanoparticles for enhanced breast cancer immunotherapy

作者：Yibin Cheng, Caixia Wang, Huihui Wang, Zhiwei Zhang, Xiaopeng Yang, Yanming Dong, Lixin Ma, Jingwen Luo · 发表于：BMC Medicine · 年份：2022 · DOI：10.1186/s12916-022-02614-8 · 被引用次数：43 · 研究领域：Nanoplatforms for cancer theranostics、Autophagy in Disease and Therapy、Nanoparticle-Based Drug Delivery

BACKGROUND: The application of combination therapy for cancer treatment is limited due to poor tumor-specific drug delivery and the abscopal effect. METHODS: Here, PD-L1- and CD44-responsive multifunctional nanoparticles were developed using a polymer complex of polyethyleneimine and oleic acid (PEI-OA) and loaded with two chemotherapeutic drugs (paclitaxel and chloroquine), an antigen (ovalbumin), an immunopotentiator (CpG), and an immune checkpoint inhibitor (anti-PD-L1 antibody). RESULTS: PEI-OA greatly improved the drug loading capacity and encapsulation efficiency of the nanoplatform, while the anti-PD-L1 antibody significantly increased its cellular uptake compared to other treatment formulations. Pharmacodynamic experiments confirmed that the anti-PD-L1 antibody can strongly inhibit primary breast cancer and increase levels of CD4+ and CD8+ T cell at the tumor site. In addition, chloroquine reversed the "immune-cold" environment and improved the anti-tumor effect of both chemotherapeutics and immune checkpoint inhibitors, while it induced strong immune memory and prevented lung metastasis. CONCLUSIONS: Our strategy serves as a promising approach to the rational design of nanodelivery systems for simultaneous active targeting, autophagy inhibition, and chemotherapy that can be combined with immune-checkpoint inhibitors for enhanced breast cancer treatment.