cRGD-modified nanoparticles of multi-bioactive agent conjugate with pH-sensitive linkers and PD-L1 antagonist for integrative collaborative treatment of breast cancer
Chenming Zou, Yuepeng Tang, Ping Zeng, Derong Cui, Majdi Al Amili, Ya Fang Chang, Jin Zhu, Yuanyuan Shen, Songwei Tan, Shengrong Guo
Abstract
Targeted co-delivery and co-release of multi-drugs is essential to have an integrative collaborative effect on treating cancer. It is valuable to use few drug carriers for multi-drug delivery. Herein, we develop cRGD-modified nanoparticles (cRGD-TDA) of a conjugate of doxorubicin as cytotoxic agent, adjudin as an anti-metastasis agent and D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) as a reactive oxygen species inducer linked with pH-sensitive bonds, and then combine the nanoparticles with PD-L1 antagonist to treat 4T1 triple-negative breast cancer. cRGD-TDA NPs present tumor-targeted co-delivery and pH-sensitive co-release of triple agents. cRGD-TDA NPs combined with PD-L1 antagonist much more significantly inhibit tumor growth and metastasis than single-drug treatment, which is due to their integrative collaborative effect. It is found that TPGS elicits a powerful immunogenic cell death effect. Meanwhile, PD-L1 antagonist mitigates the immunosuppressive environment and has a synergistic effect with the cRGD-TDA NPs. The study provides a new strategy to treat refractory cancer integratively and collaboratively.