Paclitaxel derivative-based liposomal nanoplatform for potentiated chemo-immunotherapy

The combination of chemotherapy with the immune checkpoint blockade (ICB) therapy is bringing a tremendous hope in the treatment of malignant tumors. However, the treatment efficacy of the existing chemoimmunotherapy is not satisfactory due to the high cost and immunogenicity of ICB antibodies, low response rate to ICB, off-target toxicity of therapeutic agents, and low drug co-delivery efficacy. Therefore, a high-efficient nanosystem combining the delivery of chemotherapeutics with small molecule ICB inhibitors may be promising for an efficient cancer therapy. Herein, a novel reactive oxygen species (ROS)-activated liposome nanoplatform was constructed by the loading of a ROS-sensitive paclitaxel derivative (PSN) into liposomes to overcome the difficulties on delivering paclitaxel mostly represented by premature drug release and a low amount accumulated into the tumor. The innovative liposomal nanosystem was rationally designed by a remote loading of BMS-202 (a small molecule PD-1/PD-L1 inhibitor) and PSN into the liposomes for a ROS-sensitive paclitaxel release and sustained BMS-202 release. The co-loaded liposomes resulted in a high co-loading ability and improved pharmacokinetic properties. An orthotopic 4 T1 breast cancer model was used to evaluate the efficiency of our nanoplatform in vivo, resulting in a superior antitumor activity. The antitumor immunity was activated by paclitaxel-mediated immunogenic cell death, while BMS-202 continuously blocked PD-L1 which could be upregulated by paclitaxel in tumors to increase the response to ICB and further recover the host immune surveillance. These results revealed that this dual-delivery liposome might provide a promising strategy for a highefficient chemo-immunotherapy, exhibiting a great potential for clinical translation.

Automated summary

The combination of chemotherapy with immune checkpoint blockade therapy holds great promise for the treatment of malignant tumors, but current chemoimmunotherapy faces challenges such as high cost, low response rate, and off-target toxicity. Developing a high-efficient nanosystem that combines chemotherapeutics with small molecule ICB inhibitors could be a promising approach. By constructing a ROS-activated liposome nanoplatform, co-loading ROS-sensitive paclitaxel derivative and small molecule PD-1/PD-L1 inhibitor, this study demonstrated improved pharmacokinetic properties and superior antitumor activity in an orthotopic breast cancer model. The dual-delivery liposome system showed potential for high-efficient chemo-immunotherapy and clinical translation.