47P - An ozone delivery system by cisplatin prodrug self-assembling micelles combining microwave to sensitizing immune checkpoint inhibitor in triple-negative breast cancer

Background

Immunotherapy based on T cells has gained great success and is now in its infancy. Despite a high mutation load, triple-negative breast cancer (TNBC) remains a poor response to the immune checkpoint blockades (ICBs) due to an infertile tumor microenvironment (TME). Chemotherapy shows an outstanding synergizing effect with ICB in TNBC due to its cell lysis effect. However, limited bioavailability, significant systematic toxicity, and immunosuppressive metastatic niche induced by chemotherapy restrict its systematic application.

Methods

We constructed self-assembled micelles consisting of fluorocarbon chain-modified cisplatin prodrugs, which loaded ozone-saturated perfluorodecalin (PFD) emulsion as a cargo. Cisplatin is controllably released from the prodrug by ROS triggered by the microwave excitation of ozone. The appearance of the ozone carried prodrug was visualized by Transmission electron microscope and the hydrodynamic sizes and stability were measured with nanoparticle tracking analysis. Cell function experiments were performed to assess the biological effect of the ozone-delivery prodrug in vitro. The biodistribution and biological effect of the ozone-loaded prodrug were also verified in 4T1 tumor-bearing mice model.

Results

The hydrodynamic sizes were about 130.5 nm of PtF and 174.7 nm of PFD@PtF, and both of the two showed good stability in weak acidic (pH = 6.0), neutral (pH = 7.0), and weak alkaline (pH = 8.0) environment at 4°C, room temperature, and 37°C. Ozone was well stabilized by the PFD@PtF as the ROS donor which in turn boosts the intracellular GSH concentration, and decomposed rapidly upon the excitation of microwave. Once endocytosed by TNBC cells, Pt(IV) can be reduced and released from the prodrug upon the triggering of reducing substance (e.g. GSH). The released cisplatin crosses cell membranes to form cross-links with DNA, resulting in cell cycle arrest, apoptosis, and immunogenic cell death. A significant inhibiting effect of tumor proliferation and TME reediting effect were observed in mice model.

Conclusions

We successfully constructed an ozone-delivery cisplatin prodrug with enhanced anti-tumor activity and attenuated toxicity.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.