Abstract 47P
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.
Resources from the same session
14P - Peripheral immune kinetics in survival prediction of small cell lung cancer patients treated with immune checkpoint blockade therapy
Presenter: MIGUEL GALINDO CAMPOS
Session: Poster session 09
15P - CBL E3 ubiquitin ligases are key inhibitory regulators in PD-1/LAG-3 co-signaling in human cancers, targeted through bispecific co-blockade
Presenter: Luisa Chocarro
Session: Poster session 09
16P - Terminally exhausted CD8+ T cells and increased immunosuppressive soluble factors in malignant ascites of patients with gastric cancer with peritoneal metastasis
Presenter: Hye Sook Han
Session: Poster session 09
17P - Continued expansion of long-lived effect CD8+ T cells associates with durable response post-PD-1 blockade
Presenter: Robert Watson
Session: Poster session 09
18P - Exposure of calreticulin is required for vitamin C immunomediated cancer surveillance
Presenter: Alessandro Cavaliere
Session: Poster session 09
19P - Preclinical and clinical significance of VEGF deprivation in ovarian cancer through a specific active immunotherapy
Presenter: Yanelys Morera
Session: Poster session 09
20P - The essential role of DNA repair in the pharmacological activities of AST-3424
Presenter: Fanying Meng
Session: Poster session 09
21P - Implications of KMT2C knockdown for DNA damage repair in breast cancer
Presenter: Philip Bredin
Session: Poster session 09
22P - Clinical significance of DNA damage response mutations in early stage NSCLC
Presenter: Haoran Zhang
Session: Poster session 09
23P - PMC-309: A highly selective anti-VISTA antibody reverses immunosuppressive TME to immune-supportive
Presenter: Cheon Ho Park
Session: Poster session 09