A Trisulfide Bond Containing Biodegradable Polymer Delivering Pt(IV) Prodrugs to Deplete Glutathione and Donate H<sub>2</sub>S to Boost Chemotherapy and Antitumor Immunity.
basic_science · Level V
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- Record sourced from PubMed, PMID 38437513.
- Also identified by DOI 10.1021/acsnano.3c06194.
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Abstract
The clinical application of cisplatin (CisPt) is limited by its dose-dependent toxicity. To overcome this, we developed reduction-responsive nanoparticles (NP(3S)s) for the targeted delivery of a platinum(IV) (Pt(IV)) prodrug to improve efficacy and reduce the toxicity. NP(3S)s could release Pt(II) and hydrogen sulfide (H<sub>2</sub>S) upon encountering intracellular glutathione, leading to potent anticancer effects. Notably, NP(3S)s induced DNA damage and activated the STING pathway, which is a known promoter for T cell activation. Comparative RNA profiling revealed that NP(3S)s outperformed CisPt in enhancing T cell immunity, antitumor immunity, and oxidative stress pathways. <i>In vivo</i> experiments showed that NP(3S)s accumulated in tumors, promoting CD8<sup>+</sup> T cell infiltration and boosting antitumor immunity. Furthermore, NP(3S)s exhibited robust <i>in vivo</i> anticancer efficacy while minimizing the CisPt-induced liver toxicity. Overall, the results indicate NP(3S)s hold great promise for clinical translation due to their low toxicity profile and potent anticancer activity.
Medical subject headings
- Prodrugs
- Antineoplastic Agents