1. TME-Responsive Nanoplatform with Glutathione Depletion for Enhanced Tumor-Specific Mild Photothermal/Gene/Ferroptosis Synergistic Therapy.
- Author
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Tian Y, He X, Yuan Y, Zhang S, Wang C, Dong J, Liu Z, and Jing H
- Subjects
- Humans, Cell Line, Tumor, Female, Fluorocarbons chemistry, Fluorocarbons pharmacology, Tripartite Motif Proteins genetics, Tripartite Motif Proteins metabolism, Genetic Therapy methods, Combined Modality Therapy methods, Animals, Iron chemistry, Hyaluronoglucosaminidase genetics, Hyaluronoglucosaminidase metabolism, Ferroptosis drug effects, Glutathione metabolism, Glutathione chemistry, Tumor Microenvironment drug effects, Tannins chemistry, Tannins pharmacology, Nanoparticles chemistry, Hyaluronic Acid chemistry, Triple Negative Breast Neoplasms therapy, Triple Negative Breast Neoplasms genetics, RNA, Small Interfering chemistry, RNA, Small Interfering pharmacology, RNA, Small Interfering genetics, Photothermal Therapy methods
- Abstract
Background: Triple negative breast cancer (TNBC) is one of the worst prognosis types of breast cancer that urgently needs effective therapy methods. However, cancer is a complicated disease that usually requires multiple treatment modalities., Methods: A tumor microenvironment (TME)-responsive PFC/TRIM37@Fe-TA@HA (abbreviated as PTFTH) nanoplatform was constructed by coating Fe
3+ and tannic acid (TA) on the surface of TRIM37-siRNA loaded phase-transition perfluorocarbon (PFC) nanodroplets and further modifying them with hyaluronic acid (HA) to achieve tumor-specific mild photothermal/gene/ferroptosis synergistic therapy (MPTT/GT/ Ferroptosis) in vitro. Once internalized into tumor cells through CD44 receptor-mediated active targeting, the HA shell of PTFTH would be preliminarily disassembled by hyaluronidase (HAase) to expose the Fe-TA metal-phenolic networks (MPNs), which would further degrade in response to an acidic lysosomal environment, leading to HAase/pH dual-responsive release of Fe3+ and PFC/TRIM37., Results: PTFTH showed good biocompatibility in vitro. On the one hand, the released Fe3+ could deplete the overexpressed glutathione (GSH) through redox reactions and produce Fe2+ , which in turn converts endogenous H2 O2 into highly cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT). On the other hand, the local hyperthermia generated by PTFTH under 808 nm laser irradiation could not only improve CDT efficacy through accelerating the Fe2+ -mediated Fenton reaction, but also enhance TRIM37-siRNA delivery for gene therapy (GT). The consumption of GSH and accumulation of •OH synergistically augmented intracellular oxidative stress, resulting in substantial tumor cell ferroptosis. Moreover, PTFTH possessed outstanding contrast enhanced ultrasound (CEUS), photoacoustic imaging (PAI) and magnetic resonance imaging (MRI) ability., Conclusion: This PTFTH based multiple-mode therapeutic strategy has successfully achieved a synergistic anticancer effect in vitro and has the potential to be translated into clinical application for tumor therapy in future., Competing Interests: The authors declare that no competing interest exists in this work., (© 2024 Tian et al.)- Published
- 2024
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