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Dual-targeting fluorous peptide proteolysis-targeting chimeras for cancer therapy.

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Journal of controlled release : official journal of the Controlled Release Society 📖 저널 OA 6.3% 2024: 1/7 OA 2025: 2/59 OA 2026: 7/91 OA 2024~2026 2026 Vol.391() p. 114591
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Rong G, Li Y, Zhu F, Lu Y, Sun Z, Hong J, Cheng Y

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Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for degrading disease-causing proteins.

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APA Rong G, Li Y, et al. (2026). Dual-targeting fluorous peptide proteolysis-targeting chimeras for cancer therapy.. Journal of controlled release : official journal of the Controlled Release Society, 391, 114591. https://doi.org/10.1016/j.jconrel.2025.114591
MLA Rong G, et al.. "Dual-targeting fluorous peptide proteolysis-targeting chimeras for cancer therapy.." Journal of controlled release : official journal of the Controlled Release Society, vol. 391, 2026, pp. 114591.
PMID 41478376 ↗

Abstract

Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for degrading disease-causing proteins. Simultaneous degradation of two oncogenic proteins by PROTACs can yield synergistic therapeutic effects. Here, we developed a dual-targeting fluorous peptide-based PROTAC (DFP-PROTAC) that leverages supramolecular self-assembly for cancer therapy. By conjugating PD-L1- and Bcl-xL-binding peptides to fluorous tags, we generated carrier-free nanoparticles that enter cells via macropinocytosis and achieve efficient endosomal escape, mediating simultaneous degradation of both extracellular PD-L1 and cytosolic Bcl-xL through the ubiquitin-proteasome system. Our results demonstrate that DFP-PROTAC coordinately restores antitumor immunity and apoptotic sensitivity while achieving superior antitumor efficacy with excellent biocompatibility in B16-F10 melanoma-bearing mice, highlighting its therapeutic potential for cancer treatment. This modular fluorous platform offers a versatile strategy for degrading multiple protein targets in the treatment of various diseases.

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