Peptide-Guided System with Programmable Subcellular Translocation for Targeted Therapy and Bypassing Multidrug Resistance.
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| Abstract |
Nonselectivity and drug resistance are two major obstacles for cancer treatment. Although great advances have been made toward cell targeting or discovering novel delivery pathways, it is still desirable to simultaneously overcome the two hurdles for successful cancer theranostics. Herein, a peptide-guided system was tailored by modular integration of a cancer biomarker-specific peptide, a mitochondria-targeting motif and a cell toxin. Cell imaging analysis revealed that the dual-targeting peptide-drug conjugate (PDC) features in cancer cell-specific uptake, strong drug retention, and programmable intracellular translocation. Facilitated by in situ bond cleavage, PDC successfully diverted the toxic effect of nucleus-localized drug to mitochondria. Mechanism investigation demonstrated that the cell damage pathway of the drug was also transformed, which is beneficial to reverse drug resistance in cancer cells. The effectiveness of PDC for cancer therapy was further demonstrated by in vivo imaging and tumor inhibition assay. With intravenous injection, targeted accumulation in the tumor site, and tumor suppressing efficacy without side effects exhibit its perspective for cancer treatment. The dual-targeting peptide-drug conjugate featuring tailored transportation route highlights a promising and generally applicable way to enhance the overall therapeutic index of conventional anticancer drugs.
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| Authors | Yuanyuan Zhu, Yanyan Huang, Yulong Jin, Shilang Gui, Rui Zhao |
| Journal | Analytical chemistry (Anal Chem) Vol. 91 Issue 3 Pg. 1880-1886 (02 05 2019) ISSN: 1520-6882 [Electronic] United States |
| PMID | 30525475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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