Precisely Assembled Nanoparticles against Cisplatin Resistance via Cancer-Specific Targeting of Mitochondria and Imaging-Guided Chemo-Photothermal Therapy
Autor: | Gang-Gang Yang, Dong-Yang Zhang, Zong-Wan Mao, Zheng-Yin Pan, Liang-Nian Ji, Qian Cao |
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Rok vydání: | 2020 |
Předmět: |
Materials science
Photothermal Therapy Surface Properties DNA repair Mice Nude Antineoplastic Agents Apoptosis 02 engineering and technology Mitochondrion 010402 general chemistry DNA Mitochondrial 01 natural sciences Mice In vivo medicine Animals Humans Prodrugs General Materials Science Particle Size Cisplatin Mice Inbred BALB C Molecular Structure Neoplasms Experimental Photothermal therapy Prodrug 021001 nanoscience & nanotechnology Mitochondria 0104 chemical sciences A549 Cells Drug Resistance Neoplasm Cancer cell Cancer research Nanoparticles Female 0210 nano-technology medicine.drug Nucleotide excision repair |
Zdroj: | ACS Applied Materials & Interfaces. 12:43444-43455 |
ISSN: | 1944-8252 1944-8244 |
Popis: | Cisplatin resistance in tumor cells is known mainly due to the reduced accumulation of platinum ions by efflux, detoxification by intracellular GSH, and nucleotide excision repair machinery-mediated nuclear DNA repair. In this work, theranostic Pt(IV)-NPs, which are precisely self-assembled by biotin-labeled Pt(IV) prodrug derivative and cyclodextrin-functionalized IR780 in a 1:1 molecular ratio, have been developed for addressing all these hurdles via mitochondria-targeted chemotherapy solely or chemophotothermal therapy. In these nanoparticles, IR780 as a small-molecule dye acts as a mitochondria-targeting ligand to make Pt(IV)-NPs relocate finally in the mitochondria and release cisplatin. As demonstrated by in vitro and in vivo experiments, Pt(IV)-NPs can markedly facilitate cancer-specific mitochondrial targeting, inducing mitochondrial dysfunction and mitochondrial DNA (mtDNA) damage, thus greatly increasing the Pt accumulation, reducing the GSH levels, and avoiding DNA repair machinery in cisplatin-resistant cancer cells (A549R), finally resulting in significant inhibition of A549R tumor growth on animal models by chemotherapy solely. Upon near-infrared irradiation, mitochondria-targeted chemophotothermal synergistic therapy can be realized, further overcoming cisplatin resistance and even eliminating A549R tumors completely. Moreover, such novel Pt(IV)-NPs integrate multimodal targeting (cancer and mitochondria targeting), imaging (near-infrared imaging and photoacoustic imaging), and therapeutic (chemo- and photothermal therapy) moieties in a constant ratio (1:1:1) into a single, reproducible, and structurally homogeneous entity, avoiding nonuniform drug loading and premature leakage as well as the discrete steps of imaging and therapy, which thus is more beneficial for precise therapeutics and future clinical translation. |
Databáze: | OpenAIRE |
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