Detouring of cisplatin to access mitochondrial genome for overcoming resistance
| Autor: | Rakesh K. Pathak, Sean Marrache, Shanta Dhar |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Mitochondrial DNA Oxidative phosphorylation Mitochondrion Biology Bioinformatics Neuroblastoma chemistry.chemical_compound Polylactic Acid-Polyglycolic Acid Copolymer Cell Line Tumor medicine Animals Prodrugs Tissue Distribution Lactic Acid Cisplatin Multidisciplinary Brain Prodrug Mitochondria Rats chemistry Drug Resistance Neoplasm Organ Specificity Mitochondrial matrix Genome Mitochondrial Physical Sciences Cancer research Nanoparticles Energy Metabolism Polyglycolic Acid DNA medicine.drug Nucleotide excision repair |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:10444-10449 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Chemoresistance of cisplatin therapy is related to extensive repair of cisplatin-modified DNA in the nucleus by the nucleotide excision repair (NER). Delivering cisplatin to the mitochondria to attack mitochondrial genome lacking NER machinery can lead to a rationally designed therapy for metastatic, chemoresistant cancers and might overcome the problems associated with conventional cisplatin treatment. An engineered hydrophobic mitochondria-targeted cisplatin prodrug, Platin-M, was constructed using a strain-promoted alkyne–azide cycloaddition chemistry. Efficient delivery of Platin-M using a biocompatible polymeric nanoparticle (NP) based on biodegradable poly(lactic- co -glycolic acid)-block-polyethyleneglycol functionalized with a terminal triphenylphosphonium cation, which has remarkable activity to target mitochondria of cells, resulted in controlled release of cisplatin from Platin-M locally inside the mitochondrial matrix to attack mtDNA and exhibited otherwise-resistant advanced cancer sensitive to cisplatin-based chemotherapy. Identification of an optimized targeted-NP formulation with brain-penetrating properties allowed for delivery of Platin-M inside the mitochondria of neuroblastoma cells resulting in ∼17 times more activity than cisplatin. The remarkable activity of Platin-M and its targeted-NP in cisplatin-resistant cells was correlated with the hyperpolarization of mitochondria in these cells and mitochondrial bioenergetics studies in the resistance cells further supported this hypothesis. This unique dual-targeting approach to controlled mitochondrial delivery of cisplatin in the form of a prodrug to attack the mitochondrial genome lacking NER machinery and in vivo distribution of the delivery vehicle in the brain suggested previously undescribed routes for cisplatin-based therapy. |
| Databáze: | OpenAIRE |
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