title: Detouring of cisplatin to access mitochondrial genome for overcoming resistance.
abstract: 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.
authors.affiliation: NanoTherapeutics Research Laboratory, Department of Chemistry, and.
authors.forename: Sean
authors.initials: S
authors.lastname: Marrache
authors.affiliation: NanoTherapeutics Research Laboratory, Department of Chemistry, and.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Pathak
authors.affiliation: NanoTherapeutics Research Laboratory, Department of Chemistry, andDepartment of Physiology and Pharmacology, University of Georgia, Athens, GA 30602 shanta@uga.edu.
authors.forename: Shanta
authors.initials: S
authors.lastname: Dhar
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D004734:Energy Metabolism / Q000187:drug effects; D054629:Genome, Mitochondrial / Q000235:genetics*; D019344:Lactic Acid / Q000737:chemistry; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D053758:Nanoparticles / Q000648:ultrastructure; D009447:Neuroblastoma / Q000188:drug therapy / Q000473:pathology; D009928:Organ Specificity / Q000187:drug effects; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D011355:Prodrugs; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D002945:Cisplatin
keywords: OXPHOS; brain cancer; click chemistry; pharmacokinetics