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 strainpromoted 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 cisplatinbased therapy.click chemistry | brain cancer | OXPHOS | pharmacokinetics T he cellular powerhouse, mitochondria, are implicated in the process of carcinogenesis because of their vital roles in energy production and apoptosis. Mitochondria are the key players in generating the cellular energy through oxidative phosphorylation (OXPHOS) that produces reactive oxygen species (ROS) as by-products. Mitochondrial DNA (mtDNA) plays significant roles in cell death and metastatic competence. The close proximity of mtDNA to the ROS production site makes this genome vulnerable to oxidative damage. Mitochondrial dysfunction and associated mtDNA depletion possibly reversibly control epigenetic changes in the nucleus that contributes to cancer development (1). Thus, targeting mtDNA could lead to novel and effective therapies for aggressive cancers. Cisplatin, a Food and Drug Administration-approved chemotherapeutic agent, is most extensively characterized as a DNA-damaging agent and the cytotoxicity of cisplatin is attributed to the ability to form interstrand and intrastrand nuclear DNA (nDNA) cross-links (2). The nucleotide excision repair (NER) pathway plays major roles in repairing cisplatin-nDNA adducts (3). Resistance to cisplatin can result fr...

Targeting mitochondria metabolism for cancer therapy

“…5). Commonly used chemotherapeutic agents such as cisplatin can be targeted to the mitochondrial matrix by conjugation to lipophilic cations to target mitochondrial DNA 101 . The third challenge is to understand more about the basic biology of mitochondrial metabolism in regulating tumorigenesis.…”

Nanotechnology inspired tools for mitochondrial dysfunction related diseases

“…Upon self-assembly, amphiphilic block copolymer composed of PLGA forms a core and PEG as a corona with mitochondria targeting TPP on the surface (21, 27, 42, 87). The TPP moieties on the surface of the NPs provide cumulative positive charge delocalized over a large hydrophobic phenyl rings making these NPs ideal system for penetration in the lipid membranes.…”

“…After successful demonstration of mitochondria directed delivery of the above mentioned therapeutics, recently we used these biocompatible polymeric NPs to deliver a cisplatin prodrug to the mitochondria to access mtDNA which lack NER machinery (42). Directing DNA damaging agents such as cisplatin to the mitochondria can potentially address the problems associated with conventional platinum-based compounds (88, 89).…”

Repurposing platinum-based chemotherapies for multi-modal treatment of glioblastoma

“…This targeted NP formulation exhibited reduced toxicity and prolonged the survival of glioma-bearing rats. 65 Furthermore, a mitochondrial-targeted NP loaded with the cisplatin prodrug, Platin-M, successfully delivered the drug to neuroblastoma cells 66 and has shown very little neurotoxicity in animal models despite a high level of drug accumulation in the brain. 67 Another intriguing glioma cell-specific target is the cell surface receptor fibroblast growth factor-inducible 14 (Fn14).…”