title: Nanoparticle-Mediated Mitochondrial Damage Induces Apoptosis in Cancer.
abstract: Detouring of conventional DNA damaging anticancer drugs into mitochondria to damage mitochondrial DNA is evolving as a promising strategy in chemotherapy. Inhibiting single target in mitochondria would eventually lead to the emergence of drug resistance. Moreover, targeting mitochondria selectively in cancer cells, keeping them intact in healthy cells, remains a major challenge. Herein, triphenylphosphine (TPP)-coated positively charged 131.6 nm spherical nanoparticles (NPs) comprised of α-tocopheryl succinate (TOS, inhibitor of complex II in electron transport chain) and obatoclax (Obt, inhibitor of Bcl-2) were engineered. The TOS-TPP-Obt-NPs entered into acidic lysosomes via macropinocytosis, followed by lysosomal escape and finally homed into mitochondria over a period of 24 h. Subsequently, these TOS-TPP-Obt-NPs triggered mitochondrial outer membrane permeabilization (MOMP) by inhibiting antiapoptotic Bcl-2, leading to Cytochrome C release. These TOS-TPP-Obt-NPs mediated mitochondrial damage induced cellular apoptosis through caspase-9 and caspase-3 cleavage to show improved efficacy in HeLa cells. Moreover, TOS-TPP-Obt-NPs induced MOMP in drug-resistant triple negative breast cancer cells (MDA-MB-231), leading to remarkable efficacy, compared to the combination of free drugs in higher drug concentrations. Results presented here clearly stimulate the usage of multiple drugs to perturb simultaneously diverse targets, selectively in mitochondria, as next-generation cancer therapeutics.
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune , Pune, 411008, Maharashtra, India.
authors.forename: Abhik
authors.initials: A
authors.lastname: Mallick
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune , Pune, 411008, Maharashtra, India.
authors.forename: Piyush
authors.initials: P
authors.lastname: More
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune , Pune, 411008, Maharashtra, India.
authors.forename: Muhammed Muazzam Kamil
authors.initials: MM
authors.lastname: Syed
authors.affiliation: Department of Chemistry, Indian Institute of Science Education and Research (IISER)-Pune , Pune, 411008, Maharashtra, India.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D007211:Indoles; D008928:Mitochondria / Q000187:drug effects*; D053758:Nanoparticles / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D007211:Indoles; D009943:Organophosphorus Compounds; D011758:Pyrroles; C061896:triphenylphosphine; D024502:alpha-Tocopherol; C520962:obatoclax
keywords: cancer; mitochondria; nanoparticle; obatoclax; α-tocopheryl succinate