title: Enhanced cytotoxicity to cancer cells by mitochondria-targeting MWCNTs containing platinum(IV) prodrug of cisplatin.
abstract: Among the arsenal of nano-materials, carbon nanotubes (CNTs) are becoming more prominent due to favorable attributes including their unique shape, which promotes cellular-uptake, and large aspect-ratio that facilitates functionalization of bioactive molecules on their surface. In this study, multi-walled carbon nanotubes (MWCNTs) were functionalized with either mitochondrial-targeting fluorescent rhodamine-110 (MWCNT-Rho) or non-targeting fluorescein (MWCNT-Fluo). Despite structural similarities, MWCNT-Rho associated well with mitochondria (ca. 80% co-localization) in contrast to MWCNT-Fluo, which was poorly localized (ca. 21% co-localization). Additionally, MWCNT-Rho entrapping platinum(IV) pro-drug of cisplatin (PtBz) displayed enhanced potency (IC50 = 0.34 ± 0.07 μM) compared to a construct based on MWCNT-Fluo (IC50 ≥ 2.64 μM). Concurrently, preliminary in vitro toxicity evaluation revealed that empty MWCNT-Rho neither decreased cell viability significantly nor interfered with mitochondrial membrane-potential, while seemingly being partially expelled from cells. Due to its targeting capability and apparent lack of cytotoxicity, MWCNT-Rho complex was used to co-encapsulate PtBz and a chemo-potentiator, 3-bromopyruvate (BP), and the resulting MWCNT-Rho(PtBz+BP) construct demonstrated superior efficacy over PtBz free drug in several cancer cell lines tested. Importantly, a 2-fold decrease in mitochondrial potential was observed, implying that mitochondrial targeting of compounds indeed incurred additional intended damage to mitochondria.
authors.affiliation: NUS Graduate School for Integrative Sciences and Engineering, Centre for Life Sciences (CeLS), Singapore 117456, Singapore.
authors.forename: Sia Lee
authors.initials: SL
authors.lastname: Yoong
authors.forename: Bin Sheng
authors.initials: BS
authors.lastname: Wong
authors.forename: Qi Ling
authors.initials: QL
authors.lastname: Zhou
authors.forename: Chee Fei
authors.initials: CF
authors.lastname: Chin
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Thirumalai
authors.initials: T
authors.lastname: Venkatesan
authors.forename: Han Kiat
authors.initials: HK
authors.lastname: Ho
authors.forename: Victor
authors.initials: V
authors.lastname: Yu
authors.forename: Wee Han
authors.initials: WH
authors.lastname: Ang
authors.forename: Giorgia
authors.initials: G
authors.lastname: Pastorin
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D016503:Drug Delivery Systems; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D037742:Nanotubes, Carbon / Q000737:chemistry*; D010984:Platinum / Q000737:chemistry*; D011355:Prodrugs / Q000494:pharmacology*; D011773:Pyruvates / Q000494:pharmacology; D012235:Rhodamines / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D037742:Nanotubes, Carbon; D011355:Prodrugs; D011773:Pyruvates; D012235:Rhodamines; C049025:rhodamine 110; D010984:Platinum; C017092:bromopyruvate; D002945:Cisplatin
keywords: 3-Bromopyruvate; Cisplatin; Mitochondria; Multi-walled carbon nanotubes; Platinum(IV) prodrug; Rhodamine