Design and cellular studies of a carbon nanotube-based delivery system for a hybrid platinum-acridine anticancer agent

• Published in: Journal of inorganic biochemistry Vol. 165; pp. 170 - 180
• Main Authors: Fahrenholtz, Cale D., Ding, Song, Bernish, Brian W., Wright, Mariah L., Zheng, Ye, Yang, Mu, Yao, Xiyuan, Donati, George L., Gross, Michael D., Bierbach, Ulrich, Singh, Ravi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2016
• Subjects: Acridines - chemistry; Acridines - pharmacology; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Breast Neoplasms - therapy; Cell Line, Tumor; Chemotherapy; Cytotoxicity; Drug delivery; Drug Delivery Systems - methods; Female; Humans; Hyperthermia, Induced - methods; Nanoparticle; Nanotubes, Carbon - chemistry; Phototherapy - methods; Photothermal therapy; Platinum - chemistry; Platinum - pharmacology; Triple negative breast cancer; Photothermal therapy; Cytotoxicity; Chemotherapy; Drug delivery; Nanoparticle; Triple negative breast cancer
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2016.07.016

A three-component drug-delivery system has been developed consisting of multi-walled carbon nanotubes (MWCNTs) coated with a non-classical platinum chemotherapeutic agent ([PtCl(NH3)2(L)]Cl (P3A1; L=N-(2-(acridin-9-ylamino)ethyl)-N-methylproprionimidamide) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-5000] (DSPE-mPEG). The optimized P3A1-MWCNTs are colloidally stable in physiological solution and deliver more P3A1 into breast cancer cells than treatment with the free drug. Furthermore, P3A1-MWCNTs are cytotoxic to several cell models of breast cancer and induce S-phase cell cycle arrest and non-apoptotic cell death in breast cancer cells. By contrast, free P3A1 induces apoptosis and allows progression to G2/M phase. Photothermal activation of P3A1-MWCNTs to generate mild hyperthermia potentiates their cytotoxicity. These findings suggest that delivery of P3A1 to cancer cells using MWCNTs as a drug carrier may be beneficial for combination cancer chemotherapy and photothermal therapy. A platinum-acridine derivative spontaneously forms a complex with multi-walled carbon nanotubes in aqueous buffers. This drug delivery system induces cytotoxic effects distinct from the free drug including severe replication stress and cell death without initiation of apoptosis. The nanotube enables chemo-photothermal cancer therapy with enhanced cell killing following brief laser exposure. [Display omitted] •Efficient coating of a platinum-acridine agent on multi-walled carbon nanotubes•Drug release from the nanotube complex following cell uptake•Promising therapeutic effect in triple negative breast cancer•Nanoparticle-specific induction of S-phase arrest and non-apoptotic cell death•Combined photothermal and chemotherapy on a single delivery platform