Photosensitive Pt(IV)–azide prodrug-loaded nanoparticles exhibit controlled drug release and enhanced efficacy in vivo

• Published in: Journal of controlled release 2014-01, Vol.173, p.11-17
• Main Authors: Xiao, Haihua, Noble, Gavin T., Stefanick, Jared F., Qi, Ruogu, Kiziltepe, Tanyel, Jing, Xiabin, Bilgicer, Basar
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - chemistry; Antineoplastic Agents - therapeutic use; Azides - administration & dosage; Azides - therapeutic use; Cell Line, Tumor; Cisplatin; Delayed-Action Preparations - chemistry; Drug delivery; Humans; Liver - drug effects; Liver - pathology; Liver Neoplasms - drug therapy; Liver Neoplasms - pathology; Mice; Nanomedicine; Nanoparticles - chemistry; Organoplatinum Compounds - administration & dosage; Organoplatinum Compounds - chemistry; Organoplatinum Compounds - therapeutic use; Photosensitive chemotherapy; Platinum drugs; Prodrug; Prodrugs - administration & dosage; Prodrugs - chemistry; Prodrugs - therapeutic use; Ultraviolet Rays
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2013.10.020

Cisplatin has long been the first line of treatment for a variety of solid tumors. However, poor pharmacokinetics and high incidences of resistance in the clinic have motivated the production of numerous alternative Pt-based anticancer species. Recently, photosensitive Pt(IV) complexes have garnered much interest because they offer a method of selective induction of active Pt(II) at the tumor site by UVA irradiation. Here, we report the first synthesis, in vitro and in vivo characterization of a novel series of photosensitive Pt(IV)–azide prodrugs and micellar nanoparticle formulations thereof. Upon mild UVA irradiation, both free Pt(IV) complexes and micellar nanoparticles rapidly released biologically active Pt(II), capable of binding to 5′-GMP, while remaining extremely stable in the dark. In vitro, uptake of photosensitive Pt(IV) prodrugs by ovarian cancer SKOV-3 cells was greatly enhanced with the micellar nanoparticles compared to their free prodrug analogs, as well as cisplatin and oxaliplatin. Increased cytotoxicity was observed upon UVA treatment, with up to a 13-fold enhancement over oxaliplatin for the micellar nanoparticles. In vivo bioavailability of micellar nanoparticles was enhanced ~10 fold over free Pt(IV) prodrugs. Importantly, micellar nanoparticles demonstrated significantly improved efficacy against H22 murine hepatocarcinoma, showing decreased systemic toxicity and increased tumor growth inhibition relative to small molecule drugs. These findings establish that photosensitive Pt(IV) complexes, specifically when formulated into micellar nanoparticles, have the potential to offer a robust platform for the controlled delivery and selective activation of Pt-based anticancer therapeutics. [Display omitted]