Polymer Prodrug Nanoparticles Based on Naturally Occurring Isoprenoid for Anticancer Therapy

• Published in: Biomacromolecules 2013-08, Vol.14 (8), p.2837-2847
• Main Authors: Trung Bui, Duc, Maksimenko, Andrei, Desmaële, Didier, Harrisson, Simon, Vauthier, Christine, Couvreur, Patrick, Nicolas, Julien
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemistry; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; Applied sciences; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Sciences; Chemotherapy; Colloids; Deoxycytidine - analogs & derivatives; Deoxycytidine - chemistry; Deoxycytidine - metabolism; Deoxycytidine - pharmacology; Exact sciences and technology; Humans; Life Sciences; Medical sciences; Mice; Nanocapsules - chemistry; Nanoparticles - chemistry; Nanoparticles - metabolism; Neoplasms - drug therapy; Organic polymers; Pharmacology. Drug treatments; Physicochemistry of polymers; Polyethylene Glycols - chemistry; Polymerization; Polymers with particular properties; Polymethacrylic Acids - chemical synthesis; Preparation, kinetics, thermodynamics, mechanism and catalysts; Prodrugs - chemistry; Prodrugs - metabolism; Prodrugs - pharmacology; Squalene - chemistry; Terpenes - chemistry
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/bm400657g

The synthesis of a novel class of polymer prodrug nanoparticles with anticancer activity is reported by using squalene, a naturally occurring isoprenoid, as a building block by the reversible addition–fragmentation (RAFT) technique. The RAFT agent was functionalized by gemcitabine (Gem) as anticancer drug, and the polymerization of squalenyl-methacrylate (SqMA) led to well-defined macromolecular prodrugs comprising one Gem at the extremity of each polymer chain. The amphiphilic nature of the resulting Gem–PSqMA conjugates allowed them to self-assemble into long-term stable and narrowly dispersed nanoparticles with significant anticancer activity in vitro on various cancer cell lines. To confer stealth properties on these nanoparticles, their PEGylation was successfully performed, as confirmed by X-ray photoelectron spectroscopy (XPS) and complement activation assay. It was also shown that the PEGylated nanoparticles could be internalized in cancer cells to a greater extent than their non-PEGylated counterparts.