Cationic drug-derived nanoparticles for multifunctional delivery of anticancer siRNA

• Published in: Biomaterials 2011-12, Vol.32 (36), p.9785-9795
• Main Authors: Chang, Rae Sung, Suh, Min Sung, Kim, Sunil, Shim, Gayong, Lee, Sangbin, Han, Sung Sik, Lee, Kyung Eun, Jeon, Hyesung, Choi, Han-Gon, Choi, Yongseok, Kim, Chan-Wha, Oh, Yu-Kyoung
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Animals; Anticancer chemo-gene therapy; Antineoplastic Agents - pharmacology; Cations; Cell Line, Tumor; Co-delivery; Cryoelectron Microscopy; Dentistry; Fatty Acids, Monounsaturated - chemical synthesis; Fatty Acids, Monounsaturated - chemistry; Fluorescence; Gene Expression - drug effects; Gene Transfer Techniques; Humans; Intracellular Space - drug effects; Intracellular Space - metabolism; Mice; Mice, Nude; Mitoxantrone; Mitoxantrone - chemical synthesis; Mitoxantrone - chemistry; Mitoxantrone - pharmacology; Multifunctional nanoparticles; Myeloid Cell Leukemia Sequence 1 Protein; Nanoparticles - chemistry; Nanoparticles - ultrastructure; Proto-Oncogene Proteins c-bcl-2 - metabolism; RNA, Small Interfering - metabolism; siRNA
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2011.09.017

Abstract Combined treatment of anticancer drugs and small interfering RNAs (siRNAs) have emerged as a new modality of anticancer therapy. Here, we describe a co-delivery system of anticancer drugs and siRNA in which anticancer drug-derived lipids form cationic nanoparticles for siRNA complexation. The anticancer drug mitoxantrone (MTO) was conjugated to palmitoleic acid, generating two types of palmitoleyl MTO (Pal-MTO) lipids: monopalmitoleyl MTO (mono-Pal-MTO) and dipalmitoleyl MTO (di-Pal-MTO). Among various lipid compositions of MTO, nanoparticles containing mono-Pal-MTO and di-Pal-MTO at a molar ratio of 1:1 (md11-Pal-MTO nanoparticles) showed the most efficient cellular delivery of siRNA, higher than that of Lipofectamine 2000. Delivery of red fluorescence protein-specific siRNA into B16F10-RFP cells using md11-Pal-MTO nanoparticles reduced the expression of RFP at both mRNA and protein levels, demonstrating silencing of the siRNA target gene. Moreover, delivery of Mcl-1-specific anticancer siRNA (siMcl-1) using md11-Pal-MTO enhanced antitumor activity in vitro, reducing tumor cell viability by 81% compared to a reduction of 68% following Lipofectamine 2000-mediated transfection of siMcl-1. Intratumoral administration of siMcl-1 using md11-Pal-MTO nanoparticles significantly inhibited tumor growth, reducing tumor size by 83% compared to untreated controls. Our results suggest the potential of md11-Pal-MTO multifunctional nanoparticles for co-delivery of anticancer siRNAs for effective combination therapy.