title: Cationic drug-derived nanoparticles for multifunctional delivery of anticancer siRNA.
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.
authors.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Daehak-dong, Gwanak-gu, Seoul 151-742, South Korea.
authors.forename: Rae Sung
authors.initials: RS
authors.lastname: Chang
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Suh
authors.forename: Sunil
authors.initials: S
authors.lastname: Kim
authors.forename: Gayong
authors.initials: G
authors.lastname: Shim
authors.forename: Sangbin
authors.initials: S
authors.lastname: Lee
authors.forename: Sung Sik
authors.initials: SS
authors.lastname: Han
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.forename: Hyesung
authors.initials: H
authors.lastname: Jeon
authors.forename: Han-Gon
authors.initials: HG
authors.lastname: Choi
authors.forename: Yongseok
authors.initials: Y
authors.lastname: Choi
authors.forename: Chan-Wha
authors.initials: CW
authors.lastname: Kim
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002412:Cations; D045744:Cell Line, Tumor; D020285:Cryoelectron Microscopy; D005229:Fatty Acids, Monounsaturated / Q000138:chemical synthesis / Q000737:chemistry; D005453:Fluorescence; D015870:Gene Expression / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008942:Mitoxantrone / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D002412:Cations; D005229:Fatty Acids, Monounsaturated; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; C008757:palmitoleic acid; D008942:Mitoxantrone