Trilysinoyl oleylamide-based cationic liposomes for systemic co-delivery of siRNA and an anticancer drug.
Oligolysine-based cationic lipid derivatives were synthesized for delivery of siRNA, and formulated into cationic liposomes. Among various oligolysine-based lipid derivatives differing in lysine residue number and lipid moiety, trilysinoyl oleylamide (TLO)-based liposomes (TLOL) showed the highest delivery efficiency combined with minimal cytotoxicity. Delivery of siRNA using TLOL silenced target genes both in vitro and in vivo. In green fluorescent protein (GFP)-expressing tumor tissue, a significant reduction of fluorescence was observed after intratumoral administration of siGFP using TLOL compared with control siGL2. Intravenous administration of siMcl1 employing pegylated TLOL (pTLOL) reduced the expression of human Mcl1 protein in KB-xenografted tumor tissue. Despite the reduction in target protein Mcl1 expression following such systemic delivery, tumor growth was only slightly reduced compared to a siGL2-treated control group. To potentiate the anticancer activity of siMcl1, the anticancer drug suberoylanilide hydroxamic acid (SAHA) was additionally encapsulated in pTLOL. After intravenous administration of siMcl1 using SAHA-loaded pTLOL (pSTLOL), a significant reduction in tumor growth was observed compared to that seen in animals treated with free SAHA or siGL2 complexed with pSTLOL. The results indicate that pTLOL could be further developed as a systemic delivery system for synergistic anticancer siRNA and a drug.
Shim
Gayong
G
School of Life Sciences and Biotechnology, Korea University, Anam-dong, Seungbuk-gu, Seoul, South Korea.
Han
Su-Eun
SE
Yu
Yong-Hee
YH
Lee
Sangbin
S
Lee
Han Young
HY
Kim
Kwangmeyung
K
Kwon
Ick Chan
IC
Park
Tae Gwan
TG
Kim
Young Bong
YB
Choi
Yong Seok
YS
Kim
Chan-Wha
CW
Oh
Yu-Kyoung
YK
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002412:Cations / Q000737:chemistry*; D002460:Cell Line; D005260:Female; D020868:Gene Silencing; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000627:therapeutic use; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009829:Oleic Acids / Q000737:chemistry*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000627:therapeutic use; D000077337:Vorinostat
D000970:Antineoplastic Agents; D002412:Cations; D006877:Hydroxamic Acids; D008081:Liposomes; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009829:Oleic Acids; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D000077337:Vorinostat; C029407:oleylamide