Self-crosslinked human serum albumin nanocarriers for systemic delivery of polymerized siRNA to tumors.
The safe and effective systemic delivery of siRNA is a prerequisite for the successful development of siRNA-based cancer therapeutics. For the enhanced delivery of siRNA, cationic lipids and polymers have been widely used as siRNA carriers to form electrolyte complexes with anionic siRNA. However, the considerable toxicity of strong cationic-charged molecules hampers their clinical use. In this study, we utilized human serum albumin (HSA), which is the most abundant of the plasma proteins, as a siRNA carrier for systemic tumor-targeted siRNA delivery. Both HSA and siRNA molecules were thiol-introduced to improve the binding affinity for each other. The resulting thiolated HSA (tHSA) and polymerized siRNA (psi) formed stable nanosized complexes (psi-tHSAs) by chemical crosslinking and self-crosslinking. After internalization, the psi-tHSAs showed target gene silencing activity in vitro comparable to conventional Lipofectamine™-siRNA complexes, without remarkable cytotoxicity. After intravenous injection in tumor-bearing mice, psi-tHSAs accumulated specifically at the tumor sites, leading to efficient gene silencing in the tumors in a sequential manner. The therapeutic VEGF siRNA was loaded into psi-tHSAs, which significantly inhibited tumor-related angiogenesis in PC-3 tumor xenografts and resulted in retarding the growth of PC-3 tumors. The results showed that self-crosslinked psi-tHSA nanocarriers might provide a promising approach for the systemic siRNA therapy of various human cancers.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Hwarangno 14-gil 6, Seongbuk-gu, Seoul 136-791, South Korea.
Sohee
S
Son
Seungyong
S
Song
So Jin
SJ
Lee
Solki
S
Min
Sun Ah
SA
Kim
Ji Young
JY
Yhee
Myung Sook
MS
Huh
Ick
I
Chan Kwon
Seo Young
SY
Jeong
Youngro
Y
Byun
Sun Hwa
SH
Kim
Kwangmeyung
K
Kim
D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy; D058105:Polymerization; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use; D012709:Serum Albumin / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D004337:Drug Carriers; D034741:RNA, Small Interfering; D012709:Serum Albumin; D013438:Sulfhydryl Compounds; D042461:Vascular Endothelial Growth Factor A
Cancer therapy; Human serum albumin; Polymerized siRNA; Protein based carrier; RNAi