Bioreducible hyaluronic acid conjugates as siRNA carrier for tumor targeting.
The successful clinical translation of siRNA-based therapeutics requires efficient carrier systems that can specifically deliver siRNA within the cytosol of the target cells. Although numerous polymeric nanocarriers forming ionic complexes with siRNA have been investigated for cancer therapy, their poor stability and lack of tumor targetability have impeded their in vivo applications. To surmount these limitations, we synthesized a novel type of biodegradable hyaluronic acid-graft-poly(dimethylaminoethyl methacrylate) (HPD) conjugate that can form complexes with siRNA and be chemically crosslinked via the formation of the disulfide bonds under facile conditions. The crosslinked siRNA-HPD (C-siRNA-HPD) complexes exhibited high stability in a 50% serum solution, as compared to the uncrosslinked siRNA-HPD (U-siRNA-HPD) complexes and free siRNA. Both the C-siRNA-HPD and U-siRNA-HPD complexes were efficiently taken up by the CD44-overexpressing melanoma cells (B16F10), but not by the normal fibroblast cells (NIH3T3). When the RFP-expressing B16F10 cells were treated with the complexes or free siRNA, the C-siRNA-HPD complexes showed the highest decrease in RFP expression. In vivo studies demonstrated the selective accumulation of C-siRNA-HPD complexes at the tumor site after their systemic administration into tumor-bearing mice, resulting in an efficient gene silencing effect. Overall, these results suggest that the HPD conjugate could be used as an efficient carrier for the tumor-targeted delivery of siRNA.
Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon 440-746, Republic of Korea; Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea.
Hong Yeol
HY
Yoon
Hyun Ryoung
HR
Kim
Gurusamy
G
Saravanakumar
Roun
R
Heo
Su Young
SY
Chae
Wooram
W
Um
Kwangmeyung
K
Kim
Ick Chan
IC
Kwon
Jun Young
JY
Lee
Doo Sung
DS
Lee
Jae Chan
JC
Park
Jae Hyung
JH
Park
D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D020868:Gene Silencing; D000882:Haplorhini; D006820:Hyaluronic Acid / Q000031:analogs & derivatives*; D008545:Melanoma / Q000235:genetics / Q000628:therapy; D008689:Methacrylates / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000235:genetics / Q000628:therapy*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use
D004337:Drug Carriers; D008689:Methacrylates; D034741:RNA, Small Interfering; D006820:Hyaluronic Acid
Bioreducible conjugate; Hyaluronic acid; Stability; Tumor targetability; siRNA