Systemic delivery of siRNA by chimeric capsid protein: tumor targeting and RNAi activity in vivo.
Recently, we reported that a chimeric capsid protein assembled into a macromolecular container-like structure with capsid shell and the resulting siRNA/capsid nanocarrier complexes efficiently suppressed RFP gene expression in the cell culture system. To extend RNAi to the in vivo applications, we here demonstrated that the siRNA/capsid nanocarrier complexes could have tumor-specific targeting ability in vivo as well as the increased stability of siRNA during body circulation. When systemically administered, our siRNA/capsid nanocarrier complexes delivered siRNA to tumor tissues and efficiently suppressed RFP gene expression in tumor-bearing mice. The enhanced longevity of siRNA in vivo could be explained by shielding effect derived from the capsid shell, where the encapsulated siRNAs are protected from nucleases in plasma. The multivalent RGD peptides on shell surface, as a result of self-assembling of capsid protein subunits, showed efficient delivery of siRNA to the tumor tissues in vivo, due to the RGD-mediated binding to integrin receptors overexpressed on tumor cells. Moreover, the prolonged in vivo circulation time of our siRNA/capsid nanocarrier complexes increased the potential to serve as siRNA carriers for optimal in vivo RNAi. These results provide an alternative approach to systemically deliver siRNA to the tumor sites as well as to enhance the stability of siRNA in vivo. Therefore, our results revealed the promising potential of our capsid nanocarrier system as a therapeutic siRNA carrier for cancer treatment.
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul 130-650, South Korea.
Kyung-mi
KM
Choi
Kwangmeyung
K
Kim
Ick Chan
IC
Kwon
In-San
IS
Kim
Hyung Jun
HJ
Ahn
D000818:Animals; D002213:Capsid; D036022:Capsid Proteins / Q000008:administration & dosage* / Q000235:genetics*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D004337:Drug Carriers / Q000008:administration & dosage; D016503:Drug Delivery Systems / Q000379:methods; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage; D009687:Nuclear Proteins / Q000235:genetics; D034622:RNA Interference / Q000502:physiology*; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000235:genetics; D044767:Ubiquitin-Protein Ligases; D000070584:Tripartite Motif Proteins
D036022:Capsid Proteins; D004268:DNA-Binding Proteins; D004337:Drug Carriers; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D044767:Ubiquitin-Protein Ligases; C489296:Trim27 protein, mouse; D000070584:Tripartite Motif Proteins