Versatile RNA interference nanoplatform for systemic delivery of RNAs.
Development of nontoxic, tumor-targetable, and potent in vivo RNA delivery systems remains an arduous challenge for clinical application of RNAi therapeutics. Herein, we report a versatile RNAi nanoplatform based on tumor-targeted and pH-responsive nanoformulas (NFs). The NF was engineered by combination of an artificial RNA receptor, Zn(II)-DPA, with a tumor-targetable and drug-loadable hyaluronic acid nanoparticle, which was further modified with a calcium phosphate (CaP) coating by in situ mineralization. The NF can encapsulate small-molecule drugs within its hydrophobic inner core and strongly secure various RNA molecules (siRNAs, miRNAs, and oligonucleotides) by utilizing Zn(II)-DPA and a robust CaP coating. We substantiated the versatility of the RNAi nanoplatform by demonstrating effective delivery of siRNA and miRNA for gene silencing or miRNA replacement into different human types of cancer cells in vitro and into tumor-bearing mice in vivo by intravenous administration. The therapeutic potential of NFs coloaded with an anticancer drug doxorubicin (Dox) and multidrug resistance 1 gene target siRNA (siMDR) was also demonstrated in this study. NFs loaded with Dox and siMDR could successfully sensitize drug-resistant OVCAR8/ADR cells to Dox and suppress OVCAR8/ADR tumor cell proliferation in vitro and tumor growth in vivo. This gene/drug delivery system appears to be a highly effective nonviral method to deliver chemo- and RNAi therapeutics into host cells.
Laboratory of Molecular Imaging and Nanomedicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health , Bethesda, Maryland 20892, United States.
Ki Young
KY
Choi
Oscar F
OF
Silvestre
Xinglu
X
Huang
Kyung Hyun
KH
Min
Gregory P
GP
Howard
Naoki
N
Hida
Albert J
AJ
Jin
Nicole
N
Carvajal
Sang Wook
SW
Lee
Jong-In
JI
Hong
Xiaoyuan
X
Chen
D000818:Animals; D002118:Calcium / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004317:Doxorubicin / Q000737:chemistry; D004337:Drug Carriers; D004705:Endocytosis; D005260:Female; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D006820:Hyaluronic Acid / Q000737:chemistry; D006821:Hyaluronoglucosaminidase / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007477:Ions; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000737:chemistry; D053758:Nanoparticles / Q000737:chemistry*; D049329:Nanostructures / Q000737:chemistry; D010710:Phosphates / Q000737:chemistry; D012313:RNA / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism
C497483:CD44 protein, human; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D007477:Ions; D035683:MicroRNAs; D010710:Phosphates; D034741:RNA, Small Interfering; D012313:RNA; D004317:Doxorubicin; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase; D002118:Calcium