TY - JOUR
T1 - Properties of Native High-Density Lipoproteins Inspire Synthesis of Actively Targeted In Vivo siRNA Delivery Vehicles
AU - McMahon, Kaylin M.
AU - Plebanek, Michael P.
AU - Thaxton, Colby Shad
N1 - Funding Information:
C.S.T. would like to thank the Department of Defense/Air Force Office of Scientific Research (FA95501310192) for grant funding, and grant funding from the National Institutes of Health/National Cancer Institute (U54CA151880 and R01CA167041). K.M.M. acknowledges the Ryan Family, the Malkin Family, the Driskill Family, and Chicago Baseball Charities Cancer Fellowship for financial and fellowship support. K.M.M. acknowledges fellowship support from the T32 Carcinogenesis training grant (T32CA09560). The authors acknowledge Dr. Fred W. Rademaker for assistance with statistics. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center.
Publisher Copyright:
© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2016/11/15
Y1 - 2016/11/15
N2 - Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High-density lipoproteins (HDLs) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) load single-stranded RNA; 2) are anionic, which requires charge reconciliation between the RNA and HDL, and 3) actively target scavenger receptor type B-1 (SR-B1) to deliver RNA. Emphasizing these particular parameters, templated lipoprotein particles (TLP), mimics of spherical HDLs, are employed and are self-assembled with single-stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA-TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA-TLPs actively target SR-B1 to potently reduce androgen receptor and enhancer of zeste homolog 2 proteins in multiple cancer cell lines. Systemic administration of siRNA-TLPs demonstrated no off-target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single-stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR-B1.
AB - Efficient systemic administration of therapeutic short interfering RNA (siRNA) is challenging. High-density lipoproteins (HDLs) are natural in vivo RNA delivery vehicles. Specifically, native HDLs: 1) load single-stranded RNA; 2) are anionic, which requires charge reconciliation between the RNA and HDL, and 3) actively target scavenger receptor type B-1 (SR-B1) to deliver RNA. Emphasizing these particular parameters, templated lipoprotein particles (TLP), mimics of spherical HDLs, are employed and are self-assembled with single-stranded complements of, presumably, any highly unmodified siRNA duplex pair after formulation with a cationic lipid. Resulting siRNA templated lipoprotein particles (siRNA-TLP) are anionic and tunable with regard to RNA assembly and function. Data demonstrate that the siRNA-TLPs actively target SR-B1 to potently reduce androgen receptor and enhancer of zeste homolog 2 proteins in multiple cancer cell lines. Systemic administration of siRNA-TLPs demonstrated no off-target toxicity and significantly reduced the growth of prostate cancer xenografts. Thus, native HDLs inspired the synthesis of a hybrid siRNA delivery vehicle that can modularly load single-stranded RNA complements after charge reconciliation with a cationic lipid, and that function due to active targeting of SR-B1.
KW - active delivery
KW - lipoproteins
KW - nanoparticles
KW - short interfering iRNA
KW - single-stranded RNA
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U2 - 10.1002/adfm.201602600
DO - 10.1002/adfm.201602600
M3 - Article
C2 - 28717350
AN - SCOPUS:84988447907
VL - 26
SP - 7824
EP - 7835
JO - Advanced Functional Materials
JF - Advanced Functional Materials
SN - 1616-301X
IS - 43
ER -