Cardiomyocyte-targeted siRNA delivery by prostaglandin E(2)-Fas siRNA polyplexes formulated with reducible poly(amido amine) for preventing cardiomyocyte apoptosis.
A cardiomyocyte-targeted Fas siRNA delivery system was developed using prostaglandin E(2) (PGE(2))-modified siRNA polyplexes formed by a reducible poly(amido amine) to inhibit cardiomyocyte apoptosis. PGE(2), which was used as a specific ligand for cardiomyocyte targeting, was conjugated to the terminal-end of the sense siRNA (PGE(2)-siRNA). The reducible cationic copolymer, synthesized via Michael-type polyaddition of 1,6-diaminohexane and cystamine bis-acrylamide (poly(DAH/CBA)), tightly condensed the PGE(2)-siRNA conjugate to form nanosize polyplexes having a diameter of 100-150 nm. The PGE(2)-siRNA/poly(DAH/CBA) polyplexes decomplexed to release PGE(2)-siRNA in a cytosolic reducing environment due to the degradation of the reducible poly(DAH/CBA). The cellular uptake of the PGE(2)-siRNA/poly(DAH/CBA) polyplex was increased in rat cardiomyocytes (H9C2 cells) due to PGE(2) receptor-mediated endocytosis. When H9C2 cells were transfected with siRNA against Fas, a key regulator of ischemia-induced apoptosis, the PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex delivery system led to a significant increase in Fas gene silencing, resulting in inhibition of cardiomyocyte apoptosis. The PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex did not induce interferon-alpha in peripheral blood mononuclear cells. These results suggest that the PGE(2)-Fas siRNA/poly(DAH/CBA) polyplex formulation may be clinically applicable as a cardiomyocyte-targeted Fas siRNA delivery system to inhibit apoptosis in cardiovascular disease.
Kim
Sun Hwa
SH
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
Jeong
Ji Hoon
JH
Ou
Mei
M
Yockman
James W
JW
Kim
Sung Wan
SW
Bull
David A
DA
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D015232:Dinoprostone / Q000378:metabolism*; D008954:Models, Biological; D032383:Myocytes, Cardiac / Q000378:metabolism*; D011073:Polyamines / Q000737:chemistry*; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D014162:Transfection; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D011073:Polyamines; D034741:RNA, Small Interfering; D019014:fas Receptor; D015232:Dinoprostone