Overcoming multidrug resistance by co-delivery of Mdr-1 and survivin-targeting RNA with reduction-responsible cationic poly(β-amino esters).
Multidrug resistance (MDR) remains one of the main challenges in the successful chemotherapy of human cancer. RNA interference (RNAi) strategy aiming at only one cause of MDR was widely applied, nevertheless hardly obtained satisfactory tumor-suppressing effect. In this work, a new attempt to package two kinds of RNA with different functions into one vector and reverse MDR against two different mechanisms via RNAi was carried out. A new bioreducible poly (β-amino esters) (PAEs), poly[bis(2-hydroxylethyl)-disulfide-diacrylate-β-tetraethylenepentamine] (PAP) was synthesized by Michael addition reaction. The PAEs/RNA complex nanoparticles (PAEN) were prepared. The experimental results demonstrated that co-delivery of iMdr-1-shRNA and iSurvivin-shRNA could be achieved by a single vector, and interfering two genes simultaneously had a synergistic effect on overcoming MDR. PAEN lowered the IC(50) value of doxorubicin (DOX) in MDR tumor cells to a comparable level to that in the sensitive cell line through down-regulating the expression of P-gp and Survivin, and decreased the tumor volumes in mice xenograft model bearing DOX-resistant human breast cancer when combined with DOX. These results illustrated that PAEN could be applied as potential efficient non-viral RNA carriers for reversing MDR.
Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Qi
Q
Yin
Jianan
J
Shen
Lingli
L
Chen
Zhiwen
Z
Zhang
Wangwen
W
Gu
Yaping
Y
Li
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002412:Cations; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects; D018014:Gene Transfer Techniques; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism*; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry / Q000633:toxicity; D010084:Oxidation-Reduction / Q000187:drug effects; D011108:Polymers / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000138:chemical synthesis / Q000737:chemistry; D034622:RNA Interference / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002412:Cations; D051034:Inhibitor of Apoptosis Proteins; D011108:Polymers; D000644:Quaternary Ammonium Compounds; D034741:RNA, Small Interfering; C507253:poly(beta-amino ester); C040648:pentamine; D004317:Doxorubicin