Reversal of multidrug resistance by reduction-sensitive linear cationic click polymer/iMDR1-pDNA complex nanoparticles.
A reduction-sensitive linear cationic click polymer (RCP) was specially designed for the efficient gene delivery to overcome multidrug resistance (MDR) by RNA interference to silence the expression of P-glycoprotein (P-gp). RCP was synthesized via the "click chemistry" with disulfide bonds, amide-triazole moieties and secondary amine groups in the main chain. RCP could efficiently condense pDNA into nanoparticles (RCPNs) around 150 nm. Polyplex dissociation was observed in the presence of 2.5 mm DTT due to the cleavage of disulfide bonds, which indicated the efficient DNA release under the reduction condition. In vitro transfection and cytotoxicity experiments against human breast cancer MCF-7 cells and drug-resistant MCF-7/ADR cells showed that RCPNs could bring about higher transfection efficiency with much lower cytotoxicity than PEI/DNA nanoparticles. RCPNs loaded with plasmid iMDR1-pDNA could inhibit P-gp expression, increase adriamycin (ADR) accumulation and enhance cytotoxicity of ADR against MCF-7/ADR cells. Combination of RCPNs and ADR could suppress the tumor growth more efficiently than using ADR only on mouse xenograft model bearing ADR resistant human breast cancer. These results suggested that this RCP could be a potential, safe and efficient non-viral vector for reversing MDR.
Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
Yu
Y
Gao
Lingli
L
Chen
Zhiwen
Z
Zhang
Yi
Y
Chen
Yaping
Y
Li
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002412:Cations / Q000737:chemistry*; D045744:Cell Line, Tumor; D057930:Click Chemistry; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000235:genetics / Q000502:physiology; D014162:Transfection
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002412:Cations; D011108:Polymers; D034741:RNA, Small Interfering; D004317:Doxorubicin