Sequential treatment of drug-resistant tumors with RGD-modified liposomes containing siRNA or doxorubicin.
Tumor targeting drug delivery systems are being the ideal carriers of systemic administration for tumor therapy. We have reported previously that RGD peptide (arginine-glycine-aspartic acid)-modified liposomes containing drugs could increase targeting to tumor by binding with the integrin receptors overexpressed on tumor cells. RNA interference plays an important role on down-regulation of P-glycoprotein (P-gp), which is a drug efflux transporter overexpressed on multi-drug-resistant (MDR) tumor cells. To improve MDR tumor therapy, sequential treatment strategy with RGD-modified liposomes containing P-gp targeted small interference (siRNA) or doxorubicin (DOX) was reported in this study. When targeted via RGD to tumor-cell-surface and tumor neovasculature endothelial cell receptors, cationic liposomes could specifically deliver siRNAs to tumor cells and thus reverse drug resistance by down-regulation of P-gp, following administration of targeted liposomes containing DOX that inhibit formerly drug-resistant tumors. From the current results, the combination use of DOX and P-gp targeted siRNA showed significantly higher in vitro cytotoxicity in tumor cells than liposomal DOX alone. In vivo studies in a mouse model of drug-resistant MCF7/A tumor demonstrated significantly greater inhibition of tumor growth followed by the sequential treatment of RGD-modified liposomes containing siRNA or DOX when compared to liposomal DOX alone. Also, ex vivo tissue imaging studies have shown the accumulation of siRNA and DOX in tumors at same site-specific manner. These results suggested that the sequential treatment of P-gp gene silencing and cytotoxic drug with RGD-modified liposome drug delivery system could be a promising clinical treatment for drug-resistant tumors.
Jiang
Juan
J
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, PR China.
Yang
Shi-Jin
SJ
Wang
Jian-Cheng
JC
Yang
Li-Juan
LJ
Xu
Zhen-Zhong
ZZ
Yang
Ting
T
Liu
Xiao-Yan
XY
Zhang
Qiang
Q
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000494:pharmacology*; D016503:Drug Delivery Systems; D019008:Drug Resistance, Neoplasm; D005260:Female; D020868:Gene Silencing; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D008081:Liposomes; D009842:Oligopeptides; D034741:RNA, Small Interfering; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin