Inhibition of hepatocellular carcinoma growth using immunoliposomes for co-delivery of adriamycin and ribonucleotide reductase M2 siRNA.
The chemotherapy combined with gene therapy has received great attention. We developed targeted LPD (liposome-polycation-DNA complex) conjugated with anti-EGFR (epidermal growth factor receptor) Fab' co-delivering adriamycin (ADR) and ribonucleotide reductase M2 (RRM2) siRNA (ADR-RRM2-TLPD), to achieve combined therapeutic effects in human hepatocellular carcinoma (HCC) overexpressing EGFR. The antitumor activity and mechanisms of ADR-RRM2-TLPD were investigated. The results showed that RRM2 expression was higher in HCC than in non-HCC tissue, and RRM2 siRNA inhibited HCC cell proliferation, suggesting that RRM2 is a candidate target for HCC therapy. ADR-RRM2-TLPD delivered ADR and RRM2 siRNA to EGFR overexpressing HCC cells specifically and efficiently both in vitro and in vivo, resulting in enhanced therapeutic effects (cytotoxicity, apoptosis and senescence-inducing activity) compared with single-drug loaded or non-targeted controls, including ADR-NC-TLPD (targeted LPD co-delivering ADR and negative control siRNA), RRM2-TLPD (targeted LPD delivering RRM2 siRNA) and ADR-RRM2-NTLPD (non-targeted LPD co-delivering ADR and RRM2 siRNA). Mechanism studies showed that p21 is involved in the combined therapeutic effect of ADR-RRM2-TLPD. The average weight of the orthotopic HCC in mice treated with ADR-RRM2-TLPD was significantly lighter than that of mice treated with other controls. Thus, ADR-RRM2-TLPD represents a potential strategy for combined therapy of HCC overexpressing EGFR.
International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine & Shanghai Key Laboratory of Cell Engineering and Antibody, 399 Libing Road, Shanghai 201203, China. Electronic address: gaojiehighclea@163.com.
Jie
J
Gao
Huaiwen
H
Chen
Yongsheng
Y
Yu
Jinjing
J
Song
Hao
H
Song
Xiao
X
Su
Wei
W
Li
Xin
X
Tong
Weizhu
W
Qian
Hao
H
Wang
Jianxin
J
Dai
Yajun
Y
Guo
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018613:Microscopy, Confocal; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics* / Q000627:therapeutic use; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors / Q000235:genetics*
D008081:Liposomes; D034741:RNA, Small Interfering; D004317:Doxorubicin; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase
Chemotherapy; Gene therapy; Hepatocellular carcinoma; Immunoliposomes; Targeted therapy