title: Novel drug delivery liposomes targeted with a fully human anti-VEGF165 monoclonal antibody show superior antitumor efficacy in vivo.
abstract: Immunoliposomes modified by monoclonal antibodies are promising agents for tumor-targeted drug delivery. Here, we designed a novel long-circulating liposome conjugated to a fully human anti-vascular endothelial growth factor (VEGF) monoclonal antibody (mAb) as a targeting modification. VEGF mAb selectively accumulates in tumor tissue over-expressing VEGF; therefore, drugs accumulate within tumors to enhance antitumor efficacy. For this study, paclitaxel (PTX), a chemotherapeutic agent with potent antiangiogenic activity, was used as a prototype drug. PEGylated liposomes loaded with paclitaxel were successfully prepared using the thin-film hydration method with appropriate amounts of S100PC, cholesterol, and mPEG2000-DSPE at a molar ratio of 90:10:5. The VEGF mAb was then conjugated to the Mal-PEG2000-DSPE liposome at a ratio of 6.65mg of VEGF mAb/μmol Mal-PEG2000-DSPE, producing completely stable VEGF mAb-liposomes. The anticancer activity was evaluated in BALB/c nude mice bearing SGC-7901 xenografts. The results indicate that VEGF-targeted mAb-liposomes are visualized in the interior of the tumor and taken up by tumor cells. After receiving five i.v. injections, the mice treated with mAb-liposomal paclitaxel showed superior anticancer activity than the commercial formulation Taxol(®) and unmodified liposomal formulations. Immunohistochemical analysis of the tumor tissues showed weaker VEGF and CD31 signals in mAb-liposome-treated tumors compared to treatment with no mAb-liposomes. Immunohistology analysis results demonstrated that the tumors treated with VEGF mAb-liposomes had the lowest concentration of Ki67-labeled cells and the greatest number of TUNEL-positive cells. All data showed that the novel VEGF mAb-liposomes carried anticancer drugs, such as paclitaxel, to the interior of solid tumors and inhibited tumor growth effectively.
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Chenyang
authors.initials: C
authors.lastname: Shi
authors.affiliation: Shanghai Institute for Food and Drug Control, Shanghai 200131, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: He
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: Department of Biochemistry, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: liuyuyaoda@163.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lifangyin@hotmail.com.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yin
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008081:Liposomes; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008081:Liposomes; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Gastric cancer; PEGylated liposome; Paclitaxel; Targeted delivery; VEGF mAb