title: Dual targeting for metastatic breast cancer and tumor neovasculature by EphA2-mediated nanocarriers.
abstract: EphA2 is a transmembrane receptor tyrosine kinase that is highly expressed on both tumor neovasculature and some kinds of tumor cells. Here, a homing peptide with a sequence of YSAYPDSVPMMSK (YSA) that binds specifically with EphA2 was utilized to modify the stealth liposomes (YSA-LP). With a particle size of about 85 nm, this functionalized nanocarrier was loaded with fluorescent probe or doxorubicin (DOX) and investigated in vitro and in vivo. In the cellular endocytosis studies in vitro, coumarin-6 loaded YSA-LP exhibited significant specificity to both EphA2-overexpressing tumor cells (MDA-MB-231) and human umbilical vein endothelial cells (HUVEC) via a YSA mediated interaction. In a MDA-MB-231 xenograft tumor mouse model, DiR-loaded YSA-LP showed more lasting accumulation in tumor tissue by small animal imaging compared to unmodified liposomes (LP). Further, YSA-LP greatly facilitated the efficacy of DOX loaded against both tumor cells and tumor angiogenesis in the same mouse model, evidenced by inhibiting tumor growth, metastasis and CD31 expression as well as inducing cancer cell apoptosis. Additionally, YSA-LP (DOX) showed relatively low systemic and cardiac toxicity compared with control groups. In conclusion, YSA might be a promising targeting motif for EphA2-overexpressing tumor cells and tumor neovasculature, which could be used to mediate drug delivery for chemotherapy agents.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China; School of Life Science and Medicine, Dalian University of Technology, Panjin, Liaoning 124221, China.
authors.forename: Zhaoming
authors.initials: Z
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: Medical and Healthy Analytical Center, Peking University, Beijing 100191, China.
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Dai
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xueqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Jiancheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: zqdodo@bjmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008081:Liposomes; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D036104:Receptor, EphA2 / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000970:Antineoplastic Agents; D008081:Liposomes; D010455:Peptides; D010714:Phosphatidylethanolamines; D011092:Polyethylene Glycols; D004317:Doxorubicin; D036104:Receptor, EphA2
keywords: Liposome; Metastatic breast cancer; Targeted delivery; Tumor cells; Tumor neovasculature