title: The impact of a chlorotoxin-modified liposome system on receptor MMP-2 and the receptor-associated protein ClC-3.
abstract: Currently, it is unknown whether a receptor-associated protein will be affected when a ligand modified delivery system interacts with its receptor. Besides, chlorotoxin (ClTx)-modified liposomes can target to glioma cells, but the target molecule is not clear: MMP-2, ClC-3 or both? Here a comparative study of ClTx-conjugated liposomes was conducted on two types of tumor cells: U87, a human glioma cell line with high expression of both MMP-2 and ClC-3, and A549, a human lung cancer cell line with expression of only MMP-2. ClTx-modified liposomes behaved similarly in these two cancer cells in terms of in vitro cell uptake, endocytosis pathway, intracellular trafficking and in vivo targeting efficacy, though the two tested cell lines were very different in ClC-3 expression. These results revealed that the targeted delivery of ClTx modified liposomes to U87 tumor was MMP-2-mediated and not correlated with the chloride channel ClC-3. On the other hand, ClTx modified on the liposomes did activate the receptor-associated protein ClC-3 via the binding with MMP-2, leading to the inhibition on cell migration and chloride currents. This is significant because cell migration is a key step in tumor metastasis. Interestingly, higher in vitro cellular uptake and lower in vivo tumor accumulation of liposomal systems was found in U87 compared to the A549 model, possibly due to the biological differences between in vitro and in vivo models. In general, ClTx-modified delivery systems may potentially target to tumors other than glioma that express a high level of MMP-2, and its effect on ClC-3 may help prevent tumor metastasis.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road, Beijing 100191, China; Key Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Tongjia Xiang, Nanjing 210009, Jiangsu, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road, Beijing 100191, China.
authors.forename: Bing
authors.initials: B
authors.lastname: He
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road, 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, Xueyuan Road, Beijing 100191, China.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road, 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, Xueyuan Road, 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, Xueyuan Road, 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, Xueyuan Road, Beijing 100191, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Tongjia Xiang, Nanjing 210009, Jiangsu, China. Electronic address: guangjiwang@hotmail.com.
authors.forename: Guangji
authors.initials: G
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road, Beijing 100191, China; Key Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Tongjia Xiang, Nanjing 210009, Jiangsu, China. Electronic address: lifangyin@hotmail.com.
authors.forename: Lifang
authors.initials: L
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xueyuan Road, Beijing 100191, China. Electronic address: zqdodo@bjmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000378:metabolism*; D016503:Drug Delivery Systems; D006801:Humans; D008081:Liposomes / Q000737:chemistry* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D012604:Scorpion Venoms / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018118:Chloride Channels; C115376:ClC-3 channel; D008081:Liposomes; D012604:Scorpion Venoms; C091539:Chlorotoxin; D020778:Matrix Metalloproteinase 2
keywords: Chlorotoxin; ClC-3; MMP-2; Receptor-associated protein; Targeting drug delivery system