title: GE11-modified liposomes for non-small cell lung cancer targeting: preparation, ex vitro and in vivo evaluation.
abstract: Non-small cell lung cancer (NSCLC) is a serious threat to human health, and 40%-80% of NSCLCs express high levels of epidermal growth factor receptor (EGFR). GE11 is a novel peptide and exhibits high affinity for EGFR binding. The aim of this study was to construct and evaluate GE11-modified liposomes for targeted drug delivery to EGFR-positive NSCLC. Doxorubicin, a broad-spectrum antitumor agent, was chosen as the payload. GE11 was conjugated to the distal end of DSPE-PEG2000-Mal by an addition reaction with a conjugation efficiency above 90%. Doxorubicin-loaded liposomes containing GE11 (GE11-LP/DOX) at densities ranging from 0% to 15% were prepared by combination of a thin film hydration method and a post insertion method. Irrespective of GE11 density, the physicochemical properties of these targeted liposomes, including particle size, zeta potential, and drug entrapment efficiency, were nearly identical. Interestingly, the cytotoxic effect of the liposomes on A549 tumor cells was closely related to GE11 density, and liposomes with 10% GE11 had the highest tumor cell killing activity and a 2.6-fold lower half maximal inhibitory concentration than that of the nontargeted counterpart (PEG-LP/DOX). Fluorescence microscopy and flow cytometry analysis revealed that GE11 significantly increased cellular uptake of the liposomes, which could be ascribed to specific EGFR-mediated endocytosis. It was found that multiple endocytic pathways were involved in entry of GE11-LP/DOX into cells, but GE11 assisted in cellular internalization mainly via the clathrin-mediated endocytosis pathway. Importantly, the GE11-modified liposomes showed enhanced accumulation and prolonged retention in tumor tissue, as evidenced by a 2.2-fold stronger mean fluorescence intensity in tumor tissue than the unmodified liposomes at 24 hours. In summary, GE11-modified liposomes may be a promising platform for targeted delivery of chemotherapeutic drugs in NSCLC.
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China ; Department of Pharmacy, Central Hospital of Zaozhuang Minging Group, Zaozhuang, Shandong Province, People's Republic of China.
authors.forename: Fa-Zhen
authors.initials: FZ
authors.lastname: Huang
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Li-Fang
authors.initials: LF
authors.lastname: Cheng
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Ya-Qin
authors.initials: YQ
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wei
authors.affiliation: Department of Pharmaceutics, College of Pharmaceutical Science, Soochow University, Suzhou, Jiangsu Province, People's Republic of China.
authors.forename: Da-Wei
authors.initials: DW
authors.lastname: Chen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001693:Biological Transport, Active; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage; D016503:Drug Delivery Systems; D004705:Endocytosis; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D008081:Liposomes / Q000008:administration & dosage / Q000737:chemistry; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050997:Nanomedicine; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; C572557:GE11 peptide; D008081:Liposomes; D010455:Peptides; D004317:Doxorubicin; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: cellular uptake mechanism; epidermal growth factor receptor; in vivo imaging; nanosized carrier; targeted drug delivery