title: Vascular-targeted TNFα improves tumor blood vessel function and enhances antitumor immunity and chemotherapy in colorectal cancer.
abstract: Delivery and penetration of chemotherapeutic drugs into neoplasm through the tumor vasculature are essential mechanisms to enhance the efficiency of chemotherapy. "Vascular targeting" strategy focuses on promoting the infiltration of chemotherapeutic drugs into neoplastic tissues. In this study, we achieved a targeted therapy by coupling tumor necrosis factor α (TNFα) with TCP-1, a novel vascular-targeting peptide, in an orthotopic colorectal cancer model in mice. High dose of TCP-1-conjugated TNFα (TCP-1/TNFα: 5μg/mouse) displayed potent antitumor activity by inducing apoptosis and reducing microvessel number in tumors than unconjugated TNFα, with no evidence of increased toxicity. In the combined therapy, the antitumor action of 5-fluorouracil (5-FU) was potentiated when the mice were pretreated with a low dose of TNFα (1ng/mouse) and to a greater extent by the same concentration of TCP-1/TNFα. In this regard, TCP-1/TNFα combined with 5-FU synergistically inhibited the tumor growth, induced apoptosis and reduced cell proliferation. More importantly, TCP-1/TNFα normalized the tumor vasculature and facilitated the infiltration of immune cells to neoplasm as well as attenuated the immunosuppressing effects of TNFα in bone marrow and spleen. At the same time, TCP-1/TNFα significantly improved 5-FU absorption into the tumor mass. Taken together, these findings underscore the therapeutic potential of TCP-1 as a drug carrier in cancer therapy. TCP-1 is a novel vascular-targeting peptide and appears to be a promising agent for drug delivery. TCP-1 fused with TNFα holds great promise for colorectal cancer therapy.
authors.affiliation: Sichuan Industrial Institute of Antibiotics, Chengdu University, Chengdu, PR China.; School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Lan
authors.initials: L
authors.lastname: Lu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China. Electronic address: jackylizhijie@gmail.com.
authors.forename: Zhi Jie
authors.initials: ZJ
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Long Fei
authors.initials: LF
authors.lastname: Li
authors.affiliation: Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: William Ka Kei
authors.initials: WK
authors.lastname: Wu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Shen
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Ruby Lok Yi
authors.initials: RL
authors.lastname: Chan
authors.affiliation: School of Pharmacy, Southern Medical University, Guangzhou, PR China.
authors.forename: Le
authors.initials: L
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, PR China.
authors.forename: Ya Wei
authors.initials: YW
authors.lastname: Liu
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Shun Xiang
authors.initials: SX
authors.lastname: Ren
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China.
authors.forename: Kam Ming
authors.initials: KM
authors.lastname: Chan
authors.affiliation: School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, PR China. Electronic address: chcho@cuhk.edu.hk.
authors.forename: Chi Hin
authors.initials: CH
authors.lastname: Cho
mesh_terms: D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D001853:Bone Marrow / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005472:Fluorouracil / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D049452:Green Fluorescent Proteins / Q000008:administration & dosage / Q000737:chemistry; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D013154:Spleen / Q000187:drug effects; D047368:Tumor Burden / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D057846:Cell-Penetrating Peptides; D014409:Tumor Necrosis Factor-alpha; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005472:Fluorouracil
keywords: Antitumor therapy; Colorectal cancer; Drug delivery; TNFα; Vascular targeting peptide