title: Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy.
abstract: Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. We have constructed a recombinant protein named anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability. Anti-EGFR-iRGD, which targets EGFR and αvβ3, spreads extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines, multicellular spheroids, and mice. Moreover, anti-EGFR-iRGD could improve anticancer drugs, such as doxorubicin (DOX), bevacizumab, nanoparticle permeability and efficacy in multicellular spheroids. This study draws attention to the importance of iRGD peptide in the therapeutic approach of anti-EGFR-iRGD. As a consequence, anti-EGFR-iRGD could be a drug candidate for cancer treatment and a useful adjunct of other anticancer drugs.
authors.affiliation: The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
authors.forename: Huizi
authors.initials: H
authors.lastname: Sha
authors.affiliation: The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
authors.forename: Zhengyun
authors.initials: Z
authors.lastname: Zou
authors.affiliation: The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Xin
authors.affiliation: The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Bian
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Xueting
authors.initials: X
authors.lastname: Cai
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Wuguang
authors.initials: W
authors.lastname: Lu
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors.forename: Leaf
authors.initials: L
authors.lastname: Huang
authors.affiliation: Division of Molecular Pharmaceutics and Center for Nanotechnology in Drug Delivery, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Blair
authors.affiliation: Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Chinese Medicine, Nanjing, China; Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China. Electronic address: pcao79@yahoo.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Cao
authors.affiliation: The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China. Electronic address: baoruiliu@nju.edu.cn.
authors.forename: Baorui
authors.initials: B
authors.lastname: Liu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000276:immunology*; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008813:Mice, Inbred ICR; D009842:Oligopeptides / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D061905:Single-Domain Antibodies / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D018874:Spheroids, Cellular; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D061905:Single-Domain Antibodies; C047981:arginyl-glycyl-aspartic acid; D066246:ErbB Receptors
keywords: Anti-EGFR sdAb; Doxorubicin hydrochloride (PubChem CID: 443939); Drug delivery; Drug penetration; Fluorescein isothiocyanate (PubChem CID: 18730); Isopropyl β-D-1-thiogalactopyranoside (PubChem CID: 656894); Multicellular spheroids; Paclitaxel (PubChem CID: 36314); Recombinant protein; iRGD