Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy

JOURNAL OF CONTROLLED RELEASE

卷:200

Article

Sha, Huizi^1,2  Zou, Zhengyun^1,2  Xin, Kai^1,2  Bian, Xinyu^1,2  Cai, Xueting^3,4  Lu, Wuguang^3,4  Chen, Jiao^3,4  Chen, Gang⁵  Huang, Leaf^6,7  Blair, Andrew M.^6,7  Cao, Peng^3,4  Liu, Baorui^1,2 

[1] Nanjing Univ, Ctr Comprehens Canc, Drum Tower Hosp, Sch Med, Nanjing 210008, Peoples R China

[2] Nanjing Univ, Clin Canc Inst, Nanjing 210008, Peoples R China

[3] Jiangsu Prov Acad Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Jiangsu, Peoples R China

[4] Nanjing Univ Chinese Med, Jiangsu Prov Hosp Integrat Chinese & Western Med, Nanjing, Jiangsu, Peoples R China

[5] China Pharmaceut Univ, Sch Life Sci & Technol, State Key Lab Nat Med, Nanjing, Jiangsu, Peoples R China

[6] Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC USA

[7] Univ N Carolina, Eshelman Sch Pharm, Ctr Nanotechnol Drug Delivery, Chapel Hill, NC USA

关键词: Recombinant protein;    iRGD;    Anti-EGFR sdAb;    Multicellular spheroids;    Drug penetration;    Drug delivery;   

DOI  :  10.1016/j.jconrel.2014.12.039

来源: Elsevier

【 摘 要 】

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 alpha v beta 3, 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. (C) 2014 Elsevier B.V. All rights reserved.

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