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In vivo evaluation of cetuximab-conjugated poly(γ-glutamic acid)-docetaxel nanomedicines in EGFR-overexpressing gastric cancer xenografts

Authors Sreeranganathan M, Uthaman S, Sarmento B, Mohan CG, Park IK, Jayakumar R

Received 8 June 2017

Accepted for publication 9 August 2017

Published 30 September 2017 Volume 2017:12 Pages 7165—7182


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Thomas Webster

Maya Sreeranganathan,1 Saji Uthaman,2 Bruno Sarmento,3–5 Chethampadi Gopi Mohan,1 In-Kyu Park,1 Rangasamy Jayakumar2

1Centre for Nanosciences and Molecular Medicine, Amrita University, Kochi, India; 2Department of Biomedical Science, BK21 PLUS Center for Creative Biomedical Scientists, Chonnam National University Medical School, Gwangju, Republic of Korea; 3I3S – Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal, 4INEB – Instituto de Engenharia Biomédica, University of Porto, Porto, Portugal, 5CESPU, Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Instituto Universitário de Ciências da Saúde, Gandra, Portugal

Abstract: Epidermal growth factor receptor (EGFR), upregulated in gastric cancer patients, is an oncogene of interest in the development of targeted cancer nanomedicines. This study demonstrates in silico modeling of monoclonal antibody cetuximab (CET MAb)-conjugated docetaxel (DOCT)-loaded poly(γ-glutamic acid) (γ-PGA) nanoparticles (Nps) and evaluates the in vitro/in vivo effects on EGFR-overexpressing gastric cancer cells (MKN-28). Nontargeted DOCT-γ-PGA Nps (NT Nps: 110±40 nm) and targeted CET MAb-DOCT-γ-PGA Nps (T Nps: 200±20 nm) were prepared using ionic gelation followed by 1-Ethyl-3-(3-dimethyl aminopropyl)carbodiimide­– N-Hydoxysuccinimide (EDC­– NSH) chemistry. Increased uptake correlated with enhanced cytotoxicity induced by targeted Nps to EGFR +ve MKN-28 compared with nontargeted Nps as evident from MTT and flow cytometric assays. Nanoformulated DOCT showed a superior pharmacokinetic profile to that of free DOCT in Swiss albino mice, indicating the possibility of improved therapeutic effect in the disease model. Qualitative in vivo imaging showed early and enhanced tumor targeted accumulation of CET MAb-DOCT-γ-PGA Nps in EGFR +ve MKN-28–based gastric cancer xenograft, which exhibited efficient arrest of tumor growth compared with nontargeted Nps and free DOCT. Thus, actively targeted CET MAb-DOCT-γ-PGA Nps could be developed as a substitute to conventional nonspecific chemotherapy, and hence could become a feasible strategy for cancer therapy for EGFR-overexpressing gastric tumors.

Keywords: targeted nanoparticles, poly(γ-glutamic acid) nanoparticles, docetaxel, cetuximab, epidermal growth factor receptor, gastric cancer
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