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EGFR Targeted Cetuximab-Valine-Citrulline (vc)-Doxorubicin Immunoconjugates- Loaded Bovine Serum Albumin (BSA) Nanoparticles for Colorectal Tumor Therapy

Authors Ye Z, Zhang Y, Liu Y, Liu Y, Tu J, Shen Y

Received 28 October 2020

Accepted for publication 15 February 2021

Published 26 March 2021 Volume 2021:16 Pages 2443—2459


Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Mian Wang

Zixuan Ye,1,* Yue Zhang,1,* Yuanfen Liu,2,* Yanyan Liu,1 Jiasheng Tu,1 Yan Shen1

1Department of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, Nanjing, People’s Republic of China; 2Jiangsu Health Vocational College, Nanjing, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Yan Shen; Jiasheng Tu
Department of Pharmaceutics, State Key Laboratory of Nature Medicines, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, People’s Republic of China
Tel +86 25 83271305
Email [email protected]; [email protected]

Background: Specific modifications to carriers to achieve targeted delivery of chemotherapeutics into malignant tissues are a critical point for efficient diagnosis and therapy. In this case, bovine serum albumin (BSA) was conjugated with cetuximab–valine–citrulline (vc)–doxorubicin (DOX) to target epidermal growth factor receptor (EGFR) and enable the release of drug in EGFR-overexpressed tumor cells.
Methods: Maleimidocaproyl–valine–citrulline–p-aminobenzylcarbonyl-p-nitrophenol (MC-Val-Cit-PAB-PNP) and DOX were used to synthesize MC-Val-Cit-PAB-DOX, which was further linked with cetuximab to prepare antibody–drug conjugates (ADCs). Then, the ADCs were adsorbed to the surface of the BSA nanoparticles (NPs), which were prepared by a desolvation method to obtain cetuximab-vc-DOX-BSA-NPs. The cetuximab-vc-DOX conjugates adsorbed on the surface of the BSA nanoparticles were determined and optimized by size exclusion chromatography. An in vitro cytotoxicity study was conducted using a colon carcinoma cell line with different EGFR-expression levels to test the selectivity of cetuximab-vc-DOX-NPs.
Results: The vc-DOX and cetuximab-vc-DOX conjugates were both synthesized successfully and their structural characteristics confirmed by 1H-NMR and SDS-PAGE. The MTT assay showed stronger cytotoxicity of cetuximab-vc-DOX-NPs versus control IgG-vc-DOX-NPs in EGFR–overexpressing RKO cells. Cellular binding and intracellular accumulation determined by flow cytometry and confocal laser scanning microscopy revealed the strong binding ability of cetuximab-vc-DOX-NPs to RKO cells. The in vivo imaging study demonstrated that cetuximab-vc-DOX-NPs exhibited higher fluorescent intensity in tumor tissues than non-decorated nanoparticles (IgG-vc-DOX-NPs). In vivo tumor inhibition and survival tests showed that cetuximab-vc-DOX-NPs revealed higher tumor inhibition efficacy and lower systemic toxicity than control IgG-vc-DOX- NPs
Conclusion: The obtained results emphasize that cetuximab-vc-DOX-NPs, with good tumor-targeting ability and low systemic toxicity, are a promising targeting system for drug delivery.

Keywords: bovine serum albumin, antibody–drug conjugate, cetuximab, doxorubicin, colonic carcinoma, epidermal growth factor receptor

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