Egfr targeted cetuximab-valine-citrulline (Vc)-doxorubicin immunoconjugates-loaded bovine serum albumin (bsa) nanoparticles for colorectal tumor therapy

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Abstract

Background: Specific modifications to carriers to achieve targeted delivery of chemother-apeutics 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 chromato-graphy. 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 success-fully and their structural characteristics confirmed by1H-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 demon-strated 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.

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Ye, Z., Zhang, Y., Liu, Y., Liu, Y., Tu, J., & Shen, Y. (2021). Egfr targeted cetuximab-valine-citrulline (Vc)-doxorubicin immunoconjugates-loaded bovine serum albumin (bsa) nanoparticles for colorectal tumor therapy. International Journal of Nanomedicine, 16, 2443–2459. https://doi.org/10.2147/IJN.S289228

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