Journal
ONCOTARGET
Volume 8, Issue 1, Pages 757-768Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12748
Keywords
targeted drug delivery; human metastatic melanoma; Integrin alpha v beta 3; non-RGD; conjugate
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Funding
- Ariel Center for Applied Cancer Research
- Israel Cancer Research Fund (ICRF) [14-109-RCDA]
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The newly discovered short (9 amino acid) non-RGD S-S bridged cyclic peptide ALOS-4 (H-cycl(Cys-Ser-Ser-Ala-Gly-Ser-Leu-Phe-Cys)-OH),which binds to integrin alpha(v)beta(3) is investigated as peptide carrier for targeted drug delivery against human metastatic melanoma. ALOS4 binds specifically the alpha(v)beta(3) overexpressing human metastatic melanoma WM-266-4 cell line both in vitro and in ex vivo assays. Coupling ALOS4 to the topoisomerase I inhibitor Camptothecin (ALOS4-CPT) increases the cytotoxicity of CPT against human metastatic melanoma cells while reduces dramatically the cytotoxicity against non-cancerous cells as measured by the levels of gH2A. X, active caspase 3 and cell viability. Moreover, conjugating ALOS4 to CPT even increases the chemo-stability of CPT under physiological pH. Bioinformatic analysis using Rosetta platform revealed potential docking sites of ALOS4 on the alpha(v)beta(3) integrin which are distinct from the RGD binding sites. We propose to use this specific non-RGD cyclic peptide as the therapeutic carrier for conjugation of drugs in order to improve efficacy and reduce toxicity of currently available treatments of human malignant melanoma.
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