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EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer

Prostate cancer (PCa) is the most common malignancy in men and is the leading cause of cancer-related male mortality. A disulfide cyclic peptide ligand [CTVRTSADC] 1 has been previously found to target extra domain B of fibronectin (EDB-FN) in the extracellular matrix that can differentiate aggressi...

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Autores principales: Park, Shang Eun, Shamloo, Kiumars, Kristedja, Timothy A., Darwish, Shaban, Bisoffi, Marco, Parang, Keykavous, Tiwari, Rakesh Kumar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651341/
https://www.ncbi.nlm.nih.gov/pubmed/31277465
http://dx.doi.org/10.3390/ijms20133291
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author Park, Shang Eun
Shamloo, Kiumars
Kristedja, Timothy A.
Darwish, Shaban
Bisoffi, Marco
Parang, Keykavous
Tiwari, Rakesh Kumar
author_facet Park, Shang Eun
Shamloo, Kiumars
Kristedja, Timothy A.
Darwish, Shaban
Bisoffi, Marco
Parang, Keykavous
Tiwari, Rakesh Kumar
author_sort Park, Shang Eun
collection PubMed
description Prostate cancer (PCa) is the most common malignancy in men and is the leading cause of cancer-related male mortality. A disulfide cyclic peptide ligand [CTVRTSADC] 1 has been previously found to target extra domain B of fibronectin (EDB-FN) in the extracellular matrix that can differentiate aggressive PCa from benign prostatic hyperplasia. We synthesized and optimized the stability of ligand 1 by amide cyclization to obtain [KTVRTSADE] 8 using Fmoc/tBu solid-phase chemistry. Optimized targeting ligand 8 was found to be stable in phosphate buffered saline (PBS, pH 6.5, 7.0, and 7.5) and under redox conditions, with a half-life longer than 8 h. Confocal microscopy studies demonstrated increased binding of ligand 8 to EDB-FN compared to ligand 1. Therefore, we hypothesized that the EDB-FN targeted peptides (1 and 8) conjugated with an anticancer drug via a hydrolyzable linker would provide selective cytotoxicity to the cancer cells. To test our hypothesis, we selected both the normal prostate cell line, RWPE-1, and the cancerous prostate cell lines, PC3, DU-145, LNCaP, and C4-2, to evaluate the anticancer activity of synthesized peptide–drug conjugates. Docetaxel (Doce) and doxorubicin (Dox) were used as anticancer drugs. Dox conjugate 13 containing disulfide linkage showed comparable cytotoxicity versus Dox after 72 h incubation in all the cancer cell lines, whereas it was found to be less cytotoxic on RWPE-1, suggesting that it can act as a Dox prodrug. Doce conjugate 14 was found to be less cytotoxic in all the cell lines as compared to drug alone.
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spelling pubmed-66513412019-08-08 EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer Park, Shang Eun Shamloo, Kiumars Kristedja, Timothy A. Darwish, Shaban Bisoffi, Marco Parang, Keykavous Tiwari, Rakesh Kumar Int J Mol Sci Article Prostate cancer (PCa) is the most common malignancy in men and is the leading cause of cancer-related male mortality. A disulfide cyclic peptide ligand [CTVRTSADC] 1 has been previously found to target extra domain B of fibronectin (EDB-FN) in the extracellular matrix that can differentiate aggressive PCa from benign prostatic hyperplasia. We synthesized and optimized the stability of ligand 1 by amide cyclization to obtain [KTVRTSADE] 8 using Fmoc/tBu solid-phase chemistry. Optimized targeting ligand 8 was found to be stable in phosphate buffered saline (PBS, pH 6.5, 7.0, and 7.5) and under redox conditions, with a half-life longer than 8 h. Confocal microscopy studies demonstrated increased binding of ligand 8 to EDB-FN compared to ligand 1. Therefore, we hypothesized that the EDB-FN targeted peptides (1 and 8) conjugated with an anticancer drug via a hydrolyzable linker would provide selective cytotoxicity to the cancer cells. To test our hypothesis, we selected both the normal prostate cell line, RWPE-1, and the cancerous prostate cell lines, PC3, DU-145, LNCaP, and C4-2, to evaluate the anticancer activity of synthesized peptide–drug conjugates. Docetaxel (Doce) and doxorubicin (Dox) were used as anticancer drugs. Dox conjugate 13 containing disulfide linkage showed comparable cytotoxicity versus Dox after 72 h incubation in all the cancer cell lines, whereas it was found to be less cytotoxic on RWPE-1, suggesting that it can act as a Dox prodrug. Doce conjugate 14 was found to be less cytotoxic in all the cell lines as compared to drug alone. MDPI 2019-07-04 /pmc/articles/PMC6651341/ /pubmed/31277465 http://dx.doi.org/10.3390/ijms20133291 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Park, Shang Eun
Shamloo, Kiumars
Kristedja, Timothy A.
Darwish, Shaban
Bisoffi, Marco
Parang, Keykavous
Tiwari, Rakesh Kumar
EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer
title EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer
title_full EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer
title_fullStr EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer
title_full_unstemmed EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer
title_short EDB-FN Targeted Peptide–Drug Conjugates for Use against Prostate Cancer
title_sort edb-fn targeted peptide–drug conjugates for use against prostate cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651341/
https://www.ncbi.nlm.nih.gov/pubmed/31277465
http://dx.doi.org/10.3390/ijms20133291
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