COMSTECH Distinguished Scholar Webinar on Cyclic Peptide-Doxorubicin Conjugates: A Promising Strategy to Overcome Multi-Drug Resistance and Reduce Cancer Treatment Toxicity
By: Prof. Dr. Keykavous Parang Professor, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, California, USA
Date: September 11, 2025, Time: 9:00 AM, (Pakistan Standard Time)
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Abstract of the talk:
The use of doxorubicin (Dox), an anthracycline chemotherapeutic agent, is associated with cardiotoxicity and inherent acquired resistance. Thus, there is an immediate need for delivery systems to minimize toxicity and deliver Dox to sensitive and resistant cells. We have previously shown several cyclic peptides containing alternate tryptophan (W) and arginine (R) residues act as efficient molecular transporters. The peptides were conjugated with Dox via a glutarate linker to afford cyclic peptide-Dox conjugates. While the LC50 values of free and conjugated Dox were comparable to those in wild-type MDA-MB-231 cells (0.45 vs. 0.56 µM, respectively), peptide-conjugated Dox was significantly more effective in both Dox-resistantMDA231R cells (LC50 of 2.3 vs. 14 µM, respectively) and MES-SA/MX2 cells (LC50 of 4.3 vs. 20 µM, respectively). Free Dox (5 µM) reduced the viability of the kidney (LLCP-K1, ATCC CRL-1392) and rat myocardium (H9C2, ATCC CRL 1446) cells by 85% and 44%, respectively. [R5K]W7A-Dox and [R5K]W7C-S-S-Dox showed minimal toxicity to LLCP-K1 (5-7%) and H9C2 (<9%) cells at similar or higher concentrations. Fluorescence micrographs were consistent with cytotoxicity studies, indicating minimal uptake of [R5K]W7A-Dox in heart cells. The total concentration of Dox (conjugated and released) in the nucleus after 4 h exposure to [W9R8K-β-A]-Dox was higher than free Dox. The mechanistic data indicated endocytosis independence and suggested direct trans-membrane localization. Our data show that appropriate peptide-Dox conjugates can effectively internalize into resistant cells that pump out the free drug and do not cause similar toxicity in normal non-cancerous cells.
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Webinar Coordinator:
M. Haseeb Ahmad
Program Officer
Haseeb.ahmad@comstech.org