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Published on: September 10, 2018
Synthesis and Biological Evaluation of RGD⁻Cryptophycin Conjugates for Targeted Drug Delivery
Adina Borbély1, Eduard Figueras2, Ana Martins3,4
1Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, Germany. adina.borbely@uni-bielefeld.de.
Abstract:
Cryptophycins are potent tubulin polymerization inhibitors with picomolar antiproliferative potency in vitro and activity against multidrug-resistant (MDR) cancer cells. Because of neurotoxic side effects and limited efficacy in vivo, cryptophycin-52 failed as a clinical candidate in cancer treatment. However, this class of compounds has emerged as attractive payloads for tumor-targeting applications. In this study, cryptophycin was conjugated to the cyclopeptide c(RGDfK), targeting integrin αvβ₃, across the protease-cleavable Val-Cit linker and two different self-immolative spacers. Plasma metabolic stability studies in vitro showed that our selected payload displays an improved stability compared to the parent compound, while the stability of the conjugates is strongly influenced by the self-immolative moiety. Cathepsin B cleavage assays revealed that modifications in the linker lead to different drug release profiles. Antiproliferative effects of Arg-Gly-Asp (RGD)⁻cryptophycin conjugates were evaluated on M21 and M21-L human melanoma cell lines. The low nanomolar in vitro activity of the novel conjugates was associated with inferior selectivity for cell lines with different integrin αvβ₃ expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy.
Insights
Novel drug conjugates utilize cryptophycin, a potent anticancer agent, linked to targeting peptides for improved cancer therapy. These conjugates show promise against multidrug-resistant cells, though further optimization is needed for better selectivity and in vivo efficacy.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Cryptophycins are potent tubulin polymerization inhibitors with high in vitro anticancer activity.
- Previous clinical trials failed due to neurotoxicity and limited in vivo efficacy.
- Cryptophycins are being re-evaluated as payloads for targeted cancer therapies.
Purpose of the Study:
- To develop novel cryptophycin conjugates targeting integrin αvβ3 for cancer treatment.
- To evaluate the stability, drug release, and antiproliferative activity of these conjugates.
- To investigate the drug delivery mechanism using infrared dye-labeled conjugates.
Main Methods:
- Conjugation of cryptophycin to c(RGDfK) via Val-Cit linker and self-immolative spacers.
- In vitro plasma metabolic stability and Cathepsin B cleavage assays.
- Antiproliferative assays on M21 and M21-L melanoma cell lines and confocal microscopy studies.
Main Results:
- The selected cryptophycin payload demonstrated improved metabolic stability.
- Conjugate stability and drug release profiles were influenced by the self-immolative moiety.
- Conjugates exhibited low nanomolar in vitro activity but lacked selectivity based on integrin αvβ3 expression.
Conclusions:
- Targeted cryptophycin conjugates show potential for cancer therapy, particularly against MDR cells.
- Linker modifications influence drug release and conjugate stability.
- Further research is needed to enhance selectivity and in vivo performance for clinical application.
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