Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery
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 treatmen...
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MDPI AG
2019-04-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/11/4/151 |
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doaj-8e55442c453b47dfb515e3a4632fb51a2020-11-25T01:05:22ZengMDPI AGPharmaceutics1999-49232019-04-0111415110.3390/pharmaceutics11040151pharmaceutics11040151Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug DeliveryAdina Borbély0Eduard Figueras1Ana Martins2Simone Esposito3Giulio Auciello4Edith Monteagudo5Annalise Di Marco6Vincenzo Summa7Paola Cordella8Raffaella Perego9Isabell Kemker10Marcel Frese11Paola Gallinari12Christian Steinkühler13Norbert Sewald14Organic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, GermanyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, GermanyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, GermanyIRBM S.p.A, Via Pontina km. 30,600, IT-00071 Pomezia (Rome), ItalyIRBM S.p.A, Via Pontina km. 30,600, IT-00071 Pomezia (Rome), ItalyIRBM S.p.A, Via Pontina km. 30,600, IT-00071 Pomezia (Rome), ItalyIRBM S.p.A, Via Pontina km. 30,600, IT-00071 Pomezia (Rome), ItalyIRBM S.p.A, Via Pontina km. 30,600, IT-00071 Pomezia (Rome), ItalyItalfarmaco S.p.A., Via dei Lavoratori, 54, IT-20092 Cinisello Balsamo (Milano), ItalyItalfarmaco S.p.A., Via dei Lavoratori, 54, IT-20092 Cinisello Balsamo (Milano), ItalyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, GermanyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, GermanyExiris s.r.l., Via di Castel Romano 100, IT-00128 Rome, ItalyExiris s.r.l., Via di Castel Romano 100, IT-00128 Rome, ItalyOrganic and Bioorganic Chemistry, Department of Chemistry, Bielefeld University, Universitätsstraße 25, DE-33615 Bielefeld, GermanyCryptophycins 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 <i>c</i>(RGDfK), targeting integrin α<sub>v</sub>β<sub>3</sub>, 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 α<sub>v</sub>β<sub>3</sub> expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy.https://www.mdpi.com/1999-4923/11/4/151antitumor agentssmall molecule–drug conjugatesdrug deliveryRGD peptides |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Adina Borbély Eduard Figueras Ana Martins Simone Esposito Giulio Auciello Edith Monteagudo Annalise Di Marco Vincenzo Summa Paola Cordella Raffaella Perego Isabell Kemker Marcel Frese Paola Gallinari Christian Steinkühler Norbert Sewald |
| spellingShingle |
Adina Borbély Eduard Figueras Ana Martins Simone Esposito Giulio Auciello Edith Monteagudo Annalise Di Marco Vincenzo Summa Paola Cordella Raffaella Perego Isabell Kemker Marcel Frese Paola Gallinari Christian Steinkühler Norbert Sewald Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery Pharmaceutics antitumor agents small molecule–drug conjugates drug delivery RGD peptides |
| author_facet |
Adina Borbély Eduard Figueras Ana Martins Simone Esposito Giulio Auciello Edith Monteagudo Annalise Di Marco Vincenzo Summa Paola Cordella Raffaella Perego Isabell Kemker Marcel Frese Paola Gallinari Christian Steinkühler Norbert Sewald |
| author_sort |
Adina Borbély |
| title |
Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery |
| title_short |
Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery |
| title_full |
Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery |
| title_fullStr |
Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery |
| title_full_unstemmed |
Synthesis and Biological Evaluation of RGD–Cryptophycin Conjugates for Targeted Drug Delivery |
| title_sort |
synthesis and biological evaluation of rgd–cryptophycin conjugates for targeted drug delivery |
| publisher |
MDPI AG |
| series |
Pharmaceutics |
| issn |
1999-4923 |
| publishDate |
2019-04-01 |
| description |
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 <i>c</i>(RGDfK), targeting integrin α<sub>v</sub>β<sub>3</sub>, 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 α<sub>v</sub>β<sub>3</sub> expression levels. To elucidate the drug delivery process, cryptophycin was replaced by an infrared dye and the obtained conjugates were studied by confocal microscopy. |
| topic |
antitumor agents small molecule–drug conjugates drug delivery RGD peptides |
| url |
https://www.mdpi.com/1999-4923/11/4/151 |
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