Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs
Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its...
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doaj-c0c063228ac94ad582621383e590b86a2020-11-25T03:33:11ZengMDPI AGMolecules1420-30492020-09-01254285428510.3390/molecules25184285Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic ProdrugsViktorija Herceg0Jordan Bouilloux1Karolina Janikowska2Eric Allémann3Norbert Lange4Laboratory of Pharmaceutical Technology, School of Pharmaceutical Sciences, ISPSO, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneve, SwitzerlandLaboratory of Pharmaceutical Technology, School of Pharmaceutical Sciences, ISPSO, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneve, SwitzerlandLaboratory of Pharmaceutical Technology, School of Pharmaceutical Sciences, ISPSO, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneve, SwitzerlandLaboratory of Pharmaceutical Technology, School of Pharmaceutical Sciences, ISPSO, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneve, SwitzerlandLaboratory of Pharmaceutical Technology, School of Pharmaceutical Sciences, ISPSO, University of Geneva, Rue Michel-Servet 1, CH-1211 Geneve, SwitzerlandCyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its toxicity, we used a Cathepsin B (Cat B)-sensitive prodrug concept for its targeted release since this enzyme is frequently overexpressed in cancer cells. Copper-free “click” chemistry was used to synthesize cPCPs containing up to four DOX moieties tethered to the upper face of the scaffold through a Cat B-cleavable peptidic linker (GAGRRAAG). On the lower part, PEG 5, 10 and 20 kDa and a fifth peptidyl DOX moiety were grafted in order to improve the solubility, bioavailability and pharmacokinetic profiles of the compound. In vitro results on HT1080 human fibrosarcoma cells showed that cPCPs display a delayed action that consists of a cell cycle arrest in the G2 phase comparable to DOX alone, and increased cell membrane permeability.https://www.mdpi.com/1420-3049/25/18/4285RAFTcathepsin Bprodrugdoxorubicinpoly (ethylene glycol) |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Viktorija Herceg Jordan Bouilloux Karolina Janikowska Eric Allémann Norbert Lange |
spellingShingle |
Viktorija Herceg Jordan Bouilloux Karolina Janikowska Eric Allémann Norbert Lange Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs Molecules RAFT cathepsin B prodrug doxorubicin poly (ethylene glycol) |
author_facet |
Viktorija Herceg Jordan Bouilloux Karolina Janikowska Eric Allémann Norbert Lange |
author_sort |
Viktorija Herceg |
title |
Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs |
title_short |
Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs |
title_full |
Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs |
title_fullStr |
Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs |
title_full_unstemmed |
Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs |
title_sort |
cathepsin b-cleavable cyclopeptidic chemotherapeutic prodrugs |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2020-09-01 |
description |
Cyclopeptidic chemotherapeutic prodrugs (cPCPs) are macromolecular protease-sensitive doxorubicin (DOX) prodrugs synthesized from a cyclodecapeptidic scaffold, termed Regioselectively Addressable Functionalized Template (RAFT). In order to increase the chemotherapeutic potential of DOX and limit its toxicity, we used a Cathepsin B (Cat B)-sensitive prodrug concept for its targeted release since this enzyme is frequently overexpressed in cancer cells. Copper-free “click” chemistry was used to synthesize cPCPs containing up to four DOX moieties tethered to the upper face of the scaffold through a Cat B-cleavable peptidic linker (GAGRRAAG). On the lower part, PEG 5, 10 and 20 kDa and a fifth peptidyl DOX moiety were grafted in order to improve the solubility, bioavailability and pharmacokinetic profiles of the compound. In vitro results on HT1080 human fibrosarcoma cells showed that cPCPs display a delayed action that consists of a cell cycle arrest in the G2 phase comparable to DOX alone, and increased cell membrane permeability. |
topic |
RAFT cathepsin B prodrug doxorubicin poly (ethylene glycol) |
url |
https://www.mdpi.com/1420-3049/25/18/4285 |
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