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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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2020-09, Vol.25 (18), p.4285
Main Authors: Herceg, Viktorija, Bouilloux, Jordan, Janikowska, Karolina, Allémann, Eric, Lange, Norbert
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - metabolism
cathepsin B
Cathepsin B - metabolism
Cell Line, Tumor
Cell Membrane Permeability - drug effects
Cell Survival - drug effects
Click Chemistry
doxorubicin
Doxorubicin - chemistry
Doxorubicin - metabolism
Doxorubicin - pharmacology
G2 Phase Cell Cycle Checkpoints - drug effects
Humans
Peptides, Cyclic - chemistry
Peptides, Cyclic - metabolism
poly (ethylene glycol)
Polyethylene Glycols - chemistry
prodrug
Prodrugs - chemistry
Prodrugs - metabolism
Prodrugs - pharmacology
RAFT
Solubility
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules25184285