Cathepsin B-Cleavable Cyclopeptidic Chemotherapeutic Prodrugs.
Amino Acid Sequence
Antibiotics, Antineoplastic
/ chemistry
Cathepsin B
/ metabolism
Cell Line, Tumor
Cell Membrane Permeability
/ drug effects
Cell Survival
/ drug effects
Click Chemistry
Doxorubicin
/ chemistry
G2 Phase Cell Cycle Checkpoints
/ drug effects
Humans
Peptides, Cyclic
/ chemistry
Polyethylene Glycols
/ chemistry
Prodrugs
/ chemistry
Solubility
RAFT
cathepsin B
doxorubicin
poly (ethylene glycol)
prodrug
Journal
Molecules (Basel, Switzerland)
ISSN: 1420-3049
Titre abrégé: Molecules
Pays: Switzerland
ID NLM: 100964009
Informations de publication
Date de publication:
18 Sep 2020
18 Sep 2020
Historique:
received:
13
03
2020
revised:
14
09
2020
accepted:
15
09
2020
entrez:
23
9
2020
pubmed:
24
9
2020
medline:
11
3
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32962018
pii: molecules25184285
doi: 10.3390/molecules25184285
pmc: PMC7570921
pii:
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
Peptides, Cyclic
0
Prodrugs
0
Polyethylene Glycols
3WJQ0SDW1A
Doxorubicin
80168379AG
Cathepsin B
EC 3.4.22.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
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