A 3D culture platform enables development of zinc-binding prodrugs for targeted proliferation of β cells.
Journal
Science advances
ISSN: 2375-2548
Titre abrégé: Sci Adv
Pays: United States
ID NLM: 101653440
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
23
04
2020
accepted:
07
10
2020
entrez:
19
11
2020
pubmed:
20
11
2020
medline:
15
4
2022
Statut:
epublish
Résumé
Advances in treating β cell loss include islet replacement therapies or increasing cell proliferation rate in type 1 and type 2 diabetes, respectively. We propose developing multiple proliferation-inducing prodrugs that target high concentration of zinc ions in β cells. Unfortunately, typical two-dimensional (2D) cell cultures do not mimic in vivo conditions, displaying a markedly lowered zinc content, while 3D culture systems are laborious and expensive. Therefore, we developed the Disque Platform (DP)-a high-fidelity culture system where stem cell-derived β cells are reaggregated into thin, 3D discs within 2D 96-well plates. We validated the DP against standard 2D and 3D cultures and interrogated our zinc-activated prodrugs, which release their cargo upon zinc chelation-so preferentially in β cells. Through developing a reliable screening platform that bridges the advantages of 2D and 3D culture systems, we identified an effective hit that exhibits 2.4-fold increase in β cell proliferation compared to harmine.
Identifiants
pubmed: 33208361
pii: 6/47/eabc3207
doi: 10.1126/sciadv.abc3207
pmc: PMC7673808
pii:
doi:
Substances chimiques
Prodrugs
0
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK113597
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK104165
Pays : United States
Organisme : NIDDK NIH HHS
ID : UC4 DK116255
Pays : United States
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
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