Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer.
Gemcitabine
Nanoscale delivery
Pancreatic cancer
miR-345
Journal
Journal of controlled release : official journal of the Controlled Release Society
ISSN: 1873-4995
Titre abrégé: J Control Release
Pays: Netherlands
ID NLM: 8607908
Informations de publication
Date de publication:
28 01 2019
28 01 2019
Historique:
received:
22
06
2018
accepted:
17
12
2018
pubmed:
24
12
2018
medline:
21
3
2020
entrez:
22
12
2018
Statut:
ppublish
Résumé
A polymeric dual delivery nanoscale device (DDND) was designed for combined delivery of microRNA (miR-345) and gemcitabine (GEM) to treat pancreatic cancer (PC). This temperature and pH-responsive pentablock copolymer system was able to restore miR-345, making xenograft tumors more susceptible to GEM, the standard therapy for PC. Restoration using DDND treatment results in sonic hedgehog signaling down regulation, which decreases desmoplasia, thereby resulting in improved GEM perfusion to the tumor and better therapeutic outcomes. The release of miR-345 and GEM could be tuned by using the DDND in the form of micelles or in the form of thermoreversible gels, based on polymer concentration. The DDNDs enabled miR-345 stability and sustained co-release of miR-345 and GEM, thereby facilitating dose-sparing use of GEM. Further, enhanced in vitro cellular uptake due to amphiphilic character, and endosomal escape because of the cationic end blocks led to efficient transfection with DDNDs. The combined DDND treatment enabled efficient reduction in cell viability of Capan-1 and CD18/HPAF cells in vitro compared with either GEM or miR-345 treatment alone. Mice carrying xenograft tumors treated with DDNDs carrying both miR-345 and GEM combination therapy displayed reduced tumor growth and less metastasis in distant organs compared to individual drug treatments. Immunohistochemical analysis of the xenograft tissues revealed significant down regulation of desmoplastic reaction, SHH, Gli-1, MUC4, and Ki67 compared to control groups.
Identifiants
pubmed: 30576747
pii: S0168-3659(18)30734-X
doi: 10.1016/j.jconrel.2018.12.031
pmc: PMC6379902
mid: NIHMS1517308
pii:
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
MIRN345 microRNA, human
0
MicroRNAs
0
Deoxycytidine
0W860991D6
Gemcitabine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
237-246Subventions
Organisme : NCI NIH HHS
ID : P50 CA127297
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA183459
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM113166
Pays : United States
Informations de copyright
Copyright © 2018 Elsevier B.V. All rights reserved.
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