Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer.


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
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

237-246

Subventions

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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Auteurs

Metin Uz (M)

Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA.

Manisha Kalaga (M)

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.

Ramesh Pothuraju (R)

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.

Juhyung Ju (J)

Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA.

Wade M Junker (WM)

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Sanguine Diagnostics and Therapeutics, Omaha, NE, USA.

Surinder K Batra (SK)

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Fred and Pamela Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA; Eppley Institute for Research in Cancer & Allied Diseases, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.

Surya Mallapragada (S)

Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA. Electronic address: suryakm@iastate.edu.

Satyanarayana Rachagani (S)

Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: srachagani@unmc.edu.

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