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

Autor: Uz M; Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA., Kalaga M; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Pothuraju R; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA., Ju J; Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA., Junker WM; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; Sanguine Diagnostics and Therapeutics, Omaha, NE, USA., 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., Mallapragada S; Department of Chemical and Biological Engineering, Iowa State University, Ames, IA, USA. Electronic address: suryakm@iastate.edu., Rachagani S; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: srachagani@unmc.edu.
Jazyk: angličtina
Zdroj: Journal of controlled release : official journal of the Controlled Release Society [J Control Release] 2019 Jan 28; Vol. 294, pp. 237-246. Date of Electronic Publication: 2018 Dec 18.
DOI: 10.1016/j.jconrel.2018.12.031
Abstrakt: 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.
(Copyright © 2018 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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