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

Metin Uz, Manisha Kalaga, Ramesh Pothuraju, Juhyung Ju, Wade M. Junker, Surinder Kumar Batra, Surya Mallapragada, Satyanarayana Rachagani

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)237-246
Number of pages10
JournalJournal of Controlled Release
Volume294
DOIs
StatePublished - Jan 28 2019

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gemcitabine
Pancreatic Neoplasms
Equipment and Supplies
Heterografts
Neoplasms
Down-Regulation
Hedgehogs
Micelles
MicroRNAs
Transfection
Cell Survival

Keywords

  • Gemcitabine
  • Nanoscale delivery
  • Pancreatic cancer
  • miR-345

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer. / Uz, Metin; Kalaga, Manisha; Pothuraju, Ramesh; Ju, Juhyung; Junker, Wade M.; Batra, Surinder Kumar; Mallapragada, Surya; Rachagani, Satyanarayana.

In: Journal of Controlled Release, Vol. 294, 28.01.2019, p. 237-246.

Research output: Contribution to journalArticle

Uz, Metin ; Kalaga, Manisha ; Pothuraju, Ramesh ; Ju, Juhyung ; Junker, Wade M. ; Batra, Surinder Kumar ; Mallapragada, Surya ; Rachagani, Satyanarayana. / Dual delivery nanoscale device for miR-345 and gemcitabine co-delivery to treat pancreatic cancer. In: Journal of Controlled Release. 2019 ; Vol. 294. pp. 237-246.
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abstract = "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.",
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