Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy

Ying Xie, Yu Hang, Yazhe Wang, Richard Sleightholm, Dipakkumar R. Prajapati, Johannes Bader, Ao Yu, Weimin Tang, Lee Jaramillo, Jing Li, Rakesh K. Singh, David Oupický

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Nanomedicines achieve tumor-targeted delivery mainly through enhanced permeability and retention (EPR) effect following intravenous (IV) administration. Unfortunately, the EPR effect is severely compromised in pancreatic cancer due to hypovascularity and dense desmoplastic stroma. Intraperitoneal (IP) administration may be an effective EPR-independent local delivery approach to target peritoneal tumors. Besides improved delivery, effective combination delivery strategies are needed to improve pancreatic cancer therapy by targeting both cancer cells and cellular interactions within the tumor stroma. Here, we described simple cholesterol-modified polymeric CXCR4 antagonist (PCX) nanoparticles (to block cancer-stroma interactions) for codelivery of anti-miR-210 (to inactivate stroma-producing pancreatic stellate cells (PSCs)) and siKRASG12D (to kill pancreatic cancer cells). IP administration delivered the nanoparticles to an orthotopic syngeneic pancreatic tumors as a result of preferential localization to the tumors and metastases with disrupted mesothelium and effective tumor penetration. The local IP delivery resulted in nearly 15-fold higher tumor accumulation than delivery by IV injection. Through antagonism of CXCR4 and downregulation of miR-210/KRASG12D, the triple-action nanoparticles favorably modulated desmoplastic tumor microenvironment via inactivating PSCs and promoting the infiltration of cytotoxic T cells. The combined therapy displayed improved therapeutic effect when compared with individual therapies as documented by the delayed tumor growth, depletion of stroma, reduction of immunosuppression, inhibition of metastasis, and prolonged survival. Overall, we present data that a local IP delivery of a miRNA/siRNA combination holds the potential to improve pancreatic cancer therapy.

Original languageEnglish (US)
Pages (from-to)255-271
Number of pages17
JournalACS Nano
Volume14
Issue number1
DOIs
StatePublished - Jan 28 2020

Keywords

  • CXCR4
  • immunosuppression
  • intraperitoneal administration
  • metastasis
  • miRNA-210
  • pancreatic cancer
  • tumor stroma

ASJC Scopus subject areas

  • Materials Science(all)
  • Engineering(all)
  • Physics and Astronomy(all)

Fingerprint Dive into the research topics of 'Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy'. Together they form a unique fingerprint.

  • Cite this

    Xie, Y., Hang, Y., Wang, Y., Sleightholm, R., Prajapati, D. R., Bader, J., Yu, A., Tang, W., Jaramillo, L., Li, J., Singh, R. K., & Oupický, D. (2020). Stromal Modulation and Treatment of Metastatic Pancreatic Cancer with Local Intraperitoneal Triple miRNA/siRNA Nanotherapy. ACS Nano, 14(1), 255-271. https://doi.org/10.1021/acsnano.9b03978