Effect of tocopherol conjugation on polycation-mediated siRNA delivery to orthotopic pancreatic tumors

Biomater Adv. 2023 Feb:145:213236. doi: 10.1016/j.bioadv.2022.213236. Epub 2022 Dec 6.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a five-year survival rate of around 10 %. CXCR4 and STAT3 display crucial effects on proliferation, metastasis, angiogenesis, and formation of immunosuppressive microenvironment in pancreatic tumors. Here, we have tested the hypothesis that conjugation of α-tocopherol (TOC) to a polycation (PAMD), synthesized from CXCR4-antagonist AMD3100, will improve delivery of therapeutic siRNA to silence STAT3 in PDAC tumors. PAMD-TOC/siSTAT3 nanoparticles showed superior anti-cancer and anti-migration performance compared to the parent PAMD/siSTAT3 nanoparticles in both murine and human PDAC cell lines. The biodistribution of the nanoparticles in orthotropic mouse KPC8060 and human PANC-1 models, indicated that tumor accumulation of PAMD-TOC/siRNA nanoparticles was improved greatly as compared to PAMD/siRNA nanoparticles. This improved cellular uptake, penetration, and tumor accumulation of PAMD-TOC/siSTAT3 nanoparticles, also contributed to the suppression of tumor growth, metastasis and improved survival. Overall, this study presents a prospective treatment strategy for PDAC.

Keywords: CXCR4 antagonism; Intraperitoneal administration; Nanoparticles; PDAC; STAT3; siRNA delivery.

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal* / drug therapy
  • Carcinoma, Pancreatic Ductal* / genetics
  • Humans
  • Mice
  • Pancreatic Neoplasms* / drug therapy
  • Pancreatic Neoplasms* / genetics
  • RNA, Small Interfering / genetics
  • Tissue Distribution
  • Tocopherols / pharmacology
  • Tocopherols / therapeutic use
  • Tumor Microenvironment

Substances

  • RNA, Small Interfering
  • polycations
  • Tocopherols