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

Siyuan Tang; Ekta Kapoor; Ling Ding; Ao Yu; Weimin Tang; Yu Hang; Lynette M. Smith; Diptesh Sil; David Oupický

doi:10.1016/j.bioadv.2022.213236

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

Siyuan Tang, Ekta Kapoor, Ling Ding, Ao Yu, Weimin Tang, Yu Hang, Lynette M. Smith, Diptesh Sil, David Oupický

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	213236
Journal	Biomaterials Advances
Volume	145
DOIs	https://doi.org/10.1016/j.bioadv.2022.213236
State	Published - Feb 2023

Keywords

CXCR4 antagonism
Intraperitoneal administration
Nanoparticles
PDAC
STAT3
siRNA delivery

ASJC Scopus subject areas

Biomedical Engineering
Biomaterials
Bioengineering

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10.1016/j.bioadv.2022.213236

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title = "Effect of tocopherol conjugation on polycation-mediated siRNA delivery to orthotopic pancreatic tumors",

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",

author = "Siyuan Tang and Ekta Kapoor and Ling Ding and Ao Yu and Weimin Tang and Yu Hang and Smith, {Lynette M.} and Diptesh Sil and David Oupick{\'y}",

note = "Funding Information: This work was supported by start-up funds from the University Of Nebraska Medical Center and by NIH grant R01 CA235863 . Publisher Copyright: {\textcopyright} 2022 Elsevier B.V.",

year = "2023",

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doi = "10.1016/j.bioadv.2022.213236",

language = "English (US)",

volume = "145",

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T1 - Effect of tocopherol conjugation on polycation-mediated siRNA delivery to orthotopic pancreatic tumors

AU - Tang, Siyuan

AU - Kapoor, Ekta

AU - Ding, Ling

AU - Yu, Ao

AU - Tang, Weimin

AU - Hang, Yu

AU - Smith, Lynette M.

AU - Sil, Diptesh

AU - Oupický, David

PY - 2023/2

Y1 - 2023/2

N2 - 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.

AB - 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.

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KW - Intraperitoneal administration

KW - Nanoparticles

KW - PDAC

KW - STAT3

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

Abstract

Keywords

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