Fluorination Enhances Serum Stability of Bioreducible Poly(amido amine) Polyplexes and Enables Efficient Intravenous siRNA Delivery

Gang Chen, Kaikai Wang, Yixin Wang, Pengkai Wu, Minjie Sun, David Oupicky

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The use of small interfering RNA (siRNA) in cancer treatment has been limited by the lack of effective systemic delivery methods. Although synthetic polycations have been widely explored in siRNA delivery, polycation/siRNA polyplexes often suffer from insufficient stability in vivo. Here, rationally designed siRNA delivery systems that meet the requirements for systemic siRNA delivery to distant tumors are reported. The hypothesis that modular design of delivery systems based on poly(amido amine)s that combine fluorination for systemic stability with bioreducibility for easy intracellular siRNA release, and PEGylation for improved safety and colloidal stability will overcome problems with contradicting siRNA delivery demands is tested. PEGylated, fluorinated, and bioreducible copolymers (PEG-PCD-F) with different degree of fluorination are thus synthesized. The fluorinated copolymers readily formed polyplexes with siRNA and achieved greatly improved gene silencing efficacy in multiple cell lines in vitro when compared with nonfluorinated controls. The results show fluorination-induced enhancement of stability, cellular uptake, and endosomal escape of the polyplexes, while exhibiting efficient siRNA release in reducing intracellular environment. PEG-PCD-F polyplexes with siRNA against Bcl2 inhibit breast tumor growth following systemic intravenous administration. The results provide strong evidence of successful combination of bioreducibility with fluorination and PEGylation to achieve systemic siRNA polyplex delivery.

Original languageEnglish (US)
JournalAdvanced healthcare materials
DOIs
StateAccepted/In press - Jan 1 2017

Fingerprint

Fluorination
Halogenation
RNA
Small Interfering RNA
Amines
Serum
Polyethylene glycols
Tumors
Copolymers
Oncology
Gene Silencing
Intravenous Administration
Neoplasms
Genes
Cells
Breast Neoplasms

Keywords

  • Bioreducible poly(amido amine)s
  • Fluorination
  • Polyplexes
  • Tumor siRNA delivery

ASJC Scopus subject areas

  • Biomaterials
  • Biomedical Engineering
  • Pharmaceutical Science

Cite this

Fluorination Enhances Serum Stability of Bioreducible Poly(amido amine) Polyplexes and Enables Efficient Intravenous siRNA Delivery. / Chen, Gang; Wang, Kaikai; Wang, Yixin; Wu, Pengkai; Sun, Minjie; Oupicky, David.

In: Advanced healthcare materials, 01.01.2017.

Research output: Contribution to journalArticle

@article{b166151ac2aa49f6a600bfe841744740,
title = "Fluorination Enhances Serum Stability of Bioreducible Poly(amido amine) Polyplexes and Enables Efficient Intravenous siRNA Delivery",
abstract = "The use of small interfering RNA (siRNA) in cancer treatment has been limited by the lack of effective systemic delivery methods. Although synthetic polycations have been widely explored in siRNA delivery, polycation/siRNA polyplexes often suffer from insufficient stability in vivo. Here, rationally designed siRNA delivery systems that meet the requirements for systemic siRNA delivery to distant tumors are reported. The hypothesis that modular design of delivery systems based on poly(amido amine)s that combine fluorination for systemic stability with bioreducibility for easy intracellular siRNA release, and PEGylation for improved safety and colloidal stability will overcome problems with contradicting siRNA delivery demands is tested. PEGylated, fluorinated, and bioreducible copolymers (PEG-PCD-F) with different degree of fluorination are thus synthesized. The fluorinated copolymers readily formed polyplexes with siRNA and achieved greatly improved gene silencing efficacy in multiple cell lines in vitro when compared with nonfluorinated controls. The results show fluorination-induced enhancement of stability, cellular uptake, and endosomal escape of the polyplexes, while exhibiting efficient siRNA release in reducing intracellular environment. PEG-PCD-F polyplexes with siRNA against Bcl2 inhibit breast tumor growth following systemic intravenous administration. The results provide strong evidence of successful combination of bioreducibility with fluorination and PEGylation to achieve systemic siRNA polyplex delivery.",
keywords = "Bioreducible poly(amido amine)s, Fluorination, Polyplexes, Tumor siRNA delivery",
author = "Gang Chen and Kaikai Wang and Yixin Wang and Pengkai Wu and Minjie Sun and David Oupicky",
year = "2017",
month = "1",
day = "1",
doi = "10.1002/adhm.201700978",
language = "English (US)",
journal = "Advanced healthcare materials",
issn = "2192-2640",
publisher = "John Wiley and Sons Ltd",

}

TY - JOUR

T1 - Fluorination Enhances Serum Stability of Bioreducible Poly(amido amine) Polyplexes and Enables Efficient Intravenous siRNA Delivery

AU - Chen, Gang

AU - Wang, Kaikai

AU - Wang, Yixin

AU - Wu, Pengkai

AU - Sun, Minjie

AU - Oupicky, David

PY - 2017/1/1

Y1 - 2017/1/1

N2 - The use of small interfering RNA (siRNA) in cancer treatment has been limited by the lack of effective systemic delivery methods. Although synthetic polycations have been widely explored in siRNA delivery, polycation/siRNA polyplexes often suffer from insufficient stability in vivo. Here, rationally designed siRNA delivery systems that meet the requirements for systemic siRNA delivery to distant tumors are reported. The hypothesis that modular design of delivery systems based on poly(amido amine)s that combine fluorination for systemic stability with bioreducibility for easy intracellular siRNA release, and PEGylation for improved safety and colloidal stability will overcome problems with contradicting siRNA delivery demands is tested. PEGylated, fluorinated, and bioreducible copolymers (PEG-PCD-F) with different degree of fluorination are thus synthesized. The fluorinated copolymers readily formed polyplexes with siRNA and achieved greatly improved gene silencing efficacy in multiple cell lines in vitro when compared with nonfluorinated controls. The results show fluorination-induced enhancement of stability, cellular uptake, and endosomal escape of the polyplexes, while exhibiting efficient siRNA release in reducing intracellular environment. PEG-PCD-F polyplexes with siRNA against Bcl2 inhibit breast tumor growth following systemic intravenous administration. The results provide strong evidence of successful combination of bioreducibility with fluorination and PEGylation to achieve systemic siRNA polyplex delivery.

AB - The use of small interfering RNA (siRNA) in cancer treatment has been limited by the lack of effective systemic delivery methods. Although synthetic polycations have been widely explored in siRNA delivery, polycation/siRNA polyplexes often suffer from insufficient stability in vivo. Here, rationally designed siRNA delivery systems that meet the requirements for systemic siRNA delivery to distant tumors are reported. The hypothesis that modular design of delivery systems based on poly(amido amine)s that combine fluorination for systemic stability with bioreducibility for easy intracellular siRNA release, and PEGylation for improved safety and colloidal stability will overcome problems with contradicting siRNA delivery demands is tested. PEGylated, fluorinated, and bioreducible copolymers (PEG-PCD-F) with different degree of fluorination are thus synthesized. The fluorinated copolymers readily formed polyplexes with siRNA and achieved greatly improved gene silencing efficacy in multiple cell lines in vitro when compared with nonfluorinated controls. The results show fluorination-induced enhancement of stability, cellular uptake, and endosomal escape of the polyplexes, while exhibiting efficient siRNA release in reducing intracellular environment. PEG-PCD-F polyplexes with siRNA against Bcl2 inhibit breast tumor growth following systemic intravenous administration. The results provide strong evidence of successful combination of bioreducibility with fluorination and PEGylation to achieve systemic siRNA polyplex delivery.

KW - Bioreducible poly(amido amine)s

KW - Fluorination

KW - Polyplexes

KW - Tumor siRNA delivery

UR - http://www.scopus.com/inward/record.url?scp=85039064445&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85039064445&partnerID=8YFLogxK

U2 - 10.1002/adhm.201700978

DO - 10.1002/adhm.201700978

M3 - Article

JO - Advanced healthcare materials

JF - Advanced healthcare materials

SN - 2192-2640

ER -