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 - Oupický, David
N1 - Funding Information:
This work was financially supported by the National Science and Technology Major Project (2017YFA0205400), Changjiang Scholar program from the Chinese Ministry of Education, University of Nebraska Medical Center, China National Science Foundation (Nos. 81373983 and 81573377), China Postdoctoral Science Foundation (No. 2016M601923), and Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX17_0671).
Publisher Copyright:
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2018/3/7
Y1 - 2018/3/7
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
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U2 - 10.1002/adhm.201700978
DO - 10.1002/adhm.201700978
M3 - Article
C2 - 29280311
AN - SCOPUS:85039064445
VL - 7
JO - Advanced healthcare materials
JF - Advanced healthcare materials
SN - 2192-2640
IS - 5
M1 - 1700978
ER -