PEGylated block copolymers containing tertiary amine side-chains cleavable via acid-labile ortho ester linkages for pH-triggered release of DNA

Junping Lai; Zhangyan Xu; Rupei Tang; Weihang Ji; Rui Wang; Jun Wang; Chun Wang

doi:10.1016/j.polymer.2014.04.036

PEGylated block copolymers containing tertiary amine side-chains cleavable via acid-labile ortho ester linkages for pH-triggered release of DNA

Junping Lai, Zhangyan Xu, Rupei Tang, Weihang Ji, Rui Wang, Jun Wang, Chun Wang

Biomedical Engineering

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

21 Scopus citations

Abstract

A new type of acid-labile cationic copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a polymethacrylamide block bearing tertiary amines linked by acid-labile ortho ester rings in side chains (PAOE), with defined chain length, had been synthesized via RAFT polymerization. The copolymers could efficiently bind and condense plasmid DNA at neutral pH into narrowly dispersed nano-scale polyplexes. The hydrolysis of ortho ester group in the side-chains of PAOE followed a distinct exocyclic mechanism and the rate of hydrolysis was much accelerated at mildly acidic pH, resulting in the accelerated disruption of polyplexes and the release of intact plasmid DNA. The three polymers were not toxic to cultured COS-7 cells as measured by MTT assay. As expected, PEG segments of the PEG-b-PAOE copolymers prevented nonspecific transfection of COS-7 cells. Once conjugated to a targeting ligand to enhance cell-specific entry, PEG-b-PAOE with its pH-triggered DNA release properties may achieve efficient intracellular delivery of DNA or other nucleic acid therapeutics.

Original language	English (US)
Pages (from-to)	2761-2771
Number of pages	11
Journal	Polymer
Volume	55
Issue number	12
DOIs	https://doi.org/10.1016/j.polymer.2014.04.036
State	Published - Jun 6 2014

Bibliographical note

Funding Information:
This work is financially supported by the Chinese Program for New Century Excellent Talents in Universities (No. NCET-11-0661 ), the National Natural Science Foundation of China (No. 21174054 , 21004030 ), the Scientific Research Foundation for Returned Scholars from Ministry of Education of China , the Natural Science Foundation of Anhui Province of China (No. 1408085MB26 ), and the Academic and Technology Introduction Project of Anhui University of China ( AU02303203 ). W. Ji and C. Wang acknowledge the support by the US National Institutes of Health (Grant No. R01CA129189 .)

Keywords

Gene delivery
Ortho ester
PEGylation

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title = "PEGylated block copolymers containing tertiary amine side-chains cleavable via acid-labile ortho ester linkages for pH-triggered release of DNA",

abstract = "A new type of acid-labile cationic copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a polymethacrylamide block bearing tertiary amines linked by acid-labile ortho ester rings in side chains (PAOE), with defined chain length, had been synthesized via RAFT polymerization. The copolymers could efficiently bind and condense plasmid DNA at neutral pH into narrowly dispersed nano-scale polyplexes. The hydrolysis of ortho ester group in the side-chains of PAOE followed a distinct exocyclic mechanism and the rate of hydrolysis was much accelerated at mildly acidic pH, resulting in the accelerated disruption of polyplexes and the release of intact plasmid DNA. The three polymers were not toxic to cultured COS-7 cells as measured by MTT assay. As expected, PEG segments of the PEG-b-PAOE copolymers prevented nonspecific transfection of COS-7 cells. Once conjugated to a targeting ligand to enhance cell-specific entry, PEG-b-PAOE with its pH-triggered DNA release properties may achieve efficient intracellular delivery of DNA or other nucleic acid therapeutics.",

keywords = "Gene delivery, Ortho ester, PEGylation",

author = "Junping Lai and Zhangyan Xu and Rupei Tang and Weihang Ji and Rui Wang and Jun Wang and Chun Wang",

note = "Funding Information: This work is financially supported by the Chinese Program for New Century Excellent Talents in Universities (No. NCET-11-0661 ), the National Natural Science Foundation of China (No. 21174054 , 21004030 ), the Scientific Research Foundation for Returned Scholars from Ministry of Education of China , the Natural Science Foundation of Anhui Province of China (No. 1408085MB26 ), and the Academic and Technology Introduction Project of Anhui University of China ( AU02303203 ). W. Ji and C. Wang acknowledge the support by the US National Institutes of Health (Grant No. R01CA129189 .) ",

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AU - Ji, Weihang

AU - Wang, Rui

AU - Wang, Jun

AU - Wang, Chun

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N2 - A new type of acid-labile cationic copolymer consisting of a hydrophilic poly(ethylene glycol) (PEG) block and a polymethacrylamide block bearing tertiary amines linked by acid-labile ortho ester rings in side chains (PAOE), with defined chain length, had been synthesized via RAFT polymerization. The copolymers could efficiently bind and condense plasmid DNA at neutral pH into narrowly dispersed nano-scale polyplexes. The hydrolysis of ortho ester group in the side-chains of PAOE followed a distinct exocyclic mechanism and the rate of hydrolysis was much accelerated at mildly acidic pH, resulting in the accelerated disruption of polyplexes and the release of intact plasmid DNA. The three polymers were not toxic to cultured COS-7 cells as measured by MTT assay. As expected, PEG segments of the PEG-b-PAOE copolymers prevented nonspecific transfection of COS-7 cells. Once conjugated to a targeting ligand to enhance cell-specific entry, PEG-b-PAOE with its pH-triggered DNA release properties may achieve efficient intracellular delivery of DNA or other nucleic acid therapeutics.

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PEGylated block copolymers containing tertiary amine side-chains cleavable via acid-labile ortho ester linkages for pH-triggered release of DNA

Abstract

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