The effect of guanidinylation of PEGylated poly(2-aminoethyl methacrylate) on the systemic delivery of siRNA

Qiang Cheng; Yuanyu Huang; Hua Zheng; Tuo Wei; Shuquan Zheng; Shuaidong Huo; Xiaoxia Wang; Quan Du; Xiaoning Zhang; Hong Yan Zhang; Xing Jie Liang; Chun Wang; Rupei Tang; Zicai Liang

doi:10.1016/j.biomaterials.2013.01.043

The effect of guanidinylation of PEGylated poly(2-aminoethyl methacrylate) on the systemic delivery of siRNA

Qiang Cheng, Yuanyu Huang, Hua Zheng, Tuo Wei, Shuquan Zheng, Shuaidong Huo, Xiaoxia Wang, Quan Du, Xiaoning Zhang, Hong Yan Zhang, Xing Jie Liang, Chun Wang, Rupei Tang, Zicai Liang

Biomedical Engineering

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

43 Scopus citations

Abstract

Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various diseases. However, to realize the therapeutic potential of siRNA drugs, efficient, tissue-specific and safe delivery technologies must be developed. Here we synthesized two kinds of polymers (PEGylated poly(2-aminoethyl methacrylate) labeled as PEG-b-PAEM or PEA, and guanidinylated PEGylated poly(2-aminoethyl methacrylate) marked as PEG-b-PAEM-co-PGEM or PEAG) using atom transfer radical polymerization and evaluated their capability of mediating siRNA delivery in vitro and in vivo. Both polymers presented excellent siRNA encapsulation ability, formed regular nanostructures with siRNA, robustly mediated cellular internalization and cytoplasmic localization of siRNA, and resulted in targeted gene knockdown efficiently. However, PEAG showed much more outstanding abilities referring to above evaluating indicators compared with PEA. Both PEA/siRNA and PEAG/siRNA polyplexes displayed strong liver, lung and spleen accumulation in mice for a long time after intravenous administration. PEAG/siApoB polyplexes (single dose at 1 mg/kg) further repressed ApoB expression in liver and resulted in block of lipid transportation. In addition, both polymers delivered high amounts of siRNA into tumor tissue in the Hela-Luc xenograft murine model. More siRNA accumulated in tumor with the increase of N/. P ratio and PEAG/siRNA polyplexes showed higher siRNA accumulation than PEA/siRNA polyplexes at the same N/. P ratio. These findings set the stage for further studies of structural-functional mechanisms and developments of siRNA therapeutics.

Original language	English (US)
Pages (from-to)	3120-3131
Number of pages	12
Journal	Biomaterials
Volume	34
Issue number	12
DOIs	https://doi.org/10.1016/j.biomaterials.2013.01.043
State	Published - Apr 2013

Bibliographical note

Funding Information:
We thank Jun Zhang (Institute of Molecular Medicine, Peking University) for technical support in cryosection preparation; Junde Yang, Huichen Bai (Suzhou Ribo Life Science Co. Ltd.) for assisting in vivo functional study. This project was supported by grants from the National Drug Program of China (No. 2011ZX09102-011-12 , 2012ZX09102301-006 ), the National Natural Science Foundation of China (No. 81273422 , 31221002 , 21174054 , 21004030 and 51273156 ), the Chinese Program for New Century Excellent Talents in Universities (No. NCET-11-0661 ), the Natural Science Foundation of Jiangsu Province of China (No. BK2010145 ) and the Academic Scholarship for Doctoral Candidates of the Ministry of Education of China . The authors declare there are no conflicts of interest that relate to this paper.

Keywords

Guanidinylation
Liver targeting
Non-viral carriers
PAEM
PEG-b-PAEM
SiRNA delivery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access

10.1016/j.biomaterials.2013.01.043

OpenUrl availability

Full text

Cite this

@article{d2bf781ccf3b4fb6b0a40376741b49cc,

title = "The effect of guanidinylation of PEGylated poly(2-aminoethyl methacrylate) on the systemic delivery of siRNA",

abstract = "Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various diseases. However, to realize the therapeutic potential of siRNA drugs, efficient, tissue-specific and safe delivery technologies must be developed. Here we synthesized two kinds of polymers (PEGylated poly(2-aminoethyl methacrylate) labeled as PEG-b-PAEM or PEA, and guanidinylated PEGylated poly(2-aminoethyl methacrylate) marked as PEG-b-PAEM-co-PGEM or PEAG) using atom transfer radical polymerization and evaluated their capability of mediating siRNA delivery in vitro and in vivo. Both polymers presented excellent siRNA encapsulation ability, formed regular nanostructures with siRNA, robustly mediated cellular internalization and cytoplasmic localization of siRNA, and resulted in targeted gene knockdown efficiently. However, PEAG showed much more outstanding abilities referring to above evaluating indicators compared with PEA. Both PEA/siRNA and PEAG/siRNA polyplexes displayed strong liver, lung and spleen accumulation in mice for a long time after intravenous administration. PEAG/siApoB polyplexes (single dose at 1 mg/kg) further repressed ApoB expression in liver and resulted in block of lipid transportation. In addition, both polymers delivered high amounts of siRNA into tumor tissue in the Hela-Luc xenograft murine model. More siRNA accumulated in tumor with the increase of N/. P ratio and PEAG/siRNA polyplexes showed higher siRNA accumulation than PEA/siRNA polyplexes at the same N/. P ratio. These findings set the stage for further studies of structural-functional mechanisms and developments of siRNA therapeutics.",

keywords = "Guanidinylation, Liver targeting, Non-viral carriers, PAEM, PEG-b-PAEM, SiRNA delivery",

author = "Qiang Cheng and Yuanyu Huang and Hua Zheng and Tuo Wei and Shuquan Zheng and Shuaidong Huo and Xiaoxia Wang and Quan Du and Xiaoning Zhang and Zhang, {Hong Yan} and Liang, {Xing Jie} and Chun Wang and Rupei Tang and Zicai Liang",

note = "Funding Information: We thank Jun Zhang (Institute of Molecular Medicine, Peking University) for technical support in cryosection preparation; Junde Yang, Huichen Bai (Suzhou Ribo Life Science Co. Ltd.) for assisting in vivo functional study. This project was supported by grants from the National Drug Program of China (No. 2011ZX09102-011-12 , 2012ZX09102301-006 ), the National Natural Science Foundation of China (No. 81273422 , 31221002 , 21174054 , 21004030 and 51273156 ), the Chinese Program for New Century Excellent Talents in Universities (No. NCET-11-0661 ), the Natural Science Foundation of Jiangsu Province of China (No. BK2010145 ) and the Academic Scholarship for Doctoral Candidates of the Ministry of Education of China . The authors declare there are no conflicts of interest that relate to this paper. ",

year = "2013",

month = apr,

doi = "10.1016/j.biomaterials.2013.01.043",

language = "English (US)",

volume = "34",

pages = "3120--3131",

journal = "Biomaterials",

issn = "0142-9612",

publisher = "Elsevier BV",

number = "12",

}

TY - JOUR

T1 - The effect of guanidinylation of PEGylated poly(2-aminoethyl methacrylate) on the systemic delivery of siRNA

AU - Cheng, Qiang

AU - Huang, Yuanyu

AU - Zheng, Hua

AU - Wei, Tuo

AU - Zheng, Shuquan

AU - Huo, Shuaidong

AU - Wang, Xiaoxia

AU - Du, Quan

AU - Zhang, Xiaoning

AU - Zhang, Hong Yan

AU - Liang, Xing Jie

AU - Wang, Chun

AU - Tang, Rupei

AU - Liang, Zicai

N1 - Funding Information: We thank Jun Zhang (Institute of Molecular Medicine, Peking University) for technical support in cryosection preparation; Junde Yang, Huichen Bai (Suzhou Ribo Life Science Co. Ltd.) for assisting in vivo functional study. This project was supported by grants from the National Drug Program of China (No. 2011ZX09102-011-12 , 2012ZX09102301-006 ), the National Natural Science Foundation of China (No. 81273422 , 31221002 , 21174054 , 21004030 and 51273156 ), the Chinese Program for New Century Excellent Talents in Universities (No. NCET-11-0661 ), the Natural Science Foundation of Jiangsu Province of China (No. BK2010145 ) and the Academic Scholarship for Doctoral Candidates of the Ministry of Education of China . The authors declare there are no conflicts of interest that relate to this paper.

PY - 2013/4

Y1 - 2013/4

N2 - Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various diseases. However, to realize the therapeutic potential of siRNA drugs, efficient, tissue-specific and safe delivery technologies must be developed. Here we synthesized two kinds of polymers (PEGylated poly(2-aminoethyl methacrylate) labeled as PEG-b-PAEM or PEA, and guanidinylated PEGylated poly(2-aminoethyl methacrylate) marked as PEG-b-PAEM-co-PGEM or PEAG) using atom transfer radical polymerization and evaluated their capability of mediating siRNA delivery in vitro and in vivo. Both polymers presented excellent siRNA encapsulation ability, formed regular nanostructures with siRNA, robustly mediated cellular internalization and cytoplasmic localization of siRNA, and resulted in targeted gene knockdown efficiently. However, PEAG showed much more outstanding abilities referring to above evaluating indicators compared with PEA. Both PEA/siRNA and PEAG/siRNA polyplexes displayed strong liver, lung and spleen accumulation in mice for a long time after intravenous administration. PEAG/siApoB polyplexes (single dose at 1 mg/kg) further repressed ApoB expression in liver and resulted in block of lipid transportation. In addition, both polymers delivered high amounts of siRNA into tumor tissue in the Hela-Luc xenograft murine model. More siRNA accumulated in tumor with the increase of N/. P ratio and PEAG/siRNA polyplexes showed higher siRNA accumulation than PEA/siRNA polyplexes at the same N/. P ratio. These findings set the stage for further studies of structural-functional mechanisms and developments of siRNA therapeutics.

AB - Small interfering RNA (siRNA) has a huge potential for the treatment or prevention of various diseases. However, to realize the therapeutic potential of siRNA drugs, efficient, tissue-specific and safe delivery technologies must be developed. Here we synthesized two kinds of polymers (PEGylated poly(2-aminoethyl methacrylate) labeled as PEG-b-PAEM or PEA, and guanidinylated PEGylated poly(2-aminoethyl methacrylate) marked as PEG-b-PAEM-co-PGEM or PEAG) using atom transfer radical polymerization and evaluated their capability of mediating siRNA delivery in vitro and in vivo. Both polymers presented excellent siRNA encapsulation ability, formed regular nanostructures with siRNA, robustly mediated cellular internalization and cytoplasmic localization of siRNA, and resulted in targeted gene knockdown efficiently. However, PEAG showed much more outstanding abilities referring to above evaluating indicators compared with PEA. Both PEA/siRNA and PEAG/siRNA polyplexes displayed strong liver, lung and spleen accumulation in mice for a long time after intravenous administration. PEAG/siApoB polyplexes (single dose at 1 mg/kg) further repressed ApoB expression in liver and resulted in block of lipid transportation. In addition, both polymers delivered high amounts of siRNA into tumor tissue in the Hela-Luc xenograft murine model. More siRNA accumulated in tumor with the increase of N/. P ratio and PEAG/siRNA polyplexes showed higher siRNA accumulation than PEA/siRNA polyplexes at the same N/. P ratio. These findings set the stage for further studies of structural-functional mechanisms and developments of siRNA therapeutics.

KW - Guanidinylation

KW - Liver targeting

KW - Non-viral carriers

KW - PAEM

KW - PEG-b-PAEM

KW - SiRNA delivery

UR - http://www.scopus.com/inward/record.url?scp=84873478178&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84873478178&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2013.01.043

DO - 10.1016/j.biomaterials.2013.01.043

M3 - Article

C2 - 23375954

AN - SCOPUS:84873478178

SN - 0142-9612

VL - 34

SP - 3120

EP - 3131

JO - Biomaterials

JF - Biomaterials

IS - 12

ER -

The effect of guanidinylation of PEGylated poly(2-aminoethyl methacrylate) on the systemic delivery of siRNA

Abstract

Bibliographical note

Keywords

UN SDGs

Access

OpenUrl availability

Other files and links

Fingerprint

Cite this