Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery

Makoto Oba; Kanjiro Miyata; Kensuke Osada; R. James Christie; Mai Sanjoh; Weidong Li; Shigeto Fukushima; Takehiko Ishii; Mitsunobu R. Kano; Nobuhiro Nishiyama; Hiroyuki Koyama; Kazunori Kataoka

doi:10.1016/j.biomaterials.2010.09.022

Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery

Makoto Oba, Kanjiro Miyata, Kensuke Osada, R. James Christie, Mai Sanjoh, Weidong Li, Shigeto Fukushima, Takehiko Ishii, Mitsunobu R. Kano, Nobuhiro Nishiyama, Hiroyuki Koyama, Kazunori Kataoka

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

95 Citations (Scopus)

Abstract

Polyplex micelles formed with plasmid DNA (pDNA) and poly(ethylene glycol) (PEG)-block-poly{ N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here, PEG-PAsp(DET) polyplex micelles were further improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the ω-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole. Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles. The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally, PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following intravenous injection into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti-angiogenic protein. These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors.

Original language	English
Pages (from-to)	652-663
Number of pages	12
Journal	Biomaterials
Volume	32
Issue number	2
DOIs	https://doi.org/10.1016/j.biomaterials.2010.09.022
Publication status	Published - Jan 2011
Externally published	Yes

Keywords

Anti-angiogenic therapy
Cholesterol
Non-viral gene vector
Pancreatic tumor
Polyplex micelle

ASJC Scopus subject areas

Bioengineering
Ceramics and Composites
Biophysics
Biomaterials
Mechanics of Materials

Access to Document

10.1016/j.biomaterials.2010.09.022

Cite this

@article{35be027af42b409c92c97fe520f2bcec,

title = "Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery",

abstract = "Polyplex micelles formed with plasmid DNA (pDNA) and poly(ethylene glycol) (PEG)-block-poly{ N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here, PEG-PAsp(DET) polyplex micelles were further improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the ω-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole. Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles. The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally, PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following intravenous injection into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti-angiogenic protein. These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors.",

keywords = "Anti-angiogenic therapy, Cholesterol, Non-viral gene vector, Pancreatic tumor, Polyplex micelle",

author = "Makoto Oba and Kanjiro Miyata and Kensuke Osada and Christie, {R. James} and Mai Sanjoh and Weidong Li and Shigeto Fukushima and Takehiko Ishii and Kano, {Mitsunobu R.} and Nobuhiro Nishiyama and Hiroyuki Koyama and Kazunori Kataoka",

note = "Funding Information: This work was financially supported by the Core Research Program for Evolutional Science and Technology (CREST) from Japan Science and Technology Agency (JST) as well as by Grants-in-Aid for Young Scientists (A) (No. 20689024 to M.O.). We express our appreciation to Prof. Masabumi Shibuya (Tokyo Medical and Dental University) for providing pVL 1393 baculovirus vector pDNA encoding human sFlt-1. We thank Ms. Junko Kawakita and Ms. Satomi Ogura (The University of Tokyo) for technical assistance. ",

year = "2011",

month = jan,

doi = "10.1016/j.biomaterials.2010.09.022",

language = "English",

volume = "32",

pages = "652--663",

journal = "Biomaterials",

issn = "0142-9612",

publisher = "Elsevier BV",

number = "2",

}

TY - JOUR

T1 - Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery

AU - Oba, Makoto

AU - Miyata, Kanjiro

AU - Osada, Kensuke

AU - Christie, R. James

AU - Sanjoh, Mai

AU - Li, Weidong

AU - Fukushima, Shigeto

AU - Ishii, Takehiko

AU - Kano, Mitsunobu R.

AU - Nishiyama, Nobuhiro

AU - Koyama, Hiroyuki

AU - Kataoka, Kazunori

N1 - Funding Information: This work was financially supported by the Core Research Program for Evolutional Science and Technology (CREST) from Japan Science and Technology Agency (JST) as well as by Grants-in-Aid for Young Scientists (A) (No. 20689024 to M.O.). We express our appreciation to Prof. Masabumi Shibuya (Tokyo Medical and Dental University) for providing pVL 1393 baculovirus vector pDNA encoding human sFlt-1. We thank Ms. Junko Kawakita and Ms. Satomi Ogura (The University of Tokyo) for technical assistance.

PY - 2011/1

Y1 - 2011/1

N2 - Polyplex micelles formed with plasmid DNA (pDNA) and poly(ethylene glycol) (PEG)-block-poly{ N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here, PEG-PAsp(DET) polyplex micelles were further improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the ω-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole. Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles. The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally, PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following intravenous injection into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti-angiogenic protein. These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors.

AB - Polyplex micelles formed with plasmid DNA (pDNA) and poly(ethylene glycol) (PEG)-block-poly{ N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} [PAsp(DET)] exhibit effective endosomal escaping properties based on di-protonation of diamine side chains with decreasing pH, which improves their transfection efficiency and thus are promising candidates for local in vivo gene transfer. Here, PEG-PAsp(DET) polyplex micelles were further improved as in vivo systemic vectors by introduction of cholesterol (Chole) into the ω-terminus of PEG-PAsp(DET) to obtain PEG-PAsp(DET)-Chole. Introduction of the cholesterol resulted in enhanced association of block copolymers with pDNA, which led to increased stability in proteinous medium and also in the blood stream after systemic injection compared to PEG-PAsp(DET) micelles. The synergistic effect between enhanced polymer association with pDNA and increased micelle stability of PEG-PAsp(DET)-Chole polyplex micelles led to high in vitro gene transfer even at relatively low concentrations, due to efficient cellular uptake and effective endosomal escape of block copolymers and pDNA. Finally, PEG-PAsp(DET)-Chole micelles achieved significant suppression of tumor growth following intravenous injection into mice bearing a subcutaneous pancreatic tumor using therapeutic pDNA encoding an anti-angiogenic protein. These results suggest that PEG-PAsp(DET)-Chole micelles can be effective systemic gene vectors for treatment of solid tumors.

KW - Anti-angiogenic therapy

KW - Cholesterol

KW - Non-viral gene vector

KW - Pancreatic tumor

KW - Polyplex micelle

UR - http://www.scopus.com/inward/record.url?scp=78449236732&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=78449236732&partnerID=8YFLogxK

U2 - 10.1016/j.biomaterials.2010.09.022

DO - 10.1016/j.biomaterials.2010.09.022

M3 - Article

C2 - 20932567

AN - SCOPUS:78449236732

SN - 0142-9612

VL - 32

SP - 652

EP - 663

JO - Biomaterials

JF - Biomaterials

IS - 2

ER -

Polyplex micelles prepared from ω-cholesteryl PEG-polycation block copolymers for systemic gene delivery

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this