Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery

Lane V. Christensen; Chien Wen Chang; James W. Yockman; Rafe Conners; Heidi Jackson; Zhiyuan Zhong; Jan Feijen; David A. Bull; Sung Wan Kim

doi:10.1016/j.jconrel.2006.12.018

Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery

Lane V. Christensen, Chien Wen Chang, James W. Yockman, Rafe Conners, Heidi Jackson, Zhiyuan Zhong, Jan Feijen, David A. Bull, Sung Wan Kim

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

70 Scopus citations

Abstract

Delivery of the hypoxia-inducible vascular endothelial growth factor (RTP-VEGF) plasmid using a novel reducible disulfide poly(amido ethylenediamine) (SS-PAED) polymer carrier was studied in vitro and in vivo. In vitro transfection of primary rat cardiomyoblasts (H9C2) showed SS-PAED at a weighted ratio of 12:1 (polymer/DNA) mediates 16 fold higher expression of luciferase compared to an optimized bPEI control. FACS analysis revealed up to 57 ± 2% GFP positive H9C2s. The efficiency of plasmid delivery to H9C2 using SS-PAED was found to depend upon glutathione (GSH) levels inside the cell. SS-PAED mediated delivery of RTP-VEGF plasmid produced significantly higher levels of VEGF expression (up to 76 fold) under hypoxic conditions compared to normoxic conditions in both H9C2 and rat aortic smooth muscle cells (A7R5). Using SS-PAED, delivery of RTP-VEGF was investigated in a rabbit myocardial infarct model using 100 μg RTP-VEGF. Results showed up to 4 fold increase in VEGF protein expression in the region of the infarct compared to injections of SS-PAED/RTP-Luc. In conclusion, SS-PAED mediated therapeutic delivery improves the efficacy of ischemia-inducible VEGF gene therapy both in vitro and in vivo and therefore, has potential for the promotion of neo-vascular formation and improvement of tissue function in ischemic myocardium.

Original language	English (US)
Pages (from-to)	254-261
Number of pages	8
Journal	Journal of Controlled Release
Volume	118
Issue number	2
DOIs	https://doi.org/10.1016/j.jconrel.2006.12.018
State	Published - Apr 2 2007
Externally published	Yes

Keywords

Gene therapy
Hypoxia
Myoblasts
Reducible polymer
VEGF

ASJC Scopus subject areas

Pharmaceutical Science

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10.1016/j.jconrel.2006.12.018

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@article{bf3ef30a656c42b8b768bc649a693019,

title = "Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery",

abstract = "Delivery of the hypoxia-inducible vascular endothelial growth factor (RTP-VEGF) plasmid using a novel reducible disulfide poly(amido ethylenediamine) (SS-PAED) polymer carrier was studied in vitro and in vivo. In vitro transfection of primary rat cardiomyoblasts (H9C2) showed SS-PAED at a weighted ratio of 12:1 (polymer/DNA) mediates 16 fold higher expression of luciferase compared to an optimized bPEI control. FACS analysis revealed up to 57 ± 2% GFP positive H9C2s. The efficiency of plasmid delivery to H9C2 using SS-PAED was found to depend upon glutathione (GSH) levels inside the cell. SS-PAED mediated delivery of RTP-VEGF plasmid produced significantly higher levels of VEGF expression (up to 76 fold) under hypoxic conditions compared to normoxic conditions in both H9C2 and rat aortic smooth muscle cells (A7R5). Using SS-PAED, delivery of RTP-VEGF was investigated in a rabbit myocardial infarct model using 100 μg RTP-VEGF. Results showed up to 4 fold increase in VEGF protein expression in the region of the infarct compared to injections of SS-PAED/RTP-Luc. In conclusion, SS-PAED mediated therapeutic delivery improves the efficacy of ischemia-inducible VEGF gene therapy both in vitro and in vivo and therefore, has potential for the promotion of neo-vascular formation and improvement of tissue function in ischemic myocardium.",

keywords = "Gene therapy, Hypoxia, Myoblasts, Reducible polymer, VEGF",

author = "Christensen, {Lane V.} and Chang, {Chien Wen} and Yockman, {James W.} and Rafe Conners and Heidi Jackson and Zhiyuan Zhong and Jan Feijen and Bull, {David A.} and Kim, {Sung Wan}",

note = "Funding Information: This work was supported by NIH grants HL 071541 and HL 065477. ",

year = "2007",

month = apr,

day = "2",

doi = "10.1016/j.jconrel.2006.12.018",

language = "English (US)",

volume = "118",

pages = "254--261",

journal = "Journal of Controlled Release",

issn = "0168-3659",

publisher = "Elsevier B.V.",

number = "2",

}

TY - JOUR

T1 - Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery

AU - Christensen, Lane V.

AU - Chang, Chien Wen

AU - Yockman, James W.

AU - Conners, Rafe

AU - Jackson, Heidi

AU - Zhong, Zhiyuan

AU - Feijen, Jan

AU - Bull, David A.

AU - Kim, Sung Wan

N1 - Funding Information: This work was supported by NIH grants HL 071541 and HL 065477.

PY - 2007/4/2

Y1 - 2007/4/2

N2 - Delivery of the hypoxia-inducible vascular endothelial growth factor (RTP-VEGF) plasmid using a novel reducible disulfide poly(amido ethylenediamine) (SS-PAED) polymer carrier was studied in vitro and in vivo. In vitro transfection of primary rat cardiomyoblasts (H9C2) showed SS-PAED at a weighted ratio of 12:1 (polymer/DNA) mediates 16 fold higher expression of luciferase compared to an optimized bPEI control. FACS analysis revealed up to 57 ± 2% GFP positive H9C2s. The efficiency of plasmid delivery to H9C2 using SS-PAED was found to depend upon glutathione (GSH) levels inside the cell. SS-PAED mediated delivery of RTP-VEGF plasmid produced significantly higher levels of VEGF expression (up to 76 fold) under hypoxic conditions compared to normoxic conditions in both H9C2 and rat aortic smooth muscle cells (A7R5). Using SS-PAED, delivery of RTP-VEGF was investigated in a rabbit myocardial infarct model using 100 μg RTP-VEGF. Results showed up to 4 fold increase in VEGF protein expression in the region of the infarct compared to injections of SS-PAED/RTP-Luc. In conclusion, SS-PAED mediated therapeutic delivery improves the efficacy of ischemia-inducible VEGF gene therapy both in vitro and in vivo and therefore, has potential for the promotion of neo-vascular formation and improvement of tissue function in ischemic myocardium.

AB - Delivery of the hypoxia-inducible vascular endothelial growth factor (RTP-VEGF) plasmid using a novel reducible disulfide poly(amido ethylenediamine) (SS-PAED) polymer carrier was studied in vitro and in vivo. In vitro transfection of primary rat cardiomyoblasts (H9C2) showed SS-PAED at a weighted ratio of 12:1 (polymer/DNA) mediates 16 fold higher expression of luciferase compared to an optimized bPEI control. FACS analysis revealed up to 57 ± 2% GFP positive H9C2s. The efficiency of plasmid delivery to H9C2 using SS-PAED was found to depend upon glutathione (GSH) levels inside the cell. SS-PAED mediated delivery of RTP-VEGF plasmid produced significantly higher levels of VEGF expression (up to 76 fold) under hypoxic conditions compared to normoxic conditions in both H9C2 and rat aortic smooth muscle cells (A7R5). Using SS-PAED, delivery of RTP-VEGF was investigated in a rabbit myocardial infarct model using 100 μg RTP-VEGF. Results showed up to 4 fold increase in VEGF protein expression in the region of the infarct compared to injections of SS-PAED/RTP-Luc. In conclusion, SS-PAED mediated therapeutic delivery improves the efficacy of ischemia-inducible VEGF gene therapy both in vitro and in vivo and therefore, has potential for the promotion of neo-vascular formation and improvement of tissue function in ischemic myocardium.

KW - Gene therapy

KW - Hypoxia

KW - Myoblasts

KW - Reducible polymer

KW - VEGF

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DO - 10.1016/j.jconrel.2006.12.018

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SN - 0168-3659

VL - 118

SP - 254

EP - 261

JO - Journal of Controlled Release

JF - Journal of Controlled Release

IS - 2

ER -

Reducible poly(amido ethylenediamine) for hypoxia-inducible VEGF delivery

Abstract

Keywords

ASJC Scopus subject areas

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