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Ortho ester-based pH-sensitive catio...

Chen, Haigang.

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Ortho ester-based pH-sensitive cationic lipoplexes for gene delivery.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Ortho ester-based pH-sensitive cationic lipoplexes for gene delivery./
Author:	Chen, Haigang.
Description:	168 p.
Notes:	Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 4971.
Contained By:	Dissertation Abstracts International67-09B.
Subject:	Chemistry, Pharmaceutical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3234273
ISBN:	9780542881329

Ortho ester-based pH-sensitive cationic lipoplexes for gene delivery.
Chen, Haigang.

Ortho ester-based pH-sensitive cationic lipoplexes for gene delivery. - 168 p.

Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 4971.

Thesis (Ph.D.)--University of the Pacific, 2006.

Endosome is a major barrier to efficient gene transfection by synthetic vectors because if the vectors are trapped in the endosome, they will traffic to the lysosome where the DNA is enzymatically degraded. Our hypothesis which serves as the rationale for the design of ortho ester-based lipids and lipoplexes is that cationic lipids which can quickly hydrolyze into membrane-destabilizing fragments in response to a small drop of pH should improve the gene transfection efficiency by facilitating the endosome escape.

ISBN: 9780542881329Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Ortho ester-based pH-sensitive cationic lipoplexes for gene delivery.
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245 1 0 $a Ortho ester-based pH-sensitive cationic lipoplexes for gene delivery.
300 $a 168 p.
500 $a Source: Dissertation Abstracts International, Volume: 67-09, Section: B, page: 4971.
500 $a Adviser: Xin Guo.
502 $a Thesis (Ph.D.)--University of the Pacific, 2006.
520 $a Endosome is a major barrier to efficient gene transfection by synthetic vectors because if the vectors are trapped in the endosome, they will traffic to the lysosome where the DNA is enzymatically degraded. Our hypothesis which serves as the rationale for the design of ortho ester-based lipids and lipoplexes is that cationic lipids which can quickly hydrolyze into membrane-destabilizing fragments in response to a small drop of pH should improve the gene transfection efficiency by facilitating the endosome escape.
520 $a We designed and synthesized five ortho ester-based acid-labile cationic lipids (1-5) and developed nine lipoplexes comprising the five lipids. HPLC and LC/MS studies revealed that the ortho ester linkage in lipids (1-5) hydrolyzed at mildly acidic endosomal pH 5.5. Dioleyl glycerol was identified to be the major hydrolysis product of lipids 1, 2, and 3. Oleoyl alcohol and 1-oleyloxy-2-trimethylamionium-3-propanol were identified to be the major hydrolysis products of lipids 4 and 5. Photon Correlation Spectrometry (PCS) studies revealed that acidic endosomal pHs triggered the aggregation of lipoplexes comprising 1, 2, and 3. Lipoplexes comprising 4 and 5 retained their size over 50 hours at acidic pHs. The fluorescence assay indicated that the ortho ester-based lipoplexes comprising lipids 1, 2, and 3 quickly destabilized a model biomembrane in response to the acidic pH. Acidic pH did not cause the membrane destabilization by lipoplexes comprising 4 and 5. These results demonstrate that ortho ester-based lipoplexes comprising lipids 1, 2, and 3 hydrolyze into membrane-destabilizing fragments in response to acidic pH.
520 $a Luciferase gene transfection was conducted on CV-1cultured cells. The lipoplexes comprising ortho ester-based cationic lipids 1, 2, and 3 significantly enhanced the luciferase gene expression. Two lipoplexes 2/DOPE/DNA and 3/DOPE/DNA mediated 45-fold and 116-fold, respectively, higher luciferase expression in CV-1 cells compared to the pH-insensitive lipoplex DOTAP/DOPE/DNA. The gene transfection efficiency correlates well with the pH-triggered membrane-destabilization by the ortho ester-based lipoplexes.
590 $a School code: 0173.
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Health Sciences, Medicine and Surgery. $3 1017756
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710 2 0 $a University of the Pacific. $3 1024038
773 0 $t Dissertation Abstracts International $g 67-09B.
790 1 0 $a Guo, Xin, $e advisor
790 $a 0173
791 $a Ph.D.
792 $a 2006
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