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Biodegradable multiblock copolymers ...

Bikram, Malavosklish.

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Biodegradable multiblock copolymers for gene delivery.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Biodegradable multiblock copolymers for gene delivery./
Author:	Bikram, Malavosklish.
Description:	205 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-03, Section: B, page: 1482.
Contained By:	Dissertation Abstracts International66-03B.
Subject:	Chemistry, Pharmaceutical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3167516
ISBN:	0542030179

Biodegradable multiblock copolymers for gene delivery.
Bikram, Malavosklish.

Biodegradable multiblock copolymers for gene delivery. - 205 p.

Source: Dissertation Abstracts International, Volume: 66-03, Section: B, page: 1482.

Thesis (Ph.D.)--The University of Utah, 2005.

Nonviral gene delivery has developed into a promising alternative to viral gene delivery and has the potential to correct many genetic disorders as well as to treat acquired diseases. However, the cytotoxicities related to the high charge densities of effective high molecular weight cationic polymers represent a major hurdle to the development of gene delivery systems that limits their clinical applicability. Thus, the purpose of this research was to develop biodegradable high molecular weight multiblock copolymers (MBC). The polymers consist of repeating blocks of low molecular weight poly(ethylene glycol) (PEG) and poly(L-lysine) (PLL). PLL was used as the DNA condensing agent and PEG was used to provide steric stabilization of the polymer/pDNA complexes as well as to introduce the biodegradable ester bonds onto the backbone of the MBC. The histidine derivative, N, N-dimethylhistidine, was conjugated at various mol % to the primary epsilon-amines of PLL to produce the final PEG-PLL-g-NHis MBC, for endosomal buffering.

ISBN: 0542030179Subjects--Topical Terms:

550957
Chemistry, Pharmaceutical.

Biodegradable multiblock copolymers for gene delivery.
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100 1 $a Bikram, Malavosklish. $3 1907653
245 1 0 $a Biodegradable multiblock copolymers for gene delivery.
300 $a 205 p.
500 $a Source: Dissertation Abstracts International, Volume: 66-03, Section: B, page: 1482.
502 $a Thesis (Ph.D.)--The University of Utah, 2005.
520 $a Nonviral gene delivery has developed into a promising alternative to viral gene delivery and has the potential to correct many genetic disorders as well as to treat acquired diseases. However, the cytotoxicities related to the high charge densities of effective high molecular weight cationic polymers represent a major hurdle to the development of gene delivery systems that limits their clinical applicability. Thus, the purpose of this research was to develop biodegradable high molecular weight multiblock copolymers (MBC). The polymers consist of repeating blocks of low molecular weight poly(ethylene glycol) (PEG) and poly(L-lysine) (PLL). PLL was used as the DNA condensing agent and PEG was used to provide steric stabilization of the polymer/pDNA complexes as well as to introduce the biodegradable ester bonds onto the backbone of the MBC. The histidine derivative, N, N-dimethylhistidine, was conjugated at various mol % to the primary epsilon-amines of PLL to produce the final PEG-PLL-g-NHis MBC, for endosomal buffering.
520 $a The first section of this dissertation deals with synthesis and characterization of the conjugates PEG-PLL-g-5% NHis, PEG-PLL-g-9% NHis, PEG-PLL-g-16% NHis, and PEG-PLL-g-22% NHis MBC. The results showed that the 16% conjugated MBC produced the highest transfection efficiency with the least cytotoxicity as compared to PLL 25000. Characterization of this optimized conjugate showed that the pK of the imidazole ring was &sim;4.75 and the polymer degradation half-life (t1/2) was &sim;5 h in buffer. Thus, the MBC were shown to be effective and biocompatible polymers for gene delivery.
520 $a The second half of the research deals with degradation studies of the MBC and biodistribution in mice. The results showed that there was no significant degradation at low pH, decreased polymer t1/2 in 10% mouse serum of &sim;2 h, and polymer degradation within complexes occurred between 4--8 h in 10% mouse serum. Biodistribution data revealed that the complexes are able to circulate in the blood for up to 3 d, which was reflected in the various organs. The data suggest that PEG was able to provide steric stabilization by promoting the favorable binding of dysopsonins that prevent uptake by the reticuloendothelial system (RES).
590 $a School code: 0240.
650 4 $a Chemistry, Pharmaceutical. $3 550957
650 4 $a Chemistry, Polymer. $3 1018428
650 4 $a Health Sciences, Pharmacy. $3 1017737
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690 $a 0495
690 $a 0572
710 2 0 $a The University of Utah. $3 1017410
773 0 $t Dissertation Abstracts International $g 66-03B.
790 $a 0240
791 $a Ph.D.
792 $a 2005
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3167516