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Introducing Multifunctionality into ...

Rodriguez, April Rose.

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Introducing Multifunctionality into Polypeptide Vesicles for Biomedical Applications.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Introducing Multifunctionality into Polypeptide Vesicles for Biomedical Applications./
Author:	Rodriguez, April Rose.
Description:	241 p.
Notes:	Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
Contained By:	Dissertation Abstracts International74-07B(E).
Subject:	Engineering, Biomedical. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3556170
ISBN:	9781267979599

Introducing Multifunctionality into Polypeptide Vesicles for Biomedical Applications.
Rodriguez, April Rose.

Introducing Multifunctionality into Polypeptide Vesicles for Biomedical Applications. - 241 p.

Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.

Thesis (Ph.D.)--University of California, Los Angeles, 2013.

This item is not available from ProQuest Dissertations & Theses.

The delivery of naked drugs, DNA, RNA and proteins within living organisms is a challenging endeavor where renal clearance, liver accumulation, solubility issues, enzymatic and proteolytic degradation may reduce the effectiveness of the drug. Researchers are developing drug carriers such as liposomes, micelles, emulsions and vesicles to overcome these obstacles. Such carriers are used to encapsulate drugs and protect them from degradation, and more importantly to protect the patient from toxic side effects. Polypeptide vesicles are of interest because they are made up of long chains of amino acids and may be advantageous for in vivo applications since they can degrade to non-toxic metabolites. Natural and unnatural amino acids can be used as building blocks allowing a variety of functionality and tuning of physical properties. Polypeptides are also advantageous in that they can form secondary structures (i.e., alpha-helices, beta-sheets) stabilized by hydrogen bonding, which help to direct their self-assembly. Our group had developed polypeptide vesicles containing polyarginine hydrophilic segments of the general structure: poly(L-arginine)60-block-poly(L-leucine) 20, R60L20. The R60L20 vesicles were able to encapsulate Texas Red labeled dextran and were taken up by T84, HeLa, and HULEC-5A cell lines, indicating that polyarginine segments are useful for intracellular delivery. While these polypeptide vesicles (R60L 20) have shown promise for intracellular delivery there are issues that remain to be addressed, such as cytotoxicity and cargo release. In my research, I have focused on addressing these issues by optimizing the hydrophobic segment and introducing multifunctionality into polypeptide vesicles, creating improved drug delivery vehicle candidates.

ISBN: 9781267979599Subjects--Topical Terms:

1017684
Engineering, Biomedical.

Introducing Multifunctionality into Polypeptide Vesicles for Biomedical Applications.
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020 $a 9781267979599
035 $a (MiAaPQ)AAI3556170
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100 1 $a Rodriguez, April Rose. $3 3170750
245 1 0 $a Introducing Multifunctionality into Polypeptide Vesicles for Biomedical Applications.
300 $a 241 p.
500 $a Source: Dissertation Abstracts International, Volume: 74-07(E), Section: B.
500 $a Adviser: Timothy J. Deming.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2013.
506 $a This item is not available from ProQuest Dissertations & Theses.
506 $a This item must not be sold to any third party vendors.
520 $a The delivery of naked drugs, DNA, RNA and proteins within living organisms is a challenging endeavor where renal clearance, liver accumulation, solubility issues, enzymatic and proteolytic degradation may reduce the effectiveness of the drug. Researchers are developing drug carriers such as liposomes, micelles, emulsions and vesicles to overcome these obstacles. Such carriers are used to encapsulate drugs and protect them from degradation, and more importantly to protect the patient from toxic side effects. Polypeptide vesicles are of interest because they are made up of long chains of amino acids and may be advantageous for in vivo applications since they can degrade to non-toxic metabolites. Natural and unnatural amino acids can be used as building blocks allowing a variety of functionality and tuning of physical properties. Polypeptides are also advantageous in that they can form secondary structures (i.e., alpha-helices, beta-sheets) stabilized by hydrogen bonding, which help to direct their self-assembly. Our group had developed polypeptide vesicles containing polyarginine hydrophilic segments of the general structure: poly(L-arginine)60-block-poly(L-leucine) 20, R60L20. The R60L20 vesicles were able to encapsulate Texas Red labeled dextran and were taken up by T84, HeLa, and HULEC-5A cell lines, indicating that polyarginine segments are useful for intracellular delivery. While these polypeptide vesicles (R60L 20) have shown promise for intracellular delivery there are issues that remain to be addressed, such as cytotoxicity and cargo release. In my research, I have focused on addressing these issues by optimizing the hydrophobic segment and introducing multifunctionality into polypeptide vesicles, creating improved drug delivery vehicle candidates.
520 $a In order to optimize vesicle self-assembly and the ability to obtain diameters in the nanoscale range, the hydrophobic domain length and composition was varied. Fine-tuning the length of the poly(L-leucine) domain to 20 residues led to stable vesicular assemblies that had reduced cytotoxicity. To reduce the rigidity of the vesicle membrane a statistical copolypeptide was incorporated in the hydrophobic domain to disrupt the crystallinity of the poly(L-leucine) 20. The incorporation of L-alanine and L-phenylalanine residues allowed vesicle diameters to be manipulated below 200 nanometers with a 1 to 1 ratio of L-leucine to L-phenylalanine resulting in narrow polydispersities.
520 $a Replacing the cationically charged hydrophilic domains with neutral segments led to reduced cytotoxicity of block copolypeptide vesicles. It was found that incorporating neutrally charged segments, containing disordered chain conformations, provides the optimal conditions for obtaining minimally toxic vesicles with the ability be extruded to sizes below 200 nanometers in diameter. Glycosylated block copolypeptides not only provided a neutral non-toxic vesicle suspension, but also provide a method for incorporating biofunctionality, with the ability to bind to lectins.
520 $a Recent advances in the purification of alpha-amino acid N-carboxyanhydrides (NCAs) led to the use of L-methionine NCA, which has not been polymerized incorporated into block copolypeptides before. The unique sulfur chemistry of methionine provided a quick alternative to introducing new functionalities into polypeptide vesicles. Oxidation of poly(L-methionine) segments provided polypeptide vesicles with the ability to release its cargo within an environment containing either reducing chemicals or reductase enzymes found in human, animal and plant cells.
590 $a School code: 0031.
650 4 $a Engineering, Biomedical. $3 1017684
650 4 $a Health Sciences, Pharmacy. $3 1017737
690 $a 0541
690 $a 0572
710 2 $a University of California, Los Angeles. $b Biomedical Engineering 0289. $3 2098711
773 0 $t Dissertation Abstracts International $g 74-07B(E).
790 $a 0031
791 $a Ph.D.
792 $a 2013
793 $a English
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3556170