Abstract/Details

Polymeric designs for gene delivery, drug delivery and enzyme activity modulation


2009 2009

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Abstract (summary)

Polymers are interesting macromolecules that have gained great interest in a wide variety of applications. In this thesis, polymers have been utilized for gene and drug delivery, and to modulate enzyme activity.

Simply, the idea of gene therapy is to deliver a therapeutic gene into defective cells. This field of medicine has enormous potential to cure many genetic diseases such as cancer, Alzheimer’s, and Huntington’s disease. A major obstacle in gene therapy is in safely and efficiently delivering the exogenous DNA into the nucleus of a cell. After the tragic failures in virus based gene therapy in clinical trials, there is a necessary search for a non-viral material. Polymers have been shown to interact and facilitate the entry of therapeutic DNA into the nucleus. Several types of polymers, including polyethyleneimine and poly-lysine, have had initial success in gene delivery. The first part of this thesis discusses about interesting approaches to further enhance the level of transfection and decrease toxicity.

In one approach, an inspiration is taken from HIV-TAT protein that translocate exogenous materials into the nucleus. The basic domain of HIV-TAT protein, TAT peptide has been utilized in the polymeric design. A method has been developed to effectively display the TAT peptide on the polyplex surface. This significantly enhances the transfection efficiency of polyethylenimine polymers.

In the search for a successful polymeric design for gene delivery, several naturally occurring amino acids are placed on a biocompatible polymer backbone. These polymers have high transfection and low toxicity when compared to the polymeric gold standards for gene delivery PEI and PLL. The design of these polymers also provided an opportunity to understand the structure-property relationships of different amino acid based polymers.

Polymeric materials are also an interesting candidate for drug delivery. Polymeric micelles are designed to incorporate the cytotoxic anti-cancer drug, doxorubicin, and target it to cancer cells. These amphiphilic polymers have redox sensitive disulfide bonds and their cleavage causes the micelle to fall apart. This helps the polymeric micelles to selectively release the drug in high redox environment of cancer cells.

Proteins regulate most of the cellular functions in our bodies and the alteration of their activities can lead to life threatening diseases. In the final part of this thesis, polymeric scaffolds are designed and developed to tune enzyme activity. The cationic polymers have the ability to electrostatically interact with proteins, namely serine protease chymotrypsin. At the physiological pH, these polymers can regulate chymotrypsin activity from 20% to 200% at nanomolar concentration without denaturing the protein.

Indexing (details)


Subject
Polymer chemistry
Classification
0495: Polymer chemistry
Identifier / keyword
Pure sciences; Amino acid polymers; Cationic polymers; Drug delivery; Enzyme activity; Enzyme modulation; Gene delivery; Transfection
Title
Polymeric designs for gene delivery, drug delivery and enzyme activity modulation
Author
Roy, Raghunath
Number of pages
193
Publication year
2009
Degree date
2009
School code
0118
Source
DAI-B 70/12, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9781109500868
Advisor
Thayumanavan, Sankaran
Committee member
Jerry, D. J.; Venkataraman, Dhandapani; Weis, Robert M.
University/institution
University of Massachusetts Amherst
Department
Chemistry
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3380012
ProQuest document ID
304927649
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304927649
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