Interactions of macromolecules with enzymes: implications for the development of soluble polymeric drug conjugates

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Title Interactions of macromolecules with enzymes: implications for the development of soluble polymeric drug conjugates
Publication Type dissertation
School or College College of Pharmacy
Department Pharmaceutics & Pharmaceutical Chemistry
Author Chiu, Hsin-Cheng
Date 1994-06
Description The biocompatibility of polymeric drug delivery systems is very important to the success of their clinical applications. The fate of lysosomotropic polymeric drug carriers in vivo as well as the biological activity of the conjugates may be greatly influenced by the lysosomal degradability of the polymeric carriers. The relationship between the structures of macromolecules and their biorecognizability was studied in order to: 1) gain insight into the interactions of macromolecular drug carriers with enzymes; and 2) optimize the polymer structures of lysosomotropic drug carriers. Poly(a-amino acids) were studied for the effects of structural differences upon their lysosomal degradability. The results showed that the incorporation of hydrophobic amino acid residues into the polymer backbone and the modification of L-glutamic carboxylic side chains with hydroxyalkylamines enhanced the lysosomal degradability of the polymers. Further study on the products of degradation using electrospray mass spectroscopy showed that no low molecular weight fragments were generated by lysosomal enzymes. It is known that the permeability of the lysosomal membrane is limited to materials with molecular weights similar to dipeptides. Therefore, macromolecules, if to be used as lysosomotropic drug carriers, may become confined and accumulate within the lysosomal compartment following endocytosis. Consequently, the decreased biorecognizability of macromolecular drug conjugates by lysosomal enzymes should be considered during the development of polymeric drug delivery systems. Bloactive macromolecules, such as enzymes, may be chemically modified by polymers to improve their biocompatibility and therapeutic efficiency. To evaluate the influence of such chemical modifications upon the biorecognizability of the enzymes, the catalytic activities of chymotrypsins modified with poly(ethylene glycol) were determined. The studies showed that the modified enzymes retained good catalytic activity toward low molecular weight substrates, slight activity against denatured protein substrates, and no activity against native protein substrates. The complete lack of activity toward native protein substrates was attributed to the poly(ethylene glycol's unique ability to exclude proteins from its surroundings. To elucidate the influence of poly(ethylene glycol) upon enzyme-substrate interactions, poly(ethylene glycol)-dextran conjugates were synthesized and tested for their degradability catalyzed by dextranase, rat cecum cell free extracts, and rat liver lysosomal enzymes. It was found that whereas the conjugates were not hydrolyzed by lysosomal enzymes, the degradability of the conjugates by dextranase and the cell free extracts decreased with an increase in their degree of substitution as well as with the molecular weight of the poly(ethylene glycol).
Type Text
Publisher University of Utah
Subject Polymeric drug delivery systems
Subject MESH Drug Delivery Systems; Macromolecular Substances; Polymers; Polymers
Dissertation Institution University of Utah
Dissertation Name PhD
Language eng
Relation is Version of Digital reproduction of "Interactions of macromolecules with enzymes: implications for the development of soluble polymeric drug conjugates". Spencer S. Eccles Health Sciences Library.
Rights Management © Hsin-Cheng Chiu.
Format application/pdf
Format Medium application/pdf
Format Extent 3,008,457 bytes
Identifier undthes,4363
Source Original: University of Utah Spencer S. Eccles Health Sciences Library (no longer available).
Master File Extent 3,008,526 bytes
ARK ark:/87278/s67m09rg
Setname ir_etd
ID 191410
Reference URL https://collections.lib.utah.edu/ark:/87278/s67m09rg
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