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    DESIGN AND SYNTHESIS OF BLOCK COPOLYMERS THAT SELF ASSEMBLE INTO MICELLES WITH CONTROLLED ACID AND LIPASE CATALYZED DEGRADATION

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    Genre
    Thesis/Dissertation
    Date
    2013
    Author
    Zhu, Xiaobo
    Advisor
    Wayland, Bradford B.
    Committee member
    Wunder, Stephanie L.
    Valentine, Ann M.
    Fryd, Michael
    Department
    Chemistry
    Subject
    Chemistry, Polymer
    Materials Science
    Acid Hydrolysis
    Degradation
    Lipase Enzyme
    Pcl
    Peg
    Polymer Micelle
    Permanent link to this record
    http://hdl.handle.net/20.500.12613/4102
    
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    DOI
    http://dx.doi.org/10.34944/dspace/4084
    Abstract
    Poly (ε-caprolactone) block poly (ethylene glycol) (PCL-b-PEG) is typical amphiphilic block copolymer that self assembles into micelles in water where the hydrolytically stable hydrophilic PEG segment forms the exterior corona and the core contains the hydrophobic degradable PCL block. Micelles from PCL-b-PEG block copolymers are among the top candidates for application as transport and delivery systems. The efficiency for micellar transported therapeutics to reach the desired site is currently limited by processes that prematurely degrade the micelle and this issue is stimulating increased effort in evaluating how micelles respond to the conditions encountered in the digestive and circulatory systems. Drug loaded micelles introduced into the blood and digestive systems encounter a wide range of conditions, enzymes and other substances that can promote micelle precipitation, degradation and premature release of therapeutics. Furthermore, PEG-b-PCL diblock copolymer micelle stability in aqueous suspension, low drug loading content and burst drug releasing are also the critical issues in drug delivery system. One central objective for this research is to identify and utilize polymer structural features that influence the hydrolytic stability of micelles toward acid, base and enzyme catalyzed hydrolysis of the polyester cores. The strategy of by preparing a set of triblock copolymers (PEG-b-PBO-b-PCL) formed by inserting a short hydrophobic non-hydrolyzable PBO segment between the PEG and PCL blocks as an approach to increase the barrier for water to reach the sensitive interface ester at the surface of the PCL core and thus increase the micelle stability at acidic aqueous medium. However, the triblock micelle doesn't significantly reduce the rate of lipase enzyme catalyzed degradation of micelle from PCL-b-PEG-OMe. Another objective for this research is to prepare PCL-b-PEG diblock copolymer micelles that have high stability in aqueous suspensions, high drug loading content and selective reactions with lipase enzymes. The working hypothesis is that the micelles with charged groups at the terminus of PEG corona will increase the micelle dispersion stability and stabilize micelles with much larger hydrophobic cores through intermicelle electrostatic repulsions. When the micelle corona and lipase enzyme have the same charge there will be an increased barrier to reaction. The comparison of micelle dispersion stabilities micelles from HO-PCL-b-PEG-CH2CH=CH, [PCL-b-PEG-RCO2]- Na+ and [PCL-b-PEG-RSO3]-Na+ demonstrates that the micelles with ionic coronas have significantly higher suspension stability. Kinetic of lipase catalyzed degradation of micelles with corona charges shows that lipases selective reaction with corona charged micelles which could be used as design feature to selectivity for therapeutic transport and release. Modification hydrophilic-hydrophobic interface and corona charges of PCL-b-PEG diblock copolymer micelle are successful chemical strategies to increase micelle stability and control acid and lipase enzymes catalytic degradation.
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