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PH SENSITIVE RNA AND DRUG DELIVERY SYSTEMS

Sutton, Damon Michael

Abstract Details

2007, Doctor of Philosophy, Case Western Reserve University, Macromolecular Science.
There has been a recent shift in the development of pharmaceutical delivery systems from systems which solubilize agents to systems that respond to external stimuli. Because of this, there is much focus on the development of systems that are responsive within the relatively narrow ranges that are expected to be seen in vivo. This work focuses on the development of drug delivery systems for the purposes of pH sensitive delivery. Initially, poly(ethylenimine) (PEI) derivatives were used as a basis for an siRNA delivery system. PEI graft copolymers were found to be efficient siRNA delivery vectors. The pH sensitivity of PEI could then subsequently be used for drug delivery via blending with poly(lactide-co-glycolide). Full miscibility was observed between these polymers via a mechanism of amide formation, with the result being a material suitable for pH sensitive drug delivery. Efforts to use this system on the nanoscale, however, were unsuccessful, leading to an alternate strategy. The alternate strategy initially quantified the factors dominating drug release from polymeric micelles, with drug solubility being found to be a major determinant. The conclusions here were used to create a system for the pH sensitive release of Β -lapachone. In this case, pH sensitive drug solubility was induced by using hydrophobic prodrugs of Β -lapachone which converted to the more soluble parent drug upon exposure to acid. These prodrugs were found to load into polymeric micelles as a function of drug solubility in core polymer. Finally, pH sensitive release of the parent drug was observed via a mechanism of intramicellar hydrolysis of prodrug into parent drug. On a larger scale, this work represents efforts leading to novel routes to pH sensitive pharmaceutical delivery systems. The buffer capacity of PEI, though observed in gene delivery, has not been previously used for drug delivery. Meanwhile, the hydrophobic prodrug strategy in a novel innovation that allows for the facile customization of drugs for improved loading into micelles and pH sensitive release. This work expands the knowledge and ability in creation of pH sensitive drug and RNA delivery systems.
Jinming Gao (Advisor)
270 p.

Recommended Citations

Citations

  • Sutton, D. M. (2007). PH SENSITIVE RNA AND DRUG DELIVERY SYSTEMS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1179847644

    APA Style (7th edition)

  • Sutton, Damon. PH SENSITIVE RNA AND DRUG DELIVERY SYSTEMS. 2007. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1179847644.

    MLA Style (8th edition)

  • Sutton, Damon. "PH SENSITIVE RNA AND DRUG DELIVERY SYSTEMS." Doctoral dissertation, Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1179847644

    Chicago Manual of Style (17th edition)