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Title page for ETD etd-06032010-172126


Type of Document Dissertation
Author van der Ende, Alice Elizabeth
URN etd-06032010-172126
Title Polyester based ‘nanosponges’ as a delivery platform for diverse therapeutics to advance the treatment of a broad range of diseases
Degree PhD
Department Chemistry
Advisory Committee
Advisor Name Title
Dr. Eva Harth Committee Chair
Dr. Charles Lukehart Committee Member
Dr. Rick Haselton Committee Member
Dr. Tim Hanusa Committee Member
Keywords
  • cell penetrating
  • targeting peptides
  • targeting units
  • functionalized nanoparticles
  • alkyne-azide click chemistry
  • thiol-ene chemistry
  • amine-epoxide cross-linking
  • controlled release
  • burst effect
  • drug delivery system
  • platform
  • nanosponge
  • polyester nanoparticles
  • molecular transporter
  • amorphous
  • semicrystalline
  • drug encapsulation
  • formulation technique
  • vitamin E TPGS
Date of Defense 2010-05-28
Availability unrestricted
Abstract
While traditional polyesters, such as poly(lactic acid) and poly(glycolic acid), have long been of interest for the development of nanoparticles as effective drug delivery devices, they are restricted in their utility due to several major drawbacks. To circumvent these limitations, a practical approach has been developed for the formation of discrete functionalized polyester particles, which have been termed as ‘nanosponges’, with amorphous and semicrystalline morphologies in selected nanoscale size dimensions via a controlled intermolecular chain cross-linking process. This technique involves the coupling of epoxide functionalized polyesters with diamine to give well-defined multifunctional nanoparticles. The synthesis of discrete polyester nanoparticles using the intermolecular chain cross-linking process has also been successfully facilitated via click chemistry approaches, employing alkyne-azide click chemistry and the more recently developed thiol-ene reaction.

The formation of functionalized polyester nanoparticles containing amine, keto, and allyl groups has allowed for the tailoring of the particles towards the conjugation of bioactive building blocks, such as a dendritic molecular transporter and peptides. Synthetic strategies that enable efficient chemistries to conjugate targeting units and molecular transporter entities to the functionalized polyester particles have been developed to form potent carrier systems for targeted drug delivery and transport across biological barriers.

The versatile nature of the nanoparticle platform has allowed for the tailoring of the particles to meet the needs of specific drug delivery applications. The cross-linked supramolecular structure of the prepared polyester based nanoparticle has enabled the increased and efficient encapsulation of drug molecules and the post-modification with targeting peptides. These drug loaded particles, or nanosponges, have been shown to maintain a linear therapeutic release profile which can be tuned to the demands of a disease as a result of the adjustable supramolecular architecture. The ability to incorporate all of these properties into a single nanoparticle carrier system has demonstrated that the particles have been efficiently optimized for numerous therapeutic applications, such as the treatment of cancer and glaucoma, and the encapsulation of macromolecular therapeutics.

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