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Modifications of the Target or Therapeutic for Improved Drug Delivery

  • Author(s): Dolor, Aaron
  • Advisor(s): Szoka, Francis C
  • et al.
Abstract

Liposomes featuring a lipid bilayer surrounding an aqueous core, have been utilized as carriers for drugs and macromolecules since the 1970s. Liposomal drug encapsulation improves the pharmacokinetics, biodistribution, and pharmacodynamics of drugs. This research has culminated in over ten approved liposomal therapies, including Doxil® for the treatment of Kaposi’s sarcoma.

Despite the longevity, further clinical adoption of liposomes and nanomaterials has been limited due to a lack of effective targeting, undesired drug release kinetics, or inadequate drug penetration. In this dissertation, we present strategies to improve nanoparticle drug delivery through synthetic modifications of the particle or alterations of the target tissue. Our initial efforts centered on synthesizing novel lipids to focus the release of drugs or augment nanoparticle stability. Specifically, we detail the synthesis and characterization of sulfolipids with the potential for triggered-release of drug cargo in the tumor microenvironment through the use of sulfatases. These sulfolipids formed highly stable aggregates that were unable to form vesicles. Next, we describe the synthesis and biophysical characteristics of a modified polyethylene glycol (PEG), a key component for extending the circulation of nanomaterials. We anchored PEG to cholesterol to improve the interactions with neighboring lipids. These sterol-anchored PEG molecules exhibited an array of canonical liposome behaviors including the formation of vesicles, encapsulation of drugs, and limited non-specific protein adhesion.

Subsequently, we turned our focus to approaches to make the target tissue more receptive to drug delivery. We communicate procedures to recombinantly purify matrix metalloproteinase-8 (MMP-8), a key enzyme for tissue remodeling. We demonstrate methods to utilize MMPs in drug delivery through the attachment to the surface of liposomes. These procedures enabled the use of MMP-8 to improve the permeability of cartilage endplate tissue through removal of inhibitory extracellular matrix components. Altogether, the work presented provides several strategies to enhance the utility of liposomes through improvements in the release of drug cargo, particle stability and tissue penetration.

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