University of Notre Dame
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Engineering Multivalent Systems for Improved Drug Delivery, Allergy Diagnosis, and Bioprocess Development

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posted on 2021-04-19, 00:00 authored by Franklin Eduardo Mejia Frias

This dissertation focuses on the design, synthesis, characterization, and mechanistic evaluation of selective targeted nanomedicines with endosomolytic properties for efficient intracellular delivery of chemotherapeutic agents. Targeted nanomedicine result from modification of nanoparticles (e.g., liposomes) with ligands capable of binding to cell-surface receptors with high specificity and the ability trigger cellular uptake or internalization. Targeted nanoparticles have been shown to provide significant enhancements in receptor-mediated internalization with great promise for personalized medicine but have yet to reach the clinic.

Three separate components of rational nanomedicine design are explored throughout this dissertation. In chapter one, the rational design of multivalent systems is explained, suggesting a paradigm shift in the optimization parameters for targeted nanomedicines: prioritize selectivity, not avidity. Next, chapters two and three focus on how targeted nanomedicines can be rationally designed for tackling one of the major bottlenecks in nanoparticle-based drug delivery: endosomal escape. In short, following internalization, nanoparticles are shuttled through endosomal vesicles leading to exocytosis/recycling or lysosomal degradation, rarely reaching the cytosolic compartment. Using a modular liposomal nanoparticle system, we have studied the implications of endosomal escape moieties in targeted drug delivery and determined optimizable parameters for optimization, improving targeted nanoparticle internalization >10-fold and nanomedicine potency by ~3-fold. Importantly mechanistic differences between the endosomal escape of targeted and non-targeted nanomedicines were evaluated, providing further insight into endosomal escape for basic and applied sciences. Finally, lessons learned from targeting and endosomolytic design are combined with the design of prodrugs that improve selectivity of nanomedicines by optimizing for intracellular release rather than sustained released.

Altogether, this work provides guideline for the rational design of targeted nanomedicines and highlights the value of systematic analysis for the basic understanding of biological problems, followed by application of this knowledge for engineering solutions that improve patient outcome.

History

Alt Title

Engineering Multivalent Systems for Improved Drug Delivery, Allergy Diagnosis, and Bioprocess Development

Date Modified

2021-05-22

Defense Date

2021-03-29

CIP Code

  • 14.0701

Research Director(s)

Başar Bilgiçer

Committee Members

Jeremiah Zartman Matt Webber Siyuan Zhang

Degree

  • Doctor of Philosophy

Degree Level

  • Doctoral Dissertation

Alternate Identifier

1252217399

Library Record

6025399

OCLC Number

1252217399

Program Name

  • Chemical and Biomolecular Engineering

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