Multivalent Design in Nanomedicine: Diagnostics, Therapeutic Targeting, and Inhibitor Development

This dissertation describes the design and optimization of several multivalent nanomedicines for use in allergies and cancer. Targeted nanomedicines can improve diagnostics and therapeutics for many diseases. Yet, despite decades of research, most nanomedicines fail in clinical trials. The addition of targeting to nanomedicines may improve their efficacy, yet each component and characteristic must be tuned to make precision medicines. This requires understanding of complex parameters such as selectivity over avidity and navigating immune system involvement.

First, two allergy systems are studied here, exploring improvements to diagnostics and therapeutics via multivalent nanomedicines. Chapter two covers cephalosporin antibiotic (i.e., small molecule drug) allergies, while chapter 3 studies house dust mite (HDM) protein allergies. Multivalent liposomal nanoallergens are used to determine the immunogenic structures of the drug and protein allergens. These immunogenic structures inform the design of improved allergy diagnostics and therapeutics. In chapter four, multivalent inhibitor designs are evaluated in vitro for two protein allergy systems: peanut and HDM. Several covalent heterobivalent inhibitors, containing various peanut and HDM immunogenic epitopes, are evaluated for inhibition of cellular allergic response and compared to a covalent monovalent inhibitor.

Second, this work studies multivalent nanomedicines in the design and optimization of targeted nanoparticle systems for delivering chemotherapeutics to cancer. Chapter five evaluates two targeted nanoparticle systems (CD38 versus CD138) for delivery of a doxorubicin-prodrug to multiple myeloma. In vitro and in vivo optimization of the targeted nanoparticles show opposite trends, due to the poor selectivity of the CD138-targeted nanoparticles in vivo. Chapter six explores the complexity of targeting metastatic ovarian cancer, with a combination of nontargeted (NP) and GRP78-targeted (TNP^GRP78pep) nanoparticles displaying optimal drug delivery of a novel DM1-prodrug in vivo. Further, the prodrug-loaded nanoparticles enhance immune cell involvement. We propose two mechanisms of action for the NP and TNP^GRP78pep components to function synergistically, which are largely dependent on their multivalent targeting or lack thereof. These chapters demonstrate the complexity of optimizing multivalent nanomedicines in vivo.

Collectively, this dissertation emphasizes the necessity of a detailed understanding of the diseases of interest and of systematically optimizing multivalent nanomedicine designs to fit the disease.