Development of Rationally Engineered Peptide-Targeted Liposomal Nanoparticles to Achieve Enhanced Therapeutic Efficacy with Selectivity and Design of Novel Inhibitors for Allergy

This dissertation demonstrates the development of optimized targeted liposomal nanoparticle formulation for cancer and inhibitors for allergies. The first part (Chapter 2-4) describes the approach to rationally engineered target-specific liposomal nanoparticles for various types of cancers, including breast cancer and B-cell malignancies. Liposomal nanoparticles have been recognized and utilized as drug delivery platforms for decades. Nevertheless, many attempts to translate targeted liposomal formulations as novel treatments to the clinic have failed. In fact, FDA hasn’t approved any targeted nanoparticle (liposomal or other materials) treatments as of this time of writing. Among many reasons for failure, one of the main ones regards issues surrounding consistent reproducibility of targeted nanomaterials during manufacturing. To address this limitation, our lab has developed a patented technology for the synthesis of peptide-targeted liposomes with highly consistent batch-to-batch production that reproducibly achieves reliable outcomes in vivo experiments. Furthermore, by taking advantage of multivalency in our design and using weak-to-moderate monovalent affinity ligand peptides as the targeting elements, we are able to achieve selectivity by designing avidity for cancer cells while avoiding healthy cells/tissue. This is accomplished by evaluating the liposomal formulation first in vitro, and then further optimizing it in vivo by adjusting the individual design parameters, such as peptide density, linker length, peptide hydrophilicity, and particle size, to achieve maximal cellular uptake while preserving the selectivity for specific target cancer cells. In each Chapter, we show optimized targeted liposomal nanoparticles that achieved enhanced therapeutic efficacy to significantly inhibit tumor growth with reduced toxicity.

The second part (Chapter 5 and 6) describes the development of allergen-specific inhibitors. Allergic reactions can vary from mild (rash, itchiness, runny nose, etc.) to a life-threatening anaphylaxis. Currently, there are no prophylactic treatments available that prevents the allergic reaction prior to its initiation. To address this problem, we developed a two-step process where we first identify immunodominant epitopes/haptens, and then develop specific inhibitors for these epitopes/haptens. We start by using our patented liposome-based synthetic allergen platform, named nanoallergens, to identify immunogenic epitopes that are responsible for triggering the degranulation response. Then, using the identified immunogenic epitopes, we develop inhibitors, named cHBIs, that bind to allergen-specific IgEs and inhibit their interaction with the allergen and thereby inhibit the allergic response. In the Chapter 5, we demonstrated in vivo efficacy of cHBIs that effectively and persistently inhibit Ara h 2-induced anaphylaxis in the humanized mice. Furthermore, in the Chapter 6, we identified immunogenic epitopes of shrimp protein, pen a 1, and developed a cocktail of cHBIs that showed more than 90% inhibition in the in vitro cellular degranulation response.