Date of Award

5-2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Industrial and Physical Pharmacy

Committee Chair

Yoon Yeo

Committee Member 1

Kinam Park

Committee Member 2

Chiwook Park

Committee Member 3

Elizabeth M. Topp

Abstract

Nanoparticles have been pursued as a promising strategy to improve the safety and therapeutic efficacy of systemic chemotherapy, but clinical translation of nanoparticle drug carriers has been slow. Several reasons account for the tedious progress. From the formulation perspective, drug loading efficiency and circulation stability remain to be improved: Low drug loading increases the amount of co-delivered carrier materials, imposing biological burdens to patients. Poor circulation stability compromises the pharmacokinetic benefits of nanoparticles. To develop nanoparticles with high drug loading efficiency and circulation stability, albumin-coated nanocrystal (“Abxtal”) formulation of hydrophobic anti-cancer drugs was developed. Abxtal consists of drug nanocrystals and albumin coating, where albumin serves as a stealth coating to reduce protein adsorption and a mediator of cellular uptake by cancer cells. When Abxtal formulation for paclitaxel was compared with Abraxane®, an FDA-approved albumin-paclitaxel nanoparticle formulation, Abxtal showed superior anti-tumor efficacy at the equivalent dose in a mouse model of B16F10 melanoma. A comparative pharmacokinetics/biodistribution (PK/BD) study confirmed that the superior performance of Abxtal was due to its prolonged circulation in blood and greater tumor accumulation relative to Abraxane. Protein binding to surface of nanoparticles is another important factor that determines the biological fate of the nanoparticles. When the effect of surface chemistry on the formation of protein corona was studied, albumin coating provided protective effects against opsonization,

consistent with the known role of albumin as a dysopsonin. The early difference in serum protein binding led to differential macrophage uptake of nanocrystal, contributing to the superior in vivo performance of Abxtal. Overall, the improved therapeutic efficacy of Abxtal is attributable to its higher circulation stability and dysopsonin function of albumin, resulting in preferential tumor accumulation. Furthermore, the broad utility of Abxtal formulation as an enabling formulation for hydrophobic small molecule drugs was demonstrated with docetaxel and carfilzomib. Abxtal formulation of docetaxel entered drug-resistant NCI/ADR-RES ovarian cancer cells by interactions with albumin-receptors, showing the potential utility in the treatment of multidrug-resistant tumors. Abxtal formulation of carfilzomib protected the drug from enzymatic degradation, leading to enhanced bioavailability relative to the solvent- or cyclodextrin-solubilized formulations. In tandem with the robust nanoparticle platform development, the utility of nanoparticles in immune checkpoint blockade therapy has been explored. Specifically, it is envisioned that nanoparticle delivery of the chemotherapeutic that functions as immunogenic cell death inducer will synergize with immune checkpoint blockade. The underlying hypothesis is that nanoparticles will help immune checkpoint blockade therapy by (i) improving the delivery of immunogenic cell death inducers; (ii) altering the cellular uptake mechanism and intracellular stress; (iii) creating, binding and retaining neo-antigens in situ and delivering them to antigen presenting cells; and (iv) co-delivering immune adjuvants. Preliminary studies were performed to determine their ability to induce immunogenic cell death. The release of damage-associated molecular patterns from B16F10 melanoma cells treated with different nanoparticle formulations was examined as in vitro measures of immunogenic cell death induction.

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