POLYMERIC DRUG DELIVERY VEHICLES AND IMAGING AGENTS

Abstract

This thesis was motivated by the substantial need for improved treatments for non-small cell lung cancer (NSCLC). NSCLC is an aggressive subset of lung cancer, which accounts for 80 to 85% of lung cancer cases, and is responsible for over 150,000 deaths annually in the US. The work presented herein can be divided into two parts based on different length scales. On the nanoscale, nanoparticles (NPs) for therapeutic and imaging applications were developed using Flash NanoPrecipitation (FNP). On the micronscale, a novel composite microgel particle (CGMP) that specifically targets the lungs for drug delivery was created using a controlled emulsification technique.

Nanoscale: A novel, in situ hydrophobic salt forming technique for the encapsulation of weakly hydrophobic, ionizable active pharmaceutical ingredients (API) into NPs formed via FNP was developed. By forming a hydrophobic salt in situ, the API solubility and crystallinity were tuned to allow for NP formation. The process greatly expands the types of APIs that can be successfully encapsulated in NP form, including a powerful chemopotentiator, α-lipoic acid. For the detection of liver metastases, MRI-active and multi-modal-active NPs were created. The imaging NPs were synthesized in one step using FNP and were shown to be strong T2 contrast agents. The detection of small liver metastases in vivo was facilitated by these NPs. To target tumors, scVEGF decorated NPs were formed. The activity of scVEGF on the nanoparticle surface was found to be similar to the free protein.

Micronscale: For targeted lung drug delivery, CGMPs, which passively accumulated in lungs via the venous filtration system, were designed and synthesized. CGMPs were composed of NPs encapsulated in a hydrogel matrix. A controlled emulsification process was developed to create CGMPs of desired size and narrow polydispersity. The modulus of the particles was readily tuned through the hydrogel formulation. The CGMPs were shown to selectively lodge in the lung after IV administration.

In summary, the research presented in this thesis has resulted in new designs and synthesis methods for polymeric drug delivery vehicles and imaging probes, which have the potential to improve the treatment and diagnosis of NSCLC.