Engineering layer-by-layer nanoparticles for the targeted delivery of therapeutics to ovarian cancer

Abstract

Survival rates for ovarian cancer haven't meaningfully improved in thirty years. Ovarian cancer is particularly difficult to treat because it is usually discovered after it has metastasized and it quickly develops resistance to the few drugs that are initially effective at controlling it. Nanomedicine has the potential to change the paradigm for ovarian cancer treatment by delivering complex combinations of conventional drugs plus next-generation therapies like small interfering RNA (siRNA) and immunotherapy. However, nanoparticles must be tailored to the particular drug-delivery challenges and opportunities posed by ovarian cancer. In this thesis, we designed layer-by-layer (LbL) nanoparticles (NPs) to target ovarian cancer using library-based approaches. Using this approach, we identified promising formulations for developing an advanced nanotheranostic that both treats and detects ovarian cancer. In order to develop LbL NPs for treating ovarian cancer, we identified and overcame process engineering and fundamental materials challenges, thereby improving synthesis robustness, throughput and scale. Chapter 2 describes how modern tangential flow filtration significantly improves throughput and scalability in colloidal LbL assembly. Chapter 3 implements this improved synthetic approach to generate a small library of LbL NPs that screen for tumor-targeting properties on ovarian cancer cells, both in vitro and in vivo. Our results demonstrate that ovarian cancer cells have a high affinity to carboxylated LbL NPs, and we report several tumor-targeting formulations with distinct subcellular trafficking patterns. Chapter 4 explores the role of salt in LbL colloidal assembly, and we develop strategies for robustly synthesizing LbL-modified liposomes with high loading of siRNA. Chapter 5 advances a promising formulation identified by our surface chemistry screen, which we developed into an advanced nanotheranostic device that delivers siRNA and mediates urinary-based tumor detection. Future work that continues to improve the synthesis of LbL NPs will be essential to generate larger and more ambitious LbL NP libraries. In turn, these libraries will facilitate systematic studies that further tailor the LbL platform to specific diseases and biomedical applications.