Elucidating Mechanisms for Drug Combination Nanoparticles to Enhance and Prolong Lymphatic Exposure: Experimental and Modeling Approaches

Abstract

Human immunodeficiency virus (HIV) infection and metastatic cancers impact over 50 million people worldwide. Because HIV and metastatic cancers exploit the lymphatics to persist and spread, enhanced and prolonged lymphatic exposure to drug combinations is essential for treating these diseases. Unfortunately, many oral and intravenous small molecule drug therapies exhibit limited lymphatic exposure, which can lead to subtherapeutic drug levels and drug resistance. Moreover, most therapeutic strategies and decisions for these diseases are not made with lymphatic drug exposure in mind, largely because accounting for and understanding lymphatic drug levels is complex, and limited tools exist for this. Thus, there is a need for tools to better understand lymphatic drug exposure and for strategies to selectively deliver drug combinations to the lymphatics. We previously developed lymphatic-targeted drug combination nanoparticles (DcNPs), however, the mechanisms that enable DcNPs to target drug combinations to the lymphatics remained to be elucidated. Understanding these mechanisms could open up new therapeutic strategies for treating lymphatic diseases. Therefore, the goals of this thesis are 1) to develop novel tools to help understand lymphatic drug exposure and 2) to use these tools to elucidate how DcNPs enable enhanced and prolonged lymphatic exposure. First, this thesis describes for the first time that a single injection of DcNPs enabled enhanced and prolonged drug levels in HIV host cells (lymph node and blood lymphocytes) that were persistently higher than those in the plasma. Then, to assess lymphatic drug exposure and to elucidate the mechanisms of this sustained targeting of drug combinations to lymphocytes with DcNPs, novel tools were developed, namely near-infrared fluorescent DcNPs to track their in vivo distribution pathways in real-time, and mechanism-based pharmacokinetic (MBPK) models. Together these tools elucidated that DcNPs undergo lymphatic first-pass distribution and lymph node and lymphocyte retention, which leads to the enhanced and prolonged lymphatic exposure to drug combinations. This is the first time that the novel concept of lymph nodes and lymphocytes serving as body-wide drug depots to enable long-acting pharmacokinetics for drug combinations in both the lymphatics and the plasma has been described. These novel long-acting mechanisms and tools for assessing lymphatic exposure have significant potential to be used to develop new treatment strategies for lymphatic diseases.