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Kraft Washington 0250E 18634.Pdf (12.39Mb) © Copyright 2018 John Cavin Kraft II Elucidating Mechanisms for Drug Combination Nanoparticles to Enhance and Prolong Lymphatic Exposure: Experimental and Modeling Approaches John Cavin Kraft II A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2018 Reading Committee: Rodney J. Y. Ho, Chair Kenneth E. Thummel Shiu-Lok Hu Program Authorized to Offer Degree: Pharmaceutics University of Washington Abstract Elucidating Mechanisms for Drug Combination Nanoparticles to Enhance and Prolong Lymphatic Exposure: Experimental and Modeling Approaches John Cavin Kraft II Chair of the Supervisory Committee: Rodney J. Y. Ho Department of Pharmaceutics 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. Lay Abstract Over 50 million individuals worldwide are impacted by human immunodeficiency virus (HIV) infection and metastatic cancer, which exploit the lymphatic system to persist and spread. However, the lymphatics are poorly understood and this has prevented the development of effective lymphatic therapies. To address these limitations, we previously pioneered a lymphatic drug delivery platform for drug combinations. This thesis has developed and employed a suite of quantitative tools to understand the mechanisms this drug combination platform uses for enhanced and prolonged lymphatic exposure. This new understanding coupled with these quantitative tools have significant potential to be used for the development of new therapeutic strategies for lymphatic diseases. TABLE OF CONTENTS List of Figures ................................................................................................................................ vi List of Tables ............................................................................................................................... viii Chapter 1. Introduction ................................................................................................................... 1 1.1 Background and Significance ......................................................................................... 2 1.2 Disease Etiologies that Involve the Lymphatic System .................................................. 9 1.3 Factors Affecting Lymphatic Drug Distribution and Retention ................................... 14 1.3.1 Anatomical and Physiological Factors ...................................................................... 14 1.3.1.1 Interstitium, Lymphatic Endothelial Cells (LECs), and Lymph ........................... 14 1.3.1.2 Lymph Vessel and Node Networks ...................................................................... 19 1.3.1.3 Lymph Node Architecture and Cellular Composition .......................................... 22 1.3.1.4 Pathobiology of HIV-1 in Lymphoid Tissues ....................................................... 24 1.3.1.5 Lymphocytes: The Host Cells for HIV Infection ................................................. 26 1.3.2 Experimental Factors: Injection Site, Volume, and Rate .......................................... 27 1.4 Drug Distribution and Retention in Lymph Nodes and Lymphocytes ......................... 32 1.4.1 Small Molecule Distribution and Retention ............................................................. 32 1.4.2 Macromolecule Distribution and Retention .............................................................. 42 1.5 Long-Acting Drug Regimens and the TLC-ART Platform .......................................... 48 1.6 Hypotheses and Aims ................................................................................................... 54 Chapter 2. Drug Combination Nanoparticles (DcNPs) Target Lymphocytes in Lymph Nodes and Blood and Exhibit Long-Acting Pharmacokinetics ...................................................................... 64 2.1 Abstract ......................................................................................................................... 65 i 2.2 Introduction ................................................................................................................... 66 2.1 Materials and Methods .................................................................................................. 67 2.1.1 Reagents .................................................................................................................... 67 2.1.2 TLC-ART101 TFV-LPV-RTV Combination ........................................................... 67 2.1.3 Pharmacokinetic Study ............................................................................................. 67 2.1.4 Statistical Analysis .................................................................................................... 68 2.2 Results ........................................................................................................................... 68 2.3 Discussion ..................................................................................................................... 69 Chapter 3. Development of a Near-Infrared Marker to Track the In Vivo Distribution of DcNPs in Real-Time ................................................................................................................................. 77 3.1 Abstract ......................................................................................................................... 78 3.2 Introduction ................................................................................................................... 79 3.3 Materials and Methods .................................................................................................. 81 3.3.1 Chemicals .................................................................................................................. 81 3.3.2 Lipid-Nanoparticle Preparation ................................................................................ 81 3.3.3 90° Light Scattering of ICG Adsorbed to Lipid-Nanoparticles ................................ 82 3.3.4 Fluorescence ............................................................................................................. 83 3.3.5 Light Exposure and Storage Stability ....................................................................... 83 3.3.6 Tissue Depth Penetration .......................................................................................... 83 3.3.7 In Vivo NIR Lymphatic Imaging in Mice ................................................................ 84 3.4 Results ........................................................................................................................... 85 3.4.1 Lipid-Nanoparticle Lipid-ICG Interactions .............................................................. 85 3.4.2 Impact of Lipid-nanoparticle Lipid-ICG Interactions on ICG Fluorescence ............ 87 ii 3.4.3 Incorporation of ICG into Lipid-nanoparticles to Stabilize and Maximize ICG Fluorescence ......................................................................................................................... 87 3.4.4 Effects
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