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Fabrication and Characterization of Panobinostat Loaded PLA-PEG Nanoparticles View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ASU Digital Repository Fabrication and Characterization of Panobinostat Loaded PLA-PEG Nanoparticles By Shruti Dharmaraj A Master’s Thesis Presented in Partial Fulfillment of the Requirements for the Degree Master of Science Approved April 2019 by the Graduate Supervisory Committee: Rachael Sirianni; co-chair Sarah Stabenfeldt; co-chair Brent Vernon ARIZONA STATE UNIVERSITY May 2019 ABSTRACT Medulloblastoma is the most common malignant pediatric brain cancer and is classified into four different subgroups based on genetic profiling: sonic hedgehog (SHH), WNT, Group 3 and 4. Changes in gene expression often alter the progression and development of cancers. One way to control gene expression is through the acetylation and deacetylation of histones. More specifically in medulloblastoma SHH and Group 3, there is an increased deacetylation, and histone deacetylase inhibitors (HDACi) can be used to target this change. Not only can HDACi target increases in deacetylation, they are also known to induce cell cycle arrest and apoptosis. The combination of these factors has made HDACi a promising cancer therapeutic. Panobinostat, a hydrophobic, small molecule HDACi was recently identified as a potent molecule of interest for the treatment of medulloblastoma. Furthermore, panobinostat has already been FDA approved for treatment in multiple myeloma and is being explored in clinical trials against various solid tumors. The laboratory is interested in developing strategies to encapsulate panobinostat within nanoparticles composed of the biodegradable and biocompatible polymer poly(lactic acid)-poly(ethylene glycol) (PLA-PEG). Nanoparticles are formed by single emulsion, a process in which hydrophobic drugs can be trapped within the hydrophobic nanoparticle core. The goal was to determine if the molecular weight of the hydrophobic portion of the polymer, PLA, has an impact on loading of panobinostat in PLA-PEG nanoparticles. Nanoparticles formulated with PLA of varying molecular weight were characterized for loading, size, zeta potential, controlled release, and in vivo tolerability. The results of this work demonstrate that panobinostat loaded nanoparticles are optimally formulated with a 20:5kDa PLA-PEG, enabling loading of ~3.2 % w/w panobinostat within nanoparticles possessing an average diameter of 102 nm and surface charge of -8.04 mV. i Panobinostat was released from nanoparticles in a potentially biphasic fashion over 72 hours. Nanoparticles were well tolerated by intrathecal injection, although a cell culture assay suggesting reduced bioactivity of encapsulated drug warrants further study. These experiments demonstrate that the molecular weight of PLA influences loading of panobinostat into PLA-PEG nanoparticles and provide basic characterization of nanoparticle properties to enable future in vivo evaluation. ii Dedication First and foremost, I would like to thank my family for their constant encouragement and enthusiasm. Not only are you interested about my time in Houston, but also about my time in the lab including all the experiments and projects I work on. Mom and Dad, while you may not understand all the technicalities of my work, your constant excitement reminds me of why I chose biomedical engineering when I knew nothing about the subject and it makes me excited to continue working even when it gets stressful. iii Acknowledgments Thank you to Dr. Rachael Sirianni for mentoring me over the last two years and providing me the opportunity to continue this work in Houston. I am ready for the work we will have moving forward! Thank you to Dr. Sarah Stabenfeldt, who 4 years ago took a chance on a student from another university to work in her lab for the summer. I am thankful for your continued support for my career goals and my research. iv TABLE OF CONTENTS CHAPTER Page 1. INTRODUCTION .......................................................................................................1 2. MATERIALS AND METHODS .................................................................................5 2.1 MATERIALS ...........................................................................................................5 2.2 NANOPARTICLE FABRICATION ..............................................................................5 2.3 NANOPARTICLE CHARACTERIZATION ...................................................................6 2.3.1 Drug Loading ...................................................................................................6 2.3.2 Size and Zeta Potential.....................................................................................6 2.4 IN-VITRO STUDY ...................................................................................................7 2.4.1 Cell Culture ......................................................................................................7 2.4.2 Measurement of Panobinostat Activity ............................................................7 2.5 IN-VIVO TOLERABILITY.........................................................................................8 2.6 STATISTICAL ANALYSIS ........................................................................................9 3. RESULTS ..................................................................................................................10 3.1 NANOPARTICLE LOADING AND CHARACTERIZATION ..........................................10 3.2 RELEASE CHARACTERISTICS ...............................................................................14 3.3 IN-VITRO PANOBINOSTAT ACTIVITY ....................................................................15 3.4 IN-VIVO TOLERABILITY .......................................................................................16 4. DISCUSSION ............................................................................................................17 5. REFERENCES ..........................................................................................................22 1. INTRODUCTION Medulloblastoma is the most common malignant pediatric brain tumor with a peak diagnosis between the ages of six and eight years old. Standard treatment includes maximum safe resection and subsequent radiation and chemotherapy. Although the overall 5- year survival is approximately 80%, the neuroendocrine, neurological and psychological damage from the aggressive treatment leave patients with long-term health complications. Thus, researchers and clinicians are focused on finding a treatment that can reduce or eliminate these toxicities while improving the overall survival and quality of life. (30,40). At the molecular level, medulloblastoma is classified into four subtypes: WNT, sonic hedgehog (SHH), Group 3 and Group 4. Each of these subtypes are associated with distinct genetic aberrations (29). Deregulated expression of genes is associated with development of tumors due to impaired control of differentiation and the cell cycle. One of controlling expression is through the modifications of histones (37). One of the best characterized modifications, histone acetylation, is mediated by histone acetyltransferase (HAT) and histone deacetylases (HDAC). Increased deacetylation is known to play a role in SHH and group 3 subgroups of medulloblastoma, and histone deacetylase inhibitors (HDACi) have been used to target this change (4,29,33,39). Furthermore, HDACi are known to induce cell cycle arrest and apoptosis and sensitize tumor cells to radiation and chemotherapy (29,44). Although the approach of HDACi has shown preclinical and clinical efficacy for hematological cancers (27), their efficacy has largely been limited when applied to treating solid tumors (37). However, panobinostat, a hydrophobic HDACi, has be identified as a potential candidate against both hematological and solid tumors (6,14,31,42). Research 1 conducted at Sanford Burnham Prebys Medical Discovery Institute by Dr. Robert Weschler-Reya showed in a high-throughput screen against medulloblastoma human and murine group 3 cells that panobinostat potently inhibited growth and was effective against all medulloblastoma subgroups. However, in a preclinical in-vivo study panobinostat did not significantly increase survival when tolerable doses of panobinostat were administered to mice with xenograft of diffuse pontine glioma (DIPG) (17). The inconsistency of panobinostat can possibly be attributed to poor delivery to solid tumors, which have complex and abnormal vasculature that limits drug perfusion (20). However, using panobinostat as a therapy for intrathecal administration poses a few problems. Panobinostat is poorly soluble and thus delivery of the drug safely to the central nervous system is difficult. Currently there are two market products of panobinostat: Farydak’s oral capsule and Midatech’s solubilized panobinostat through their nanoinclusion technology. While Farydak developed a delivery mechanism, severe diarrhea occurred in 25% of patients, and cardiac toxicities are associated with the drug (1,4). Midatech Pharma developed MTX110, a formulation that solubilizes panobinostat with their proprietary nano-inclusion technology (2). This compound is currently being used in clinical trials to treat DIPG through convection enhanced delivery (9). While MTX110 provides a means to solubilize panobinostat without toxic solvents, it does not fully address the problems of short drug half-life and high toxicity. Efforts are also underway to encapsulate panobinostat
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