Graduation Date
Summer 8-9-2024
Document Type
Thesis
Degree Name
Master of Science (MS)
Programs
Pharmaceutical Sciences
First Advisor
Dr. Svetlana G Romanova
Abstract
Traumatic brain injury (TBI) poses a significant global health challenge, contributing to approximately 2.5 million emergency room visits annually worldwide, 56,000 fatalities, and over $60 billion in direct medical costs for palliative care and cognitive rehabilitation in the United States alone(Acosta et al., 2016). The complex pathophysiology of TBI involves a multifaceted combination of neuroinflammation, oxidative stress, blood-brain barrier disruption (BBB), and Deoxyribonucleic Acid (DNA) damage. This research examines the development of a novel therapeutic system comprising dexamethasone-conjugated block co-polymeric nanoparticles loaded with olaparib, aiming to address multiple aspects of TBI pathology, particularly secondary injury (McConeghy et al., 2012). The dual-drug approach, featuring olaparib (Ola) and dexamethasone (DXM), targets key mediators of TBI progression. Olaparib, a potent poly (ADP ribose) polymerase-1 inhibitor, interferes with the overactivated DNA repair processes in injured cells post-TBI, otherwise exacerbating neuronal damage(d'Avila et al., 2012). Dexamethasone, a glucocorticoid, offers anti-inflammatory and anti-edema effects, reducing neuroinflammation and oxidative stress. In this thesis, nanoparticles were synthesized using methoxy poly(ethylene glycol) (mPEG) and N-carboxyl-α-amino-ץ-benzyl-L-glutamic anhydride (Glu(Bzl)-NCA) to form a methoxy poly(ethylene glycol) block polyglutamate benzyl (mPEG-b-pGlu(Bzl)m) copolymer, with dexamethasone conjugated via an ester bond to create a hydrophobic domain of amphiphilic block co-polymeric micelles that self-assemble in aqueous solutions, facilitating the efficient physical loading of olaparib into the hydrophobic core (Baldwin et al., 2018). In vitro studies demonstrated no cytotoxic effects within the tested concentration range of 0-200 µM for both drugs in the macrophage RAW 264.7 cell line. This novel dual-drug combinatory approach aims to address the limitations of earlier failed monotherapies in phase III clinical trials for TBI, highlighting the potential of block copolymeric nanoparticle-based drug delivery systems in enhancing the therapeutic outcomes of TBI, particularly in improving secondary outcomes(Stein et al., 2015).
Recommended Citation
Khan, Mohammad Naseem, "Synthesis and Characterization of Block Copolymer Based Nanoparticles for Sustained Release of Therapeutics to Address Secondary Injury Events Upon Traumatic Brain Injury" (2024). Theses & Dissertations. 865.
https://digitalcommons.unmc.edu/etd/865