Development of polymeric drug delivery platforms for Alzheimer's disease

Alzheimer's disease (AD) is a progressive and long-term disorder characterized by cognitive and behavioral impairments for which no definitive cure currently exists. The pathology of AD involves the accumulation of certain proteins, changes in inflammation, oxidative stress leading to neuronal cell death, synaptic contact loss, and overall synaptic degeneration. Current pharmacological approaches to AD treatment are symptomatic and include vascular protection, cholinesterase inhibitors, and N-methyl-D-aspartate (NMDA) antagonists. Among cholinesterase inhibitors are drugs such as donepezil, rivastigmine, galantamine, and tacrine, while memantine is the commonly used NMDA antagonist. Due to the difficulty of therapeutic agents crossing the blood-brain barrier (BBB), treatment options for AD remain limited. Treatment failure is often associated with the unfavorable pharmacokinetics and pharmacodynamics of these drugs. Therefore, the use of nano-platforms for drug delivery has gained importance. These systems can improve drug bioavailability, pharmacokinetics, and pharmacodynamics, while also reducing adverse effects. Owing to their small size and ability to provide controlled release of drugs at disease sites, polymeric nanoparticles are considered promising candidates for drug delivery systems. In this thesis, polymeric micelles were developed as drug delivery platforms to enhance the BBB permeability of donepezil (DZP), the most commonly used acetylcholinesterase inhibitor in AD treatment. The first type of these drug delivery systems involved the synthesis of amphiphilic block copolymers, poly(ethylene glycol)-b-poly(tert-butyl methacrylate) (PEG-b-PtBMA), via reversible additionfragmentation chain transfer (RAFT) polymerization. As a second carrier system, folic acid (FA)-conjugated amphiphilic copolymers were synthesized using RAFT polymerization. All synthesized polymers were characterized by gel permeation chromatography (GPC), proton nuclear magnetic resonance spectroscopy (¹H NMR), and differential scanning calorimetry (DSC). Blank and donepezil loaded polymeric micelles were prepared using the dialysis method and were extensively characterized in terms of size, zeta potential, and stability using dynamic light scattering (DLS) and transmission electron microscopy (TEM). Drug loading efficiency and release behavior of the micelles were monitored using a UV/Vis microplate reader. The cytotoxicity and cellular uptake of the micelles were investigated using colorimetric assays and impedance measurements. Furthermore, the permeability of the nanocarriers was evaluated using an in vitro BBB culture model. The DZP loaded polymeric micelles were found to exhibit permeability comparable to that of free DZP. This thesis investigates the potential of polymeric micelles as a targeted drug delivery system for the treatment of neurodegenerative disorders, particularly Alzheimer's disease. Keywords: Alzheimer's disease, polymer micelles, donepezil, blood-brain barrier