FUNCTIONALIZED NANOPARTICLES AS DRUG DELIVERY EXCIPIENTS

Abstract

Delivering drugs to the brain is challenging due to the blood-brain barrier that poses a significant transport barrier for drugs to enter the brain. Those who live with mental disorders such as schizophrenia and bipolar disorder are thus often restricted to routine high dose drug regiments with a wide range of off-target effects outside of the brain. While intranasal (IN) delivery offers potential to deliver drugs with improved efficacy to the brain, this alternative drug delivery pathway is typically limited to potent, short-lasting, or toxic drugs that frequently require re-application, presenting challenges to the practical implementation of IN delivery in treating various mental illnesses including schizophrenia and bipolar disorder. Although currently approved nasal sprays have explored a limited excipients to aid in brain delivery, there is an increasing amount of literature and preclinical trials that demonstrate nanoparticle carriers can improve drug transport. This thesis identifies a sprayable hydrogel consisting of modified starch nanoparticles (SNPs) and chitosan materials that can gel in situ within the nasal cavity and release ultra-small penetrative SNPs over time. Modifications are rationally selected and optimized in each chapter to complex with each identified gold standard drug to the SNP building blocks that make the up the hydrogels, enabling the effective and prolonged delivery of hydrophobic small molecules (using hydrophobized SNPs), and therapeutic ions such as lithium (using chelating SNPs). By formulating these affinity SNPs into a sprayable hydrogel formulation enabled via Schiff base interactions between chitosan derivatives and lightly oxidized SNPs, a hydrogel depot can be easily administered into the nose that can resist nasal clearance and release the nanoparticle-drug complexes over time, with the SNP-drug complexes subsequently supporting the transport of drugs through the nerves to the brain to maximize treatment duration while also limiting drug release into the blood stream. Both the modified nanoparticles and the hydrogels made from them are thoroughly physically and chemically characterized in vitro and demonstrated to be both safe and efficacious in pre-clinical in vivo rat behavioural models. As such, hydrogel nasal sprays represent a novel excipient to support the efficacy of drug delivery to the brain.