Synthesis, Characterization, In Vitro Evaluation, and Preclinical Profiling of β-Cyclodextrin Polyrotaxane Families for Use As Potential Niemann-Pick Type C Therapeutics
Abstract
Niemann-Pick Disease Type C (NPC) is a rare, autosomal recessive genetic disorder featuring a loss of proteins responsible for unesterified cholesterol (UC) trafficking through the late endosomes/lysosomes (LE/LY) of every cell of the body. Disruption of this pathway leads to abnormal accumulation and storage of UC and other lipids. A broad range of visceral and neurological symptoms result from this accumulation exhibiting a variable age of onset and a disease progression that is ultimately fatal. The disease has an incidence of approximately 1 in 120,000 live births and has no known effective treatment. β-Cyclodextrin (β-CD) are natural small molecules macrocycles composed of glucose units with a hydrophobic inner cavity and hydrophilic outer rims. β-CD derivatives have recently been shown to be effective therapeutics for NPC in cellular and animal models. In the mouse model of the disease, β-CD therapy increases overall lifetime by as much as 50% and slows the progression of neurodegeneration. The progress has led to the initiation of a National Institutes of Health phase I clinical trial. A main drawback of β-CD administration is the poor pharmacokinetic profile characterized by rapid renal clearance of the drug through the urine. Libraries of β-CD derivative carrying high molecular weight polyrotaxane (PR) systems have been designed to prevent glomerular filtration of the injected β-CD dose. An initial family of unmodified β-CD PRs was synthesized, characterized, and their therapeutic efficacy was tested in NPC fibroblasts. This was followed by screening of PRs consisting of mixed β-CD derivative threading featuring charged sulfobutylether β-CD. Finally, we sought to define PR structure-property effects on in vivo pharmacokinetics, biodistribution, toxicity, immunogenicity, and protein hard corona composition. This was accomplished using a family of gadolinium carrying PRs composed of triblock Pluronic co-polymers of varying molecular weights and hydrophilic/lipophilic ratios. The effect of varying threaded β-CD derivative surface chemistry on PR mediated hemolysis and hard protein corona was also studied. Knowing if structure-property relationships exist in the in vivo performances of PR materials will help with building pre-clinical profile, selecting candidate materials for a given application, and understanding therapeutic outcomes.
Degree
Ph.D.
Advisors
Thompson, Purdue University.
Subject Area
Chemistry|Nanoscience|Materials science
Off-Campus Purdue Users:
To access this dissertation, please log in to our
proxy server.