Date of Award

January 2016

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Jiangbing Zhou

Abstract

SYSTEMIC DRUG DELIVERY TO THE CENTRAL NERVOUS SYSTEM USING NOVEL BRAIN-TARGETING NANOPARTICLES. Derek Kai Kong1 and Jiangbing Zhou2,3. Yale School of Medicine, New Haven, CT1. Department of Neurosurgery, Yale School of Medicine, New Haven, CT2. Department of Biomedical Engineering, Yale School of Engineering & Applied Science, New Haven, CT3.

The blood-brain-barrier (BBB) is a formidable barrier that protects the central nervous system (CNS) and prevents the transport of nearly all small- and large-molecule pharmacotherapies. Systemically administered drugs fail to achieve therapeutic concentrations in the CNS in large part because of the physical and chemical defenses of the BBB. The goal the present study was to develop nanoparticle (NP) platforms that can be administered peripherally to deliver small molecule drugs to the CNS. Herein proposed is a novel mechanism of drug delivery, termed autocatalytic brain-targeted (ABT) delivery, whereby we employ nanoparticle surface modifications and encapsulate BBB-modulating compounds to enhance nanoparticle delivery to the CNS. The ABT mechanism was tested using a novel terpolymer nanomaterial and showed that ABT NPs could mediate efficient drug delivery to primary malignant gliomas in mice. C57B16 mice bearing intracranial gliomas that received B7-1 gene therapy-loaded ABT nanoparticles had significantly prolonged survival compared to mice receiving saline or empty nanoparticles (median survival 38, 28, and 29 days, respectively, p<0.0001 for B7-1 vs. saline and B7-1 vs. empty NPs). The second-generation ABT nanoparticles developed in this study were synthesized using natural product-derived starting material. Second-generation nanoparticles were evaluated in live imaging mouse models of primary malignant glioma, stroke, and traumatic brain injury to demonstrate the versatility of the ABT mechanism. Second-generation particles homed to diseased regions of the brain with high efficiency. In the evaluation of second-generation particles in malignant glioma, mice received sterile saline, free paclitaxel, empty nanoparticles, or paclitaxel-loaded ABT nanoparticles. The median survival for C57B16 mice bearing intracranial GL261 gliomas receiving these treatments was 24.5, 24, 24, and 24 days after tumor implantation, respectively (Log-rank χ2 = 0.7014). The median survival for athymic nude mice bearing intracranial U87-MG gliomas receiving the same treatment regimen was 32, 36, 33, and 37 days after tumor implantation, respectively (Log-rank χ2 = 0.0392). The efficacy of second-generation nanoparticles was less than expected, likely due nanoparticle stability and insufficient drug release in the disease microenvironment. We conclude that the mechanism of autocatalytic drug delivery is an efficient method of overcoming the restrictive BBB to effectively deliver therapeutic doses of imaging dyes and chemotherapy agents to the brain for CNS disorders, however further optimization of second-generation nanoparticles is needed.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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