Targeted Nanoparticle Delivery of Therapeutics Across the Blood-Brain and Blood-Tumor Barriers to Breast Cancer Brain Metastases

Author: Wyatt, Emily Ann

Year: 2018

Degree: Dissertation (Ph.D.)

Advisor: Davis, Mark E.

Committee Members: Davis, Mark E.; Tirrell, David A.; Shapiro, Mikhail G.; Mazmanian, Sarkis K.

Option: Chemical Engineering

DOI: 10.7907/5qpd-0736

Abstract

Brain metastases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer are presenting an increasing problem in the clinic. While HER2-targeted therapies effectively control systemic disease, their efficacy against brain metastases is hindered by their inability to penetrate the blood-brain and blood-tumor barriers (BBB and BTB). One promising strategy to increase brain penetration of systemic therapeutics is to exploit endogenous transport systems at the BBB to shuttle drugs into the brain. Previous studies showed that gold nanoparticles designed to shed transferrin receptor (TfR)-targeting ligands under acidic conditions encountered during transcytosis of the BBB demonstrated increased accumulation in the brain. The focus of this work was to determine whether therapeutic, TfR-targeted nanoparticles using an improved acid-cleavable chemistry could be used to deliver therapeutically useful amounts of drug to the brain.

To accomplish this goal, a new animal model of HER2-positive breast cancer brain metastasis was developed in an attempt to create a clinically representative, impermeable barrier to standard therapeutics. This new model establishes brain metastases by methods that more closely resemble the human disease, forming whole-body tumors that eventually metastasize to the brain. Brain metastases formed by this new methodology show no response to standard HER2-targeted agents, mimicking the clinical situation.

Next, efficacy and brain uptake of TfR-targeted, single-agent therapeutic nanoparticles were investigated in the newly developed model, as well as two common models from the literature. These nanoparticles show significant tumor growth delay and increased accumulation in both brain metastases and healthy brain tissue in all three models, highlighting their therapeutic potential. Additionally, non-BBB-penetrant small molecule and non-targeted nanoparticle therapeutics elicit a substantial antitumor response as well as brain tumor accumulation in the most commonly used literature model. In contrast, the new model and one gaining popularity in the literature provide for a more clinically relevant, impermeable barrier to non-BBB-penetrant agents, indicating that the method used to establish brain metastases can affect efficacy and brain uptake of therapeutics.

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