Title

Preclinical Evaluation of a Novel Polysaccharide Hydrogel for Local Chemotherapy Delivery to Solid Tumors

Date of Award

5-2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program

Biomedical Sciences

Track

Molecular Therapeutics and Cell Signaling

Research Advisor

Pat Ryan, Ph.D.

Committee

Tao Lowe, Ph.D. Merry Sebelik, M.D. Stephen W. White, D. Phil. George Wood, Ph.D.

Abstract

Local delivery of chemotherapeutic agents directly to tumor sites has great advantages over traditional and emerging drug delivery technologies. Local delivery of compounds increases drug concentration at the target site, decreases drug effects on non-target tissues, and protects the drug from rapid elimination, degradation, and destruction by the body. Both old and new chemotherapy agents can be limited by their toxicity, their instability, and their ability to be formulated into practical drug products for use in the clinical setting. This dissertation entails the preclinical evaluation of a novel polysaccharide hydrogel drug delivery system. The gel is designed to be injected intratumorally to deliver a chemotherapeutic agent, to protect a fragile chemotherapy agent from being degraded quickly in vivo, to deliver the compound over an extended period of time, and to achieve a higher concentration of drug at the target site than any other method of delivery. A model compound, AD 198, was chosen to test the gel. This drug was chosen because of its lipophilic structure, its short half-life, and its potency as an anti-neoplastic agent. AD 198 is a free base and has very limited solubility in aqueous solutions, so it cannot be easily formulated as a solution for human intravenous administration. In culture, it is affected by serum esterases and is converted into multiple transformation products in less than an hour. At concentrations as low as 10 uM it is able to inhibit growth of U87, human glioma cells, by more than 90%. The U87 human glioma cell line was chosen to establish a flank model in nude mice to test the performance of the drug loaded hydrogel. Glioma was chosen for its ability to form solid tumors in a rodent flank model, its aggressive malignancy, and its resistance to treatment. AD 198 was incorporated into the hydrogel during synthesis. Mechanical testing of the polymer network revealed that there was no change in hydrogel structure with the addition of the drug compound. At the optimal murine anti-tumor dose, the drug loaded gel was stable for at least 6 months at room temperature and pressure and ambient light. In vitro cytotoxicity assays showed that the drug was released in its active form and also inhibited cell proliferation by up to 90%. In vivo ultrasound data demonstrated that the gel is present within the glioma tumors for at least 15 days. It was also apparent that tissue response to treatment occurs at the surface of the gel and radiates out towards the margins of the tumors. Fluorescence imaging of AD 198 measured more drug present in gel treated tumors at 15 days than solution treated. Histology of tumor samples indicated that the drug induced an apoptotic response in the tissue.

DOI

10.21007/etd.cghs.2014.0023

Comments

Two year embargo expired May 2016

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