Date of Award

8-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Burg, Karen

Committee Member

Alexis , Frank

Committee Member

Corbett , Joel

Committee Member

Shalaby , Waleed

Committee Member

Webb , Kenneth

Abstract

The goal of the field of Bioengineering has always been to bring about a better standard of care for patients. As a field encompassing a broad array of researchers and talents, such improvements often are brought about through the integration of different fields. This work advances the integration of controlled delivery and chemotherapy. The use of cytotoxic chemotherapy has become and will continue to be a powerful tool for the treatment of solid malignancies. Conventional dose scheduling of cytotoxic agents and newer biological response modifiers are investigated under a clinical paradigm initially designed to identify a drug dose that elicits acceptable levels of toxicity before the rigorous testing of efficacy. Newly developed regimens involving altering of the conventional scheduling are always compared to the current 'gold standard' of chemotherapy. This process of evaluation becomes quite cost prohibitive through the number of clinical trials required, and often the 'clinically meaningful endpoint' is no longer overall survival, but some more specific event, e.g. the targeted death of a specific type of cell. The traditional method for evaluating new anti-cancer drugs is appropriately intended to minimize patient toxicity and optimize safety. However, the inherent flaw in this approach is that the effective dose and the toxic dose are often not concurrently considered (e.g. the therapeutic index); rather, the approach is geared toward maximizing death of a particular cell type. That is, the traditional approach is to provide the maximum tolerated dose at defined time intervals; the intervals allow recovery of the normal tissue but they also provide time for tumor cell regrowth and potential chemo-resistance. Another obstacle is the conventional (intravenous) routes of administration which often expose the tumor to relatively short durations of drug, based on half-lives at excessively high systemic levels; toxicity is cumulative and associated with high systemic levels of drug. The theoretical benefits of controlled drug delivery can minimize significant fluctuations in systemic toxicity while optimizing efficacy. Such controlled therapy requires a defined therapeutic index and a delivery platform that can be tailored to meet the desired clinical endpoint. As understanding of cancer has grown, novel strategies have been developed to selectively administer conventional chemotherapy to manage advanced cases of solid malignancies that historically have a poor prognosis. The largest obstacle to the use of such approaches is the dearth of technology for delivering a chemotherapeutic in a repeatable controlled manner. To date, there is a paucity of existing biomaterials whose properties allow (1) in situ gelation kinetics that can be modulated to produce a predictable and sustainable drug delivery depot, (2) the ability to control in situ gelation kinetics to maximize vascular and micro-vascular access to the tumor, (3) predictable controlled release kinetics and duration of release in concert with the total drug load to minimize dose dumping and maximize release, (4) and modulated absorption kinetics to minimize collateral damage to healthy tissue and facilitate repeat administration based on tumor response or treatment requirements.
At Poly-Med Incorporated, the OC Polymer system was specifically designed to combat current issues with chemotherapy. These polymers, when combined in a novel delivery system, allow localized controlled delivery. The system advanced in this work is comprised of the OC polymer, solubilized in a low molecular weight polyethylene glycol, and further absorbable polymers to help modulate release. This system is injectable through a standard Leur-Lok needle and syringe system and forms a stable depot after injection into an aqueous environment. The primary objective of the work was to test the OC delivery system in an in vitro and an in vivo setting, laying the foundation for investigation of this system in multiple chemotherapeutic treatments. The specific aims of the project were to (1) determine the potential efficacy of the system through the performance in in vitro studies to determine release characteristics with a model drug; (2) ensure the relevancy of the results to a chemotherapy-based system through further in vitro testing with the platinum-based chemotherapeutic carboplatin; and (3) exhibit the clinical potential of the product through in vivo testing of a promising OC system in two administration methods using a mouse flank model.
The OC polymer system was examined for release in vitro and was shown capable of release of a water-soluble model drug from 3 days to greater than 45 days. Also, the OC system was shown capable of release of the chemotherapeutic carboplatin in a relatively linear manner over a period of 3 weeks, the course of a typical chemotherapeutic regimen. Finally, the OC polymer system was examined in an in vivo model and tolerance of the non-drug loaded system was exhibited. Also, mice were shown to tolerate higher levels of total carboplatin exposure than the literature suggested LD50 of 150 mg/kg. The next steps in preparing such a system involve further in vitro studies and in vivo testing to validate the efficacy of such a system prior to clinical trials.

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