DOI

10.17077/etd.ez72bzby

Document Type

Dissertation

Date of Degree

Summer 2017

Degree Name

PhD (Doctor of Philosophy)

Degree In

Pharmaceutical Sciences and Experimental Therapeutics

First Advisor

Salem, Aliasger K.

First Committee Member

An, Gouhua

Second Committee Member

Carter, Knute D.

Third Committee Member

Doorn, Jonathan A.

Fourth Committee Member

Milavetz, Gary

Abstract

The synthetic chemotherapeutic agent, 5-FU, has been used for the treatment of a variety cancers, with colorectal cancer being among the most susceptible. Administration of 5-FU by continuous intravenous infusion has proven to yield greater antitumor efficacy and lower hematotoxicity compared to administration of 5-FU by intravenous bolus injections. Nevertheless, systemic application of 5-FU is often limited by its narrow therapeutic threshold, and therefore in certain situations, such as tumor resection, it may be more appropriate to provide local rather than systemic delivery of 5-FU. It was therefore proposed that 5-FU loaded PLGA millirods may be capable of providing sustained release of 5-FU at a local level which may have equivalent or greater antitumor activity and less cytotoxicity than the systemic or local delivery of soluble 5-FU.

PLGA millirods loaded with 5-FU were successfully fabricated by a hot-melt extrusion technique and characterized for in vitro and in vivo release rates. It was demonstrated that percentage loading by weight of 5-FU could be adjusted to modify its release kinetics. It was also shown that millirods could be stably stored under a variety of conditions for at least 2 months.

An optimal millirod formulation (PLGA 50:50 loaded with 5-FU (50% w/w)) was tested for antitumor activity and general toxicity in vivo. At the dose of 120 mg/kg 5-FU, millirods (delivered peritumorally) were efficacious (with 100% survival rates) against solid thymomas in tumor-challenged mice (causing complete regression). Whilst the soluble form of 5-FU (delivered intraperitoneally (IP) at 120 mg/kg) was also highly efficacious (90% survival rates) against thymomas it was also more hematotoxic. In addition, the millirod form provided significantly greater antitumor activity against colorectal tumors in mice compared to the soluble form of 5-FU. In terms of in vivo toxicity, surprisingly, the type of formulation did not have a significant effect on mouse weight despite both IP and subcutaneous (SC) delivery causing death of some mice. Importantly, it was found that 5-FU loaded PLGA millirods were significantly less hematotoxic than soluble 5-FU delivered by either IP or SC injection at the equivalent dose. Thus, locally implanted 5-FU loaded PLGA millirods appeared to be less toxic and possessed overall greater antitumor potency than soluble 5-FU delivered by IP or SC injection.

This study further investigated whether the combination of 5-FU loaded PLGA millirods with eniluracil (in both thymoma and colorectal tumor models) or immune checkpoint inhibitors (in the colorectal tumor model) could enhance the antitumor efficacy of 5-FU millirods in mice challenged with colorectal tumors. It was found that the combination of 5-FU loaded PLGA millirods and eniluracil (millirod or solution forms) did not significantly enhance the antitumor efficacy of 5-FU millirods in either tumor models. It was also found that immune checkpoint inhibitors did not enhance the antitumor efficacy of 5-FU loaded PLGA millirods in the colorectal tumor model.

Keywords

5-fluorouracil, 5-FU, millirods, PLGA, poly(lactide-co-glycolide)

Pages

xviii, 191 pages

Bibliography

Includes bibliographical references (pages 177-191).

Copyright

Copyright © 2017 Nattawut Leelakanok

Share

COinS