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.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-7278 |
| Date | 01 August 2017 |
| Creators | Leelakanok, Nattawut |
| Contributors | Salem, Aliasger K. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2017 Nattawut Leelakanok |
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