American College of Veterinary Radiologists
Annual Scientific Meeting

December 1-5, 1999
Chicago Marriott O'Hare
Chicago, IL

HYPERTHERMIA EFFECT ON UPTAKE OF TECHNETIUM-99M LABELED LIPOSOMES IN FELINE SARCOMAS

M.L. Matteucci¹, D.E. Thrall¹, G. Anyarambhatla², G. Rosner², C. Azuma¹, P.E. Fisher¹, M.W. Dewhirst², D. Needham². ¹North Carolina State University, Raleigh, NC 27710. ²Duke University Medical Center, Durham, NC 27710

INTRODUCTION: Hyperthermia is one method used in both humans and animals for multi modality treatment of cancer. Hyperthermia may sensitize tumor cells to radiation and increase cytotoxicity based on its ability to kill cells without regard for some factors that render cells radiation resistant, such as cell cycle phase and energy status. Hyperthermia has also been shown to increase vascular permeability and therefore may useful in enhancing the delivery of substances to a tumor. Liposomes containing an anti-cancer agent could be used to therapeutic benefit and their efficacy possibly enhanced if combined with hyperthermia. Using a rat mammary adenocarcinoma model it has been shown that hyperthermia results in a significant increase in extravasation of liposomes into tumor tissue. These results have not yet been verified in spontaneous, solid tumors. In this paper we report results of the effect of hyperthermia on liposome extravasation in feline fibrosarcomas.

METHODS: The specific aim of this study was to quantify the effect of hyperthermia on liposome extravasation in feline sarcomas. Fifteen cats were studied. In 2 cats data were not useable (tumor too small in one and liposomes injected at incorrect time in the other). Liposomes were produced and tagged with ^99mTc at Duke University Medical Center using published methods. Each cat had liposomes injected intravenously twice, once under normothermic conditions and once under hyperthermic conditions. For the first injection, thermometry catheters were inserted into the tumor but hyperthermia was not applied. Liposomes were injected and planar scintigraphy was used to measure the activity of ^99mTc-liposomes within the tumor at predetermined time points up to 18 hours after injection. Approximately 48 hours later, thermometry catheters were reinserted and the tumor heated for 60 minutes using microwaves. Liposomes were injected at the start of the hyperthermia procedure. Scintigraphy was carried out as for the normothermic study. For data analysis, regions of interest (ROI) were drawn for the tumor, lungs, liver, aorta, kidney, and background muscle at each time point. Counts in the ROI were decay and background corrected and expressed as percent injected dose/pixel. Percent injected dose/pixel in the tumor were normalized to the aorta percent injected dose/pixel to determine the effect of hyperthermia on extravasation of liposomes. Aorta data were considered to represent circulating liposomes.

RESULTS: In two of the 13 cats, incomplete count data precluded analysis. In the remaining 11 cats, hyperthermia resulted in a significant increase in liposome extravasation in the tumor (p=.003). There was not a relationship between either tumor volume or hyperthermia dose and the magnitude of increased extravasation.

CONCLUSION: Hyperthermia significantly increased the extravasation of liposomes in a spontaneous, solid tumor. The ability to use liposomes to deliver drugs specifically to tumors has great potential in cancer therapy. These findings indicate that further investigation using hyperthermia for targeted delivery of liposomes and triggered drug release from thermosensitive liposomes may eventually result in increased clinical benefit.

SUPPORT: This work supported in part by the ACVR Resident Research Award, and CA 42745 from the Department of Health and Human Services, United States Public Health Service. The authors thank Anne Guiliani, and Wendy Horne for technical assistance.

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