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A Tracer Dose of Technetium-99m–Labeled Liposomes Can Estimate the Effect of Hyperthermia on Intratumoral Doxil Extravasation

Authors' Affiliations: Departments of ¹ Molecular Biomedical Sciences and ² Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina; and Departments of ³ Biostatistics and Bioinformatics, ⁴ Radiology, ⁵ Medicine, and ⁶ Radiation Oncology, Duke University Medical Center, Durham, North Carolina

Requests for reprints: Donald E. Thrall, Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, 4700 Hillsborough Street, Raleigh, NC 27606. Phone: 919-513-6292; Fax: 919-513-6578; E-mail: don_thrall{at}ncsu.edu.

Purpose: A noninvasive method to monitor intratumoral Doxil delivery in individual patients during targeted tumor therapy is important to predict treatment response. The purpose of this study was to determine if a small tracer dose of technetium-99m (^99mTc)–labeled liposomes could be used to quantify the effect of local hyperthermia on intratumoral Doxil extravasation.

Experimental Design: Experiments were carried out in a rat fibrosarcoma model with transplanted thigh tumors. Liposomes of approximately same size and composition as Doxil were radiolabeled using [technetium-99m (^99mTc)]exametazime. Eight treatment groups received either Doxil, a tracer dose or a large dose of ^99mTc-labeled liposomes, or a combination of tracer and Doxil, with or without hyperthermia. This design was chosen to assure that coadministration of both liposomal formulations did not influence their intratumoral distribution. Hyperthermia was done for 45 minutes. Scintigraphic images were obtained at 5 and 18 hours. At 18 hours, tumors were removed and gamma counts as well as doxorubicin concentrations were measured.

Results: Intratumoral extravasation of the ^99mTc-labeled tracer could be imaged scintigraphically under normothermic and hyperthermic conditions. The thermal enhancement ratio was slightly higher for radiolabeled liposomes than for doxorubicin concentration. However, there was a significant positive correlation of intratumoral doxorubicin concentration and intratumoral uptake of the radiolabeled tracer (expressed as percentage of the injected dose per gram of tissue). Coadministration of radiolabeled liposomes did not negatively influence the amount of drug delivered with Doxil.

Conclusions: The use of a radiolabeled tracer has potential value to monitor drug delivery and estimate the effect of an intervention aimed to increase liposomal accumulation, such as local hyperthermia.

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