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Chair(s): Stratford, Ian; Greco, Olga
(PD013) Liposomal drug distribution and anti-tumor effect: drug dose painting with hyperthermia using MRI.
Ponce, Ana*,1, Viglianti, Benjamin1, Yarmolenko, Pavel2, Bally, Marcel3, Woo, Janet3, Dewhirst, Mark2, 1 Dept of Biomedical Engineering, Durham, NC2 Dept of Radiation Oncology, Durham, NC3 BC Cancer Agency, Vancouver, BC
ABSTRACT- Temperature sensitive liposomes, in combination with local hyperthemia (HT), have been shown to increase solid tumor drug concentration and anti-tumor effect in preclinical studies. Moreover, rapid drug release in a narrow temperature range permits drug distribution to be precisely controlled by temperature distribution. To enable non-invasive evaluation of liposomal drug delivery, our group recently developed a novel MR imaging technique.1 The purpose of this study was to explore the relationships between temperature profile, drug distribution, and anti-tumor effect in a rat fibrosarcoma model using MRI.
Temperature-sensitive liposomes containing doxorubicin (TSL-Dox) were formed using a manganese (Mn) sulfate loading method. The paramagnetic properties of Mn cause MRI T1 shortening that is linearly related to [Mn] and [Dox]. Animals received 5 mg/kg i.v. Dox and one hour local HT while imaging. Treatment groups were (n=6-8): saline ± HT, free Dox ± HT, TSL-Dox - HT, and three schedules of TSL-Dox + HT (TSL before HT, TSL during HT, and TSL before and during HT). Reproducible temperature profiles were achieved with a central hot water catheter. After therapy, tumor volume was monitored for up to six weeks or five times original tumor volume.
The three TSL-Dox + HT protocols respectively yielded central, peripheral, and uniform drug distribution within the tumor. These markedly different patterns exhibit the potential for improved control of drug delivery according to temperature profile at the time of injection. The peripheral distribution of Dox resulted in the most significant anti-tumor effect (p<0.005), with a median of 36.6 ± 5.2 (SE) days growth delay compared with 23.5 ± 4.1 days for uniform and 20.3 ± 2.3 days for central. The mechanism for enhanced antitumor effect may be peripheral vascular destruction, as seen in window chamber xenografts treated with TSL-Dox + HT.2
1. Viglianti, et al. Magnet Reson Med 51(2004)
Key words: liposome, MRI, doxorubicin
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