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Magnetic Resonance Imaging of Temperature-Sensitive Liposome Release: Drug Dose Painting and Antitumor Effects
Affiliations of authors: Department of Biomedical Engineering (AMP, CRM, MWD) and School of Medicine (AMP, BLV), Duke University, Durham, NC; Departments of Radiation Oncology (BLV, PSY, MWD) and Biostatistics and Bioinformatics (DY), Duke University Medical Center, Durham, NC; GE Healthcare, Waukesha, WI (CRM); Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada (JW, MBB); Advanced Therapeutics-Medical Oncology, BC Cancer Agency, Vancouver, BC, Canada (MBB)
Correspondence to: Mark W. Dewhirst, DVM, PhD, 201A Medical Sciences Research Bldg., Duke University Medical Center, Durham, NC 27710 (e-mail: dewhirst{at}radonc.duke.edu).
BACKGROUND: In preclinical studies, lysolipid-based temperature-sensitive liposomes (LTSLs) containing chemotherapy drugs administered in combination with local hyperthermia have been found to increase tumor drug concentrations and improve antitumor efficacy of the drugs. We used a novel magnetic resonance imaging (MRI) method to measure the temporal and spatial patterns of drug delivery in a rat fibrosarcoma model during treatment with LTSLs containing doxorubicin and an MRI contrast agent (manganese) (Dox/Mn-LTSLs) administered at different times with respect to hyperthermia.
METHODS: Rats bearing 10- to 12-mm fibrosarcomas (n = 6–7 per group) were treated with Dox/Mn-LTSLs (at a dose of 5 mg doxorubicin/kg body weight) before and/or during 60 minutes of local tumor hyperthermia administered via a catheter inserted at the center of the tumor. Drug distribution was monitored continuously via MRI. Magnetic resonance changes were used to calculate intratumoral doxorubicin concentrations throughout treatment. Tumors were monitored until they reached five times their volume on the day of treatment or 60 days. Doxorubicin concentrations and times for tumors to reach five times their volume on the day of treatment were analyzed using the Kruskal–Wallis test and the Kaplan–Meier product-limit method, respectively. All statistical tests were two-sided.
RESULTS: Administration of Dox/Mn-LTSLs before, during, and both before and during hyperthermia yielded central, peripheral, and uniform drug distributions, respectively. Doxorubicin accumulated more quickly and reached higher concentrations in the tumor when Dox/Mn-LTSLs were administered during hyperthermia than when administered before hyperthermia (rate: 9.8 versus 1.8 µg/min, difference = 8.0 µg/min, 95% confidence interval [CI] = 6.8 to 12.8 µg/min, P = .003; concentration: 15.1 versus 8.0 ng/mg, difference = 7.1 ng/mg, 95% CI = 3.6 to 10.6 ng/mg, P = .028). LTSL administered during hyperthermia also yielded the greatest antitumor effect, with a median time for tumors to reach five times their volume on the day of treatment of 34 days (95% CI = 30 days to 
) compared with 18.5 days (95% CI = 16 to 23 days) for LTSL before hyperthermia and 22.5 days (95% CI = 15 to 25 days) for LTSL before and during hyperthermia.
CONCLUSIONS: In this rat fibrosarcoma model, LTSLs were most effective when delivered during hyperthermia, which resulted in a peripheral drug distribution.
| CONTEXT AND CAVEATS Prior knowledge Temperature-sensitive liposomes rapidly release their contents when heated to 41.3 °C and thus have the potential to target delivery of systemic chemotherapy to tumors when combined with local hyperthermia. However, the optimal timing of local hyperthermia with respect to temperature-sensitive liposome administration is not known. Study design In vivo therapeutic study in a rat fibrosarcoma model. Contribution A novel MRI method was used to show that drug-containing temperature-sensitive liposomes were most effective when intravenously injected while the tumor was being heated via a centrally placed heating catheter. Implications The timing of local hyperthermia with respect to the administration of drug-containing temperature-sensitive liposomes can be used to control intratumoral drug distribution. Limitations The heating method used in this study is not applicable to humans. Rat local tumor drug kinetics may differ from human local tumor drug kinetics.
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