Magnetic resonance imaging of temperature-sensitive liposome release: Drug dose painting and antitumor effects
Magnetic resonance imaging of temperature-sensitive liposome release: Drug dose painting and antitumor effects
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DOI：
10.1093/jnci/djk005
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发表时间：
2007-01-03
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影响因子：
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通讯作者：
Dewhirst, Mark W.
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作者：
Ponce, Ana M.;Viglianti, Benjamin L.;Dewhirst, Mark W.
在临床前研究中，已发现溶脂基温度敏感脂质体（LTSLs）含有化疗药物与局部热疗联合使用可增加肿瘤药物浓度，提高药物的抗肿瘤疗效。我们使用一种新的磁共振成像（MRI）方法来测量大鼠纤维肉瘤模型在使用含有阿霉素和MRI造影剂（锰）（Dox/Mn-LTSLs）的LTSLs治疗期间的时间和空间给药模式。方法对10 ~ 12mm纤维肉瘤大鼠（每组6 ~ 7只）在肿瘤中心插入导管进行局部肿瘤热疗前和/或60分钟内给予Dox/Mn-LTSLs（剂量为5mg /kg体重）治疗。通过MRI连续监测药物分布情况。在整个治疗过程中，磁共振变化用于计算肿瘤内阿霉素浓度。对肿瘤进行监测，直到它们在治疗当天或60天内达到其体积的五倍。使用Kruskal-Wallis试验和Kaplan-Meier产品限法分别分析阿霉素浓度和治疗当天肿瘤达到其体积5倍的时间。所有统计检验均为双侧检验。结果在热疗前、热疗期间、热疗前和热疗期间给予Dox/Mn-LTSLs分别产生了中央、外周和均匀的药物分布。与热疗前相比，在热疗期间给予Dox/Mn-LTSLs时，阿霉素在肿瘤中积累更快，浓度更高（比率：9.8 vs 1.8 μ g/min，差异= 8.0 μ g/min， 95%置信区间[CI] = 6.8 ~ 12.8 μ g/min, P = 0.003；浓度：15.1 vs 8.0 ng/mg，差异= 7.1 ng/mg, 95% CI = 3.6 ~ 10.6 ng/mg, P = 0.028）。在热疗期间给予LTSL也产生了最大的抗肿瘤效果，肿瘤在治疗当天达到其体积的5倍的中位时间为34天（95% CI = 30天至无限），而热疗前LTSL为18.5天（95% CI = 16至23天），热疗前和热疗期间LTSL为22.5天（95% CI = 15至25天）。结论在该大鼠纤维肉瘤模型中，LTSLs在热疗期间给药最有效，导致药物分布在外周。
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 mu g/min, difference = 8.0 mu g/min, 95% confidence interval [CI] = 6.8 to 12.8 mu g/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 infinity) 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.