From the Paul C. Lauterbur Research Center for Biomedical Imaging, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China (F.Y., Z.T.D., H.R.Z.); Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound (S.W., W.Y., H.W.), and Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Cell Biology Department (H.B.H.), Peking University Cancer Hospital & Institute, Beijing 100142, China; Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass (S.N.G.); Division of Image-guided Therapy, Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel (S.N.G.); and Department of Ultrasound, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, China (W.L.D.).
Radiology. 2017 Nov;285(2):462-471. doi: 10.1148/radiol.2017162405. Epub 2017 Jun 19.
Purpose To investigate the role of a tumor-penetrating peptide (internalizing CRGDRGPDC [iRGD])-integrated thermally sensitive liposomal (TSL) doxorubicin (DOX) in combination with radiofrequency (RF) ablation of liver tumors in an animal model. Materials and Methods Approval from the institutional animal care and use committee was obtained. Characterization of iRGD-TSL-DOX was performed in vitro. Next, H22 liver adenocarcinomas were implanted in 138 mice in vivo. The DOX accumulation and cell apoptosis of iRGD-TSL-DOX and TSL-DOX with or without RF were evaluated (n = 5) at different time points after treatment with quantitative analysis or pathologic staining. Mice bearing tumors were randomized into the following six groups (each group, eight mice): no treatment, iRGD-TSL-DOX, TSL-DOX, RF alone, RF ablation followed by TSL-DOX at 30 minutes (TSL-DOX combined with RF), and RF ablation followed by iRGD-TSL-DOX (iRGD-TSL-DOX combined with RF). Kaplan-Meier method was used to estimate the survival curves and log-rank test was used for comparison with statistical software. Results DOX encapsulation efficiency in iRGD-TSL-DOX was 97.5% ± 1.3 (standard deviation) with temperature-dependent drug release capability confirmed in vitro. In vivo, the iRGD-TSL-DOX group had overall higher DOX concentration in the tumor and had maximal difference at 24 hours compared with TSL-DOX group (2.7-fold). RF caused more intense cell apoptosis at 24 hours (median, 65% vs 21%, respectively; P < .001). For end-point survival, the iRGD-TSL-DOX combined with RF group had better survival (median, 32 days) than TSL-DOX combined with RF (median, 27 days; P = .035) or RF alone (median, 21 days; P < .001). Conclusion Conjugation to iRGD helped to improve intratumoral DOX accumulation and further enhanced the activity of TSL-DOX in RF ablation of liver tumors. RSNA, 2017 Online supplemental material is available for this article.
目的 研究穿透肿瘤肽（内化 CRGDRGPDC [iRGD]）整合的热敏脂质体（TSL）阿霉素（DOX）在动物模型中联合射频（RF）消融肝肿瘤中的作用。
材料与方法 获得机构动物护理和使用委员会的批准。在体外对 iRGD-TSL-DOX 进行了表征。然后，将 H22 肝癌在 138 只小鼠体内植入。在治疗后不同时间点（n = 5）通过定量分析或病理染色评估 iRGD-TSL-DOX 和 TSL-DOX 与 RF 联合应用时的 DOX 积累和细胞凋亡。将携带肿瘤的小鼠随机分为以下六组（每组 8 只小鼠）：无治疗、iRGD-TSL-DOX、TSL-DOX、单独 RF、单独 RF 消融后 30 分钟（TSL-DOX 联合 RF）和 RF 消融后 iRGD-TSL-DOX（iRGD-TSL-DOX 联合 RF）。Kaplan-Meier 法用于估计生存曲线，对数秩检验用于统计软件比较。
结果 iRGD-TSL-DOX 的 DOX 包封效率为 97.5%±1.3（标准差），体外证实具有温度依赖性药物释放能力。在体内，与 TSL-DOX 组相比，iRGD-TSL-DOX 组肿瘤内 DOX 浓度总体更高，在 24 小时时差异最大（2.7 倍）。RF 在 24 小时引起更强烈的细胞凋亡（中位数，分别为 65%和 21%；P<0.001）。终点生存方面，iRGD-TSL-DOX 联合 RF 组的生存（中位数 32 天）优于 TSL-DOX 联合 RF（中位数 27 天；P=0.035）或单独 RF（中位数 21 天；P<0.001）。
结论 与 iRGD 缀合有助于提高肿瘤内 DOX 积累，并进一步增强 TSL-DOX 在 RF 消融肝肿瘤中的活性。RSNA，2017 在线补充材料可用于本文。
