索拉非尼微球的研制及其在大鼠肝癌模型中经导管动脉化疗栓塞中的疗效增强作用。
Development and Validation of Sorafenib-eluting Microspheres to Enhance Therapeutic Efficacy of Transcatheter Arterial Chemoembolization in a Rat Model of Hepatocellular Carcinoma.
机构信息
Department of Radiology, Feinberg School of Medicine (W.P., S.C., J.J., R.J.L., A.C.L., D.H.K.), and Robert H. Lurie Comprehensive Cancer Center (R.J.L., A.C.L., D.H.K.), Northwestern University, 737 N Michigan Ave, Suite 1600, Chicago, IL 60611; Department of Biomedical Engineering (A.C.L., D.H.K.); and Department of Electrical Engineering and Computer Science (A.C.L.) and International Institute of Nanotechnology (A.C.L.), Northwestern University, Evanston, Ill.
出版信息
Radiol Imaging Cancer. 2021 Jan 8;3(1):e200006. doi: 10.1148/rycan.2021200006. eCollection 2021 Jan.
PURPOSE
To validate the therapeutic efficacy of sorafenib-eluting embolic microspheres (SOR-EMs) used in combination with transarterial chemoembolization (TACE) for treatment of hepatocellular carcinoma (HCC) in a preclinical animal model.
MATERIALS AND METHODS
SOR-EMs were prepared with poly(d,l-lactide--glycolide), iron oxide nanoparticles, and sorafenib. The morphology of the prepared SOR-EMs was confirmed by using optical microscopy. Drug release from the SOR-EMs was quantified in vitro by using high-performance liquid chromatography. In an orthotopic rat model of HCC, embolic doxorubicin-Lipiodol (ethiodized oil) emulsion (DLE) and SOR-EMs were sequentially injected into the hepatic artery of the rats: The rats in group 1 were injected with DLE; group 2 was injected with DLE plus unloaded embolic microspheres (DLE + EM); group 3, with DLE plus SOR-EMs (DLE + SOR-EM); and group 4, with saline solution. The SOR-EM and tumor size changes in each group (of six rats each) over time were measured by using MRI. Tissues were assessed by using immunohistochemistry, with hematoxylin-eosin and terminal deoxynucleotidyl transferase-mediated dUTP (2'-deoxyuridine 5'-triphosphate) nick-end labeling staining used for dead cells and CD34 staining used for new microvessel formation.
RESULTS
The SOR-EMs were a mean size of 6.6 μm ± 2.3 (standard deviation) and showed 53.7% ± 8.3 sorafenib loading efficiency with T2-weighted MRI capability. In the HCC rat model, the intra-arterially injected SOR-EMs were successfully monitored by using MRI. The DLE + SOR-EM-treated rats showed a superior tumor growth-inhibitory effect compared with the rats treated with DLE only ( < .05). Immunohistochemical assessment of tissue specimens showed that compared with the other treatment groups, the DLE + SOR-EM treatment group had the lowest number of microvessels, as quantified by using the percentage of CD34-positive stained area ( < .01 for all comparisons).
CONCLUSION
In a preclinical rat HCC model, SOR-EMs used in combination with DLE TACE were effective in treating HCC. Chemoembolization, Experimental Investigations, Laboratory Tests, Liver, Technology Assessment © RSNA, 2021See also the commentary by Yamada and Gayed in this issue.
目的
在肝细胞癌（HCC）的临床前动物模型中，验证索拉非尼洗脱栓塞微球（SOR-EMs）联合经动脉化疗栓塞（TACE）治疗的疗效。
材料与方法
采用聚（D，L-丙交酯-乙交酯）、氧化铁纳米粒子和索拉非尼制备 SOR-EMs。通过光学显微镜确认制备的 SOR-EMs 的形态。通过高效液相色谱法体外定量 SOR-EMs 的药物释放。在 HCC 的原位大鼠模型中，将栓塞阿霉素-碘化油乳剂（ethiodized oil）（DLE）和 SOR-EMs 依次注入大鼠肝动脉：第 1 组大鼠注射 DLE；第 2 组大鼠注射 DLE 加未载药栓塞微球（DLE + EM）；第 3 组大鼠注射 DLE 加 SOR-EMs（DLE + SOR-EM）；第 4 组大鼠注射生理盐水。通过 MRI 测量每组（每组 6 只大鼠）中 SOR-EM 和肿瘤大小随时间的变化。使用苏木精-伊红和末端脱氧核苷酸转移酶介导的 dUTP（2'-脱氧尿苷 5'-三磷酸）末端标记染色（用于死亡细胞）和 CD34 染色（用于新的微血管形成）评估组织。
结果
SOR-EMs 的平均粒径为 6.6μm±2.3（标准差），T2 加权 MRI 能力显示 53.7%±8.3 的索拉非尼载药效率。在 HCC 大鼠模型中，通过 MRI 成功监测了经动脉注射的 SOR-EMs。与仅接受 DLE 治疗的大鼠相比，DLE + SOR-EM 治疗组的肿瘤生长抑制效果更好（<0.05）。组织标本免疫组织化学评估显示，与其他治疗组相比，DLE + SOR-EM 治疗组的 CD34 阳性染色面积百分比（所有比较均<0.01）最低，微血管数量最少。
结论
在临床前大鼠 HCC 模型中，DLE TACE 联合 SOR-EMs 治疗 HCC 有效。化学栓塞，实验研究，实验室测试，肝，技术评估 ©RSNA，2021 也见本期 Yamada 和 Gayed 的评论。
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