A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease.
A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease.
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DOI：
10.3791/62033
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发表时间：
2021-01-29
影响因子：
1.2
通讯作者：
Forsyth, Peter A.
中科院分区：
文献类型：
--
作者：
Law, Vincent;Baldwin, Margi;Ramamoorthi, Ganesan;Kodumudi, Krithika;Nam Tran;Smalley, Inna;Duckett, Derek;Kalinski, Pawel;Czerniecki, Brian;Smalley, Keiran S. M.;Forsyth, Peter A.
摘要软脑膜疾病是一种少见的中枢神经系统转移至脑脊髓液的疾病。导致LMD的最常见癌症是乳腺癌、肺癌和黑色素瘤。诊断为LMD的患者预后非常差，通常只能存活几周或几个月。缺乏针对LMD的全身性疗法的功效的一个可能原因是由于穿过脉络丛的完整且相对不可渗透的血脑屏障（BBB）或血-CSF屏障而未能在CSF中达到治疗有效的药物浓度。因此，鞘内或心室内直接给药可以克服这些障碍。该小组已经开发出一种模型，该模型允许有效地递送治疗剂（即，药物、抗体和细胞疗法），并对CSF进行重复采样以确定CSF中的药物浓度和靶向调节（当在小鼠中靶向肿瘤微环境时）。该模型是磁共振成像兼容的Ommaya水库，这是临床使用的小鼠等效。这个模型，这是固定在头骨，已被指定为“鼠Ommaya”。作为概念的治疗证明，通过鼠Ommaya将人表皮生长因子受体2抗体（克隆7.16.4）递送至CSF中以治疗患有来自人表皮生长因子受体2阳性乳腺癌的LMD的小鼠。鼠Ommaya使用微型输液港提高了药物输送效率，并防止了多余药物的浪费;它不会干扰用于分子和免疫学研究的CSF采样。鼠Ommaya可用于在LMD的实验模型中测试新疗法。
Leptomeningeal disease (LMD) is an uncommon type of central nervous system (CNS) metastasis to the cerebral spinal fluid (CSF). The most common cancers that cause LMD are breast and lung cancers and melanoma. Patients diagnosed with LMD have a very poor prognosis and generally survive for only a few weeks or months. One possible reason for the lack of efficacy of systemic therapy against LMD is the failure to achieve therapeutically effective concentrations of drug in the CSF because of an intact and relatively impermeable blood-brain barrier (BBB) or blood-CSF barrier across the choroid plexus. Therefore, directly administering drugs intrathecally or intraventricularly may overcome these barriers. This group has developed a model that allows for the effective delivery of therapeutics (i.e., drugs, antibodies, and cellular therapies) chronically and the repeated sampling of CSF to determine drug concentrations and target modulation in the CSF (when the tumor microenvironment is targeted in mice). The model is the murine equivalent of a magnetic resonance imaging-compatible Ommaya reservoir, which is used clinically. This model, which is affixed to the skull, has been designated as the “Murine Ommaya.” As a therapeutic proof of concept, human epidermal growth factor receptor 2 antibodies (clone 7.16.4) were delivered into the CSF via the Murine Ommaya to treat mice with LMD from human epidermal growth factor receptor 2-positive breast cancer. The Murine Ommaya increases the efficiency of drug delivery using a miniature access port and prevents the wastage of excess drug; it does not interfere with CSF sampling for molecular and immunological studies. The Murine Ommaya is useful for testing novel therapeutics in experimental models of LMD.
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DOI：
10.3791/50326
发表时间：
2013-05-12
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
DeVos SL;Miller TM
通讯作者：
Miller TM
DOI：
10.1016/j.bbadis.2015.10.014
发表时间：
2016-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Simon MJ;Iliff JJ
通讯作者：
Iliff JJ
影响因子：
4.3
作者：
Glitza, Isabella C.;Smalley, Keiran S. M.;Brastianos, Priscilla K.;Davies, Michael A.;McCutcheon, Ian;Liu, James K. C.;Ahmed, Kamran A.;Arrington, John A.;Evernden, Brittany R.;Smalley, Inna;Eroglu, Zeynep;Khushalani, Nikhil;Margolin, Kim;Kluger, Harriet;Atkins, Michael B.;Tawbi, Hussein;Boire, Adrienne;Forsyth, Peter
通讯作者：
Forsyth, Peter
影响因子：
1.2
作者：
Dunn, Louise;Prosser, Hamish C. G.;Bursill, Christina A.
通讯作者：
Bursill, Christina A.
影响因子：
2.1
作者：
Znidaric, Tanja;Gugic, Jasenka;Ratosa, Ivica
通讯作者：
Ratosa, Ivica