Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1.
Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1.
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DOI：
10.1007/s11060-009-0046-7
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发表时间：
2010-05
影响因子：
3.9
通讯作者：
Sampson, John H.
中科院分区：
文献类型：
--
作者：
Ding, Dale;Kanaly, Charles W.;Bigner, Darrell D.;Cummings, Thomas J.;Herndon, James E., II;Pastan, Ira;Raghavan, Raghu;Sampson, John H.
胶质母细胞瘤治疗的主要障碍是血脑屏障（BBB）的限制性。对流增强给药（CED）是一种新的给药方法，它允许直接实质输注治疗药物，绕过血脑屏障。MR1-1是一种新的重组免疫毒素，靶向GBM肿瘤特异性抗原EGFRvIII，可以通过CED输注给药。然而，通过CED的药物分布变化很大，这需要积极监测。钆偶联二乙烯三胺五乙酸（Gd-DTPA）是一种常用的MRI造影剂，可与CED联合输注，可用于监测输注泄漏和早期分布。将40只具有免疫功能的大鼠植入连接渗透泵的脑内插管，然后随机分为四组，每组接受0.2%人血清白蛋白（HSA）混合不同的实验输注：1)25 ng/mL MR1-1；2) Gd-DTPA 7 μmol/mL；3) MR1-1 25 ng/mL, Gd-DTPA 7 μmol/mL；4) MR1-1 250 ng/mL, Gd-DTPA 7μmol/mL。临床监测大鼠6周，然后进行尸检和组织学评估中枢神经系统毒性。所有大鼠在整个研究过程中都存活了下来，没有由研究药物引起的临床或组织学毒性。各组间体重随时间变化差异无统计学意义（p>0.999）。在临床前动物模型中，MR1-1经CED与Gd-DTPA共输注是安全的。我们的数据支持使用Gd-DTPA作为替代示踪剂，与MR1-1共同输注用于GBM患者的药物分布监测。
A major obstacle in glioblastoma (GBM) therapy is the restrictive nature of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) is a novel method of drug administration which allows direct parenchymal infusion of therapeutics, bypassing the BBB. MR1-1 is a novel recombinant immunotoxin that targets the GBM tumor-specific antigen EGFRvIII and can be delivered via CED infusion. However, drug distribution via CED varies dramatically, which necessitates active monitoring. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a commonly used MRI contrast agent which can be co-infused with therapies using CED and may be useful in monitoring infusion leak and early distribution. Forty immunocompetent rats were implanted with intracerebral cannulas that were connected to osmotic pumps and subsequently randomized into four groups that each received 0.2% human serum albumin (HSA) mixed with a different experimental infusion: 1) 25 ng/mL MR1-1; 2) 7 μmol/mL Gd-DTPA; 3) 25 ng/mL MR1-1 and 7 μmol/mL Gd-DTPA; 4) 250 ng/mL MR1-1 and 7μmol/mL Gd-DTPA. The rats were monitored clinically for six weeks then necropsied and histologically assessed for CNS toxicity. All rats survived the entirety of the study without clinical or histological toxicity attributable to the study drugs. There was no statistically significant difference in weight change over time among groups (p>0.999). MR1-1 co-infused with Gd-DTPA via CED is safe in the long-term setting in a pre-clinical animal model. Our data supports the use of Gd-DTPA, as a surrogate tracer, co-infused with MR1-1 for drug distribution monitoring in patients with GBM.
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影响因子：
5.3
作者：
Saito, R;Krauze, MT;Bankiewicz, KS
通讯作者：
Bankiewicz, KS
影响因子：
4.1
作者：
Murad, Gregory J. A.;Walbridge, Stuart;Lonser, Russell R.
通讯作者：
Lonser, Russell R.
影响因子：
4.1
作者：
Oiwa, Y;Sanchez-Pernaute, R;Bankiewicz, KS
通讯作者：
Bankiewicz, KS
影响因子：
158.5
作者：
Hegi, ME;Diserens, A;Stupp, R
通讯作者：
Stupp, R
DOI：
10.1073/pnas.91.6.2076
发表时间：
1994-03-15
影响因子：
11.1
作者：
BOBO, RH;LASKE, DW;OLDFIELD, EH
通讯作者：
OLDFIELD, EH