Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321.
Long-term safety of combined intracerebral delivery of free gadolinium and targeted chemotherapeutic agent PRX321.
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DOI：
10.1179/174367509x12581069052090
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发表时间：
2010-10
影响因子：
1.9
通讯作者：
Sampson JH
中科院分区：
文献类型：
--
作者：
Ding D;Kanaly CW;Cummings TJ;Herndon JE 2nd;Raghavan R;Sampson JH
虽然对流增强递送（CED）是绕过血脑屏障（BBB）的有效递送方法，但其效用受到由于导管错位引起的输注物泄漏空间的限制。因此，评价CED输注期间的药物分布至关重要。钆共轭二亚乙基三胺五乙酸（Gd-DTPA）是一种常见的，容易获得的MRI造影剂，可以预测和主动监测药物分布。在这项研究中，我们评估了长期的安全性和毒性脑内注入Gd-DTPA沿着与实验靶向剂PRX 321。54只免疫功能正常的大鼠被植入与皮下放置的渗透泵相连的脑内套管。泵植入后，将大鼠随机分为6组，每组9只大鼠，以评估6种不同浓度的人血清白蛋白（HSA）与和不与Gd-DTPA和PRX 321的毒性。在对大鼠进行尸检并评估其中枢神经系统（CNS）的组织学毒性之前，对大鼠进行临床监测六周。在输注低浓度HSA、Gd-DTPA和PRX 321的组中有1例不明原因死亡。对该动物的CNS进行显微镜检查后，未发现非预期的组织学毒性。此外，其余大鼠均未出现临床或组织学毒性迹象，所有大鼠均存活至6周观察期结束。游离Gd-DTPA可以通过CED安全地输注到临床前动物模型中。未来的研究应包括其在早期人体临床试验中预测和积极监测CED药物输注的用途。
While convection-enhanced delivery (CED) is an effective delivery method that bypasses the blood-brain barrier (BBB), its utility is limited by infusate leakage spaces due to catheter misplacement. Therefore it is critical to evaluate drug distribution during CED infusion. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a common, readily available MRI contrast agent which may be able to predict and actively monitor drug distribution. In this study, we assess the long-term safety and toxicity of intracerebrally infused Gd-DTPA along with an experimental targeted agent PRX321. Fifty-four immunocompetent rats were implanted with intracerebral cannulas linked to subcutaneously placed osmotic pumps. After pump implantation, the rats were randomized into six groups of nine rats each in order to assess the toxicities of six different concentrations of human serum albumin (HSA) with and without Gd-DTPA and PRX321. The rats were monitored clinically for six weeks before they were autopsied and assessed for histological toxicity to their central nervous system (CNS). There was one unexplained death in a group infusing low-concentration HSA, Gd-DTPA, and PRX321. Upon microscopic examination of the CNS in that animal, no unexpected histological toxicity was found. Additionally, there were no signs of clinical or histological toxicity in any of the remaining rats, which all survived until the end of the six-week observation period. Free Gd-DTPA can be safely infused via CED in a pre-clinical animal model. Future studies should include its use in predicting and actively monitoring CED drug infusions in early phase human clinical trials.