Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging
Canine model of convection-enhanced delivery of liposomes containing CPT-11 monitored with real-time magnetic resonance imaging
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DOI：
10.3171/jns/2008/108/5/0989
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发表时间：
2008-05-01
影响因子：
4.1
通讯作者：
Bankiewicz, Krystof S.
中科院分区：
文献类型：
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作者：
Dickinson, Peter J.;LeCouteur, Richard A.;Bankiewicz, Krystof S.
Object.许多与对流增强输送（CED）入颅内肿瘤的安全性和有效性相关的因素知之甚少。为了进一步研究这些因素并建立更具临床相关性的大型动物模型，并有可能研究大型自发性肿瘤中的CED，作者开发了一种磁共振（MR）成像兼容系统，用于将脂质体纳米颗粒CED注入犬脑，并结合实时MR成像。此外，在直接脑实质内递送后评估含有Gd和化疗剂伊立替康（CPT-11）的脂质体的任何可能的毒性。四只健康的实验室犬输注含有Gd、罗丹明或CPT-11的脂质体。通过序列MR成像对对流增强输送进行真实的实时监测，并根据MR图像和组织切片计算分布容积。任何毒性的评估均基于临床和组织病理学评价。对流增强输送导致灰色和白色物质的分布体积稳健，实时MR成像允许准确计算体积和分布途径。灌注变异性在灰质中最大，并与渗漏到脑室或蛛网膜下腔相关。并发症是最小的，包括轻度短暂的本体感觉缺陷，局灶性出血在I狗，局灶性，轻度血管周围，非化脓性脑炎在I狗。在大型动物模型中，脂质体Gd/CPT-11的对流增强递送与最小的不良反应相关，并且需要进一步评估其在临床患者中的使用。未来研究实时监测CED在犬自发性胶质瘤中的可行性，并将提供一个独特的，临床相关的大型动物转化模型，用于测试这种和其他治疗策略。
Object. Many factors relating to the safety and efficacy of convection-enhanced delivery (CED) into intracranial tumors are poorly understood. To investigate these factors further and establish a more clinically relevant large animal model, with the potential to investigate CED in large, spontaneous tumors, the authors developed a magnetic resonance (MR) imaging-compatible system for CED of liposomal nanoparticles into the canine brain, incorporating real-time MR imaging. Additionally any possible toxicity of liposomes containing Gd and the chemotherapeutic agent irinotecan (CPT-11) was assessed following direct intraparenchymal delivery.Methods. Four healthy laboratory dogs were infused with liposomes containing Gd, rhodamine, or CPT-11. Convection-enhanced delivery was monitored in real time by sequential MR imaging, and the volumes of distribution were calculated from MR images and histological sections. Assessment of any toxicity was based on clinical and histopathological evaluation. Convection-enhanced delivery resulted in robust volumes of distribution in both gray and white matter, and real-time MR imaging allowed accurate calculation of volumes and pathways of distribution.Results. Infusion variability was greatest in the gray matter, and was associated with leakage into ventricular or subarachnoid spaces. Complications were minimal and included mild transient proprioceptive deficits, focal hemorrhage in I dog, and focal, mild perivascular, nonsuppurative encephalitis in I dog.Conclusions. Convection-enhanced delivery of liposomal Gd/CPT-11 is associated with minimal adverse effects in a large animal model, and further assessment for use in clinical patients is warranted. Future studies investigating real-time monitored CED in spontaneous gliomas in canines are feasible and will provide a unique, clinically relevant large animal translational model for testing this and other therapeutic strategies.