Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances.
Delivery of chemotherapeutics across the blood-brain barrier: challenges and advances.
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DOI：
10.1016/bs.apha.2014.06.002
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Neuwelt EA
中科院分区：
文献类型：
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作者：
Doolittle ND;Muldoon LL;Culp AY;Neuwelt EA
血脑屏障（BBB）限制了药物向脑肿瘤的递送。我们利用动脉内输注高渗甘露醇通过收缩内皮细胞和打开细胞之间的紧密连接来可逆地打开BBB。这种方法短暂地增加了化疗、抗体和纳米颗粒向大脑的递送。我们的临床前研究优化了BBB破坏（BBBD）技术，临床研究显示了其安全性和有效性。以甲氨蝶呤为基础的化疗联合BBBD治疗原发性中枢神经系统淋巴瘤（PCNSL）可提供极好的结局，包括生存者在诊断后中位12年（范围2-26年）的稳定或改善的认知功能。利妥昔单抗加用BBBD化疗治疗PCNSL可以安全完成，总生存率极佳。我们对巯基药物的转化研究，以防止铂诱导的毒性，导致脑肿瘤患者的双室模型的发展。我们发现，延迟的高剂量硫代硫酸钠可预防卡铂诱导的听力损失，为听力化学保护的大型合作组试验提供了框架。神经影像学研究已经确定，ferumoxytol，一种氧化铁纳米颗粒血池剂，似乎是一种上级造影剂，可以准确评估治疗诱导的脑肿瘤血管系统变化、脑肿瘤对治疗的反应以及区分具有炎症成分的中枢神经系统病变。本章回顾了BBBD的突破、挑战和未来方向。
The blood–brain barrier (BBB) limits drug delivery to brain tumors. We utilize intraarterial infusion of hyperosmotic mannitol to reversibly open the BBB by shrinking endothelial cells and opening tight junctions between the cells. This approach transiently increases the delivery of chemotherapy, antibodies, and nanoparticles to brain. Our preclinical studies have optimized the BBB disruption (BBBD) technique and clinical studies have shown its safety and efficacy. The delivery of methotrexate-based chemotherapy in conjunction with BBBD provides excellent outcomes in primary central nervous system lymphoma (PCNSL) including stable or improved cognitive function in survivors a median of 12 years (range 2–26 years) after diagnosis. The addition of rituximab to chemotherapy with BBBD for PCNSL can be safely accomplished with excellent overall survival. Our translational studies of thiol agents to protect against platinum-induced toxicities led to the development of a two-compartment model in brain tumor patients. We showed that delayed high-dose sodium thiosulfate protects against carboplatin-induced hearing loss, providing the framework for large cooperative group trials of hearing chemoprotection. Neuroimaging studies have identified that ferumoxytol, an iron oxide nanoparticle blood pool agent, appears to be a superior contrast agent to accurately assess therapy-induced changes in brain tumor vasculature, in brain tumor response to therapy, and in differentiating central nervous system lesions with inflammatory components. This chapter reviews the breakthroughs, challenges, and future directions for BBBD.