Khang Minsoo, Bindra Ranjit S, Mark Saltzman W
Department of Biomedical Engineering, Yale University, United States.
Department of Therapeutic Radiology, Yale School of Medicine, United States.
Adv Drug Deliv Rev. 2022 Jul;186:114338. doi: 10.1016/j.addr.2022.114338. Epub 2022 May 10.
Intrathecal delivery (IT) of opiates into the cerebrospinal fluid (CSF) for anesthesia and pain relief has been used clinically for decades, but this relatively straightforward approach of bypassing the blood-brain barrier has been underutilized for other indications because of its lack of utility in delivering small lipid-soluble drugs. However, emerging evidence suggests that IT drug delivery be an efficacious strategy for the treatment of cancers in which there is leptomeningeal spread of disease. In this review, we discuss CSF flow dynamics and CSF clearance pathways in the context of intrathecal delivery. We discuss human and animal studies of several new classes of therapeutic agents-cellular, protein, nucleic acid, and nanoparticle-based small molecules-that may benefit from IT delivery. The complexity of the CSF compartment presents several key challenges in predicting biodistribution of IT-delivered drugs. New approaches and strategies are needed that can overcome the high rates of turnover in the CSF to reach specific tissues or cellular targets.
将阿片类药物鞘内注射（IT）到脑脊液（CSF）中用于麻醉和缓解疼痛已在临床上使用了数十年，但这种绕过血脑屏障的相对直接的方法由于在递送小的脂溶性药物方面缺乏效用，在其他适应症中未得到充分利用。然而，新出现的证据表明，鞘内给药是治疗疾病软脑膜播散的癌症的一种有效策略。在这篇综述中，我们在鞘内给药的背景下讨论脑脊液流动动力学和脑脊液清除途径。我们讨论了几类新型治疗药物——基于细胞、蛋白质、核酸和纳米颗粒的小分子——的人体和动物研究，这些药物可能从鞘内给药中受益。脑脊液隔室的复杂性在预测鞘内给药药物的生物分布方面提出了几个关键挑战。需要新的方法和策略来克服脑脊液中的高周转率，以到达特定组织或细胞靶点。
