Stephenson School of Biomedical Engineering, The University of Oklahoma, Norman, OK, United States.
Stephenson School of Biomedical Engineering, The University of Oklahoma, Norman, OK, United States; Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; Institute for Biomedical Engineering, Science, and Technology, University of Oklahoma, Norman, OK, United States.
Adv Drug Deliv Rev. 2023 Aug;199:114949. doi: 10.1016/j.addr.2023.114949. Epub 2023 Jun 5.
The proximity and association of cerebrospinal fluid (CSF) and the intrathecal (IT) space with deep targets in the central nervous system (CNS) parenchyma makes IT injection an attractive route of administration for brain drug delivery. However, the extent to which intrathecally administered macromolecules are effective in treating neurological diseases is a question of both clinical debate and technological interest. We present the biological, chemical, and physical properties of the intrathecal space that are relevant to drug absorption, distribution, metabolism, and elimination from CSF. We then analyze the evolution of IT drug delivery in clinical trials over the last 20 years. Our analysis revealed that the percentage of clinical trials assessing IT delivery for the delivery of biologics (i.e., macromolecules, cells) for treatment of chronic conditions (e.g., neurodegeneration, cancer, and metabolic diseases) has steadily increased. Clinical trials exploring cell or macromolecular delivery within the IT space have not evaluated engineering technologies, such as depots, particles, or other delivery systems. Recent pre-clinical studies have evaluated IT macromolecule delivery in small animals, postulating that delivery efficacy can be assisted by external medical devices, micro- or nanoparticles, bulk biomaterials, and viral vectors. Further studies are necessary to evaluate the extent to which engineering technologies and IT administration improve CNS targeting and therapeutic outcome.
脑脊髓液 (CSF) 与鞘内 (IT) 空间与中枢神经系统 (CNS) 实质中的深部靶标接近和关联，使得 IT 注射成为脑内药物递送的一种有吸引力的给药途径。然而，鞘内给予的大分子在治疗神经疾病方面的有效性程度既是临床争论的问题，也是技术关注的问题。我们介绍了与 CSF 中药物吸收、分布、代谢和消除相关的 IT 空间的生物学、化学和物理特性。然后，我们分析了过去 20 年临床试验中 IT 药物输送的演变。我们的分析表明，评估 IT 输送用于治疗慢性疾病（如神经退行性疾病、癌症和代谢疾病）的生物制剂（即大分子、细胞）的临床试验百分比稳步增加。探索 IT 空间内细胞或大分子输送的临床试验尚未评估工程技术，例如储库、颗粒或其他输送系统。最近的临床前研究已经评估了 IT 大分子在小动物中的输送，推测输送效果可以通过外部医疗设备、微或纳米颗粒、大块生物材料和病毒载体来辅助。需要进一步的研究来评估工程技术和 IT 给药在多大程度上提高了 CNS 靶向和治疗效果。
