Macromolecular therapeutics for neoplastic meningitis

描述（由申请人提供）：本研究的目的是开发一种新颖、安全、有效的治疗肿瘤性脑膜炎（癌症脑膜转移）的方法。肿瘤性脑膜炎是乳腺癌和其他实体肿瘤的致命并发症。已公布的数据表明，5-8%的患者患有这种并发症。中位生存期约为3个月，如果不积极治疗，只有2-4周。目前的治疗主要是治标不治本。小脑膜间隙与身体其他部分被血脑屏障（BBB）和血脑脊液屏障（CSF）很好地隔离，这使得全身化疗无效。已经尝试用鞘内药物治疗肿瘤性脑膜炎。然而，目前可用的化疗药物会迅速从脑脊液中清除。我们对脑脊液中大分子行为的研究清楚地表明，它们不会迅速从脑脊液中清除。在鞘内施用时，大分子在脑脊液中停留数小时或数天。这表明，鞘内施用可溶性大分子药物可以有效治疗肿瘤性脑膜炎，这种药物会分布在脑脊液中，并释放一种不溶性抗肿瘤药物，这种药物会(1)留在脑膜中，(2)容易进入脑膜癌细胞群。本研究的目的是确定药物分子的大小，使药物在脑脊液中保持最佳状态，合成该大小的模型偶联物，并在动物模型中评估药物在脑膜间室中的分布、抗脑膜癌扩散的功效以及模型偶联物的安全性。该研究将利用我们实验室开发的一种新型大分子材料和一种新型药物释放系统。这两种技术已经成功地应用于新型全身药物，其中一种目前正在进行I期临床研究。我们将合成并表征以碘-124标记的高分离大分子，通过PET研究它们在脑脊液中的保留，然后合成一个最佳大小的喜树碱偶联物，通过PET研究该偶联物如何在脑脊液空间中分布喜树碱，确定该偶联物的最大耐受剂量，并在人乳腺癌细胞诱导的肿瘤性脑膜炎动物模型中确定该结合物的疗效。我们期望这项研究将导致(1)开发新的鞘内治疗乳腺癌引起的肿瘤性脑膜炎的新方法，以及(2)适合进一步开发的候选化疗药物。

DESCRIPTION (provided by applicant): The goal of the proposed study is to develop novel, safe, and efficient therapy for neoplastic meningitis (leptomeningeal metastasis of cancer). Neoplastic meningitis is a devastating complication of breast cancer and other solid tumors. Published data suggest that 5-8% of patients suffer from this complication. The median survival is about 3 months, and only 2-4 weeks if not aggressively treated. The current treatment is largely palliative. The leptomeningeal space is well isolated from the rest of the body by the blood-brain barrier (BBB) on one side, and by the blood-cerebrospinal fluid (CSF) barrier on the other, which makes systemic chemotherapy ineffective. Attempts have been made to treat neoplastic meningitis with drugs administered intrathecally. However, the currently available chemotherapeutics are rapidly cleared from CSF. Our studies on the behavior of large molecules in CSF clearly show that they are not rapidly cleared from CSF. Being administered intrathecally, large molecules stay in CSF for several hours or days. This suggests that neoplastic meningitis can be effectively treated by intrathecal administration of soluble large-molecule therapeutics that would distribute in CSF and release an insoluble antineoplastic drug that would (I) stay in the meninges and (II) readily access the meningeal population of cancer cells. The objective of this study is to determine the size of the drug molecule that would enable optimal drug retention in CSF, synthesize a model conjugate of that size, and evaluate in animal models drug distribution in the meningeal compartment, efficacy against meningeal cancer spread, and safety of the model conjugate. The study will utilize a novel macromolecular material and a novel drug release system that have been developed in our laboratory. Both technologies have been successfully used in novel systemic drugs, one of which is presently in Phase I clinical studies. We will synthesize and characterize highly fractionated macromolecules labeled with iodine-124, investigate by PET their retention in CSF, then synthesize a camptothecin conjugate of the optimal size with respect to CSF retention, investigate by PET how the conjugate distributes camptothecin in the leptomeningeal space, determine the maximum tolerated dose of the conjugate, and determine the efficacy of the conjugate in an established animal model of neoplastic meningitis induced by human breast cancer cells. We expect that the study will result in (1) a new approach to developing novel intrathecal therapies for neoplastic meningitis caused by breast cancer, and (2) a candidate chemotherapeutic suitable for further development. PUBLIC HEALTH RELEVANCE: The goal of the proposed study is to develop novel, safe, and efficient therapy for neoplastic meningitis, a devastating complication of cancer caused by the spread of cancer cells into layers of tissues surrounding the brain. Published data suggest that 5-8% of breast cancer patients suffer from this complication, and that the risk of neoplastic meningitis significantly increases on the second relapse of the disease. Presently, there is no effective treatment for neoplastic meningitis, and the median survival of cancer patients who develop this complication is reported to be about 3 months.