Macromolecular therapeutics for neoplastic meningitis

描述（由申请方提供）：拟定研究的目的是开发新的、安全的、有效的肿瘤性脑膜炎（癌症软脑膜转移）治疗方法。肿瘤性脑膜炎是乳腺癌和其他实体瘤的毁灭性并发症。已发表的数据表明，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，仅为2-4周。目前的治疗主要是治标不治本。软脑膜间隙通过一侧的血脑屏障（BBB）和另一侧的血脑脊髓液（CSF）屏障与身体的其余部分很好地隔离，这使得全身化疗无效。已经尝试用鞘内给药来治疗肿瘤性脑膜炎。然而，目前可用的化疗药物从CSF中快速清除。我们对CSF中大分子行为的研究清楚地表明，它们不能迅速从CSF中清除。鞘内给药时，大分子会在CSF中停留数小时或数天。这表明肿瘤性脑膜炎可以通过鞘内施用可溶性大分子治疗剂来有效治疗，所述可溶性大分子治疗剂将分布在CSF中并释放不溶性的抗肿瘤药物，所述不溶性抗肿瘤药物将（I）停留在脑膜中并且（II）容易进入癌细胞的脑膜群体。本研究的目的是确定能够使药物在CSF中最佳保留的药物分子的大小，合成该大小的模型缀合物，并在动物模型中评价脑膜隔室中的药物分布、抗脑膜癌扩散的功效和模型缀合物的安全性。该研究将利用我们实验室开发的新型高分子材料和新型药物释放系统。这两种技术都已成功用于新型全身药物，其中一种目前正在进行I期临床研究。我们将合成和表征用碘-124标记的高度分级的大分子，通过PET研究它们在CSF中的保留，然后合成相对于CSF保留的最佳尺寸的喜树碱缀合物，通过PET研究缀合物如何在软脑膜空间中分布喜树碱，确定缀合物的最大耐受剂量，并确定所述缀合物在由人乳腺癌细胞诱导的肿瘤性脑膜炎的已建立动物模型中的功效。我们期望该研究将导致（1）开发用于乳腺癌引起的肿瘤性脑膜炎的新型鞘内疗法的新方法，以及（2）适合进一步开发的候选化疗剂。 公共卫生相关性：这项研究的目的是开发新的，安全的，有效的治疗肿瘤性脑膜炎的方法，肿瘤性脑膜炎是一种由癌细胞扩散到大脑周围组织层引起的毁灭性癌症并发症。已发表的数据表明，5-8%的乳腺癌患者患有这种并发症，并且肿瘤性脑膜炎的风险在疾病的第二次复发时显著增加。目前，对于肿瘤性脑膜炎没有有效的治疗方法，据报道，发生这种并发症的癌症患者的中位生存期约为3个月。

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.