Targeting delivery of mAbs to CNS metastases

据估计，大约15%到40%的癌症扩散到中枢神经系统(CNS)。治疗方法 然而，由于向中枢神经系统提供治疗药物的效率低下，对脑转移癌症的研究一直受到限制。 我们在这里提出了一种新的策略，它能够有效地传递一类单抗(MAbs) 将高度特异和有效的蛋白质疗法应用于中枢神经系统，用于治疗脑转移的癌症。 这一策略是基于纳米封装技术，其中mAbs分子被封装在 表面含有丰富胆碱和乙酰胆碱类似物的纳米胶囊。这样的纳米胶囊 可以有效地跨血脑屏障运输，并在系统给药后将单抗递送到中枢神经系统。 此外，纳米胶囊可以通过与识别细胞表面标记的配体的结合而成为靶点 在肿瘤细胞上。我们最近发表了通过以下途径将利妥昔单抗(抗CD20)有效地传递到中枢神经系统的研究报告 使用纳米胶囊技术的静脉注射。纳米胶囊针对表面的CXCR5 通过与CXCL13的偶联，对肿瘤细胞进行鉴定。这种治疗方法显著减轻了肿瘤负担。 在移植了B细胞淋巴瘤的小鼠的大脑中，与直接的天然单抗进行了比较。在这份提案中， 我们将通过优化利妥昔单抗纳米胶囊的设计来进一步提高治疗效果 了解血脑屏障通路和肿瘤清除的机制。这个项目的成功可能会 使许多其他治疗性单抗能够有效地输送到中枢神经系统，为治疗 有中枢神经系统转移的癌症。

It is estimated that around 15% to 40% of cancers spread to the central nervous system (CNS). The treatment of cancers with brain metastases, however, has been limited by the inefficient deliver of therapeutics to the CNS. We propose herein a novel strategy, which enables effective delivery of monoclonal antibodies (mAbs), a class of highly specific and potent protein therapeutics, to the CNS, for the treatment of cancers with brain metastases. This strategy is based on a nano-encapsulating technology, where mAbs molecules are encapsulated within nanocapsules of which the surface contains abundant choline and acetylcholine analogues. Such nanocapsules can be effectively transported across the BBB and deliver the mAbs to the CNS upon systemic administration. Furthermore, the nanocapsules can be targeted by conjugation with ligands which recognize cell surface markers on tumor cells. We recently published effective delivery into the CNS of rituximab (anti-CD20) mAbs through intravenous route using the nanocapsule technology. The nanocapsules were targeted to CXCR5 on the surface of the tumor cells via conjugation with CXCL13. This therapeutic approach significantly reduced the tumor burden in the brains of mice xenografted with B-cell lymphomas in comparison with direct native mAbs. In this proposal, we will further improve the therapeutic efficacy by optimizing the design of the rituximab nanocapsules based on understanding of the mechanisms of BBB passage and tumor clearance. Success of this project could potentially enable effective delivery of many other therapeutic mAbs to the CNS, opening a new avenue for treatments of cancers with CNS metastases.