Tumor metastasis into the central nervous system (CNS) and lymph nodes (LNs) is a major obstacle for effective therapies. Therapeutic monoclonal antibodies (mAb) have revolutionized tumor treatment; however, their efficacy for treating metastatic tumors-particularly, CNS and LN metastases-is poor due to inefficient penetration into the CNS and LNs following intravenous injection. We recently reported an effective delivery of mAb to the CNS by encapsulating the anti-CD20 mAb rituximab (RTX) within a thin shell of polymer that contains the analogs of choline and acetylcholine receptors. This encapsulated RTX, denoted as n-RTX, eliminated lymphoma cells systemically in a xenografted humanized mouse model using an immunodeficient mouse as a recipient of human hematopoietic stem/progenitor cells and fetal thymus more effectively than native RTX; importantly, n-RTX showed notable anti-tumor effect on CNS metastases which is unable to show by native RTX. As an important step toward future clinical translation of this technology, we further analyzed the properties of n-RTX in immunocompetent animals, rats, and non-human primates (NHPs). Our results show that a single intravenous injection of n-RTX resulted in 10-fold greater levels in the CNS and 2-3-fold greater levels in the LNs of RTX, respectively, than the injection of native RTX in both rats and NHPs. In addition, we demonstrate the enhanced delivery and efficient B-cell depletion in lymphoid organs of NHPs with n-RTX. Moreover, detailed hematological analysis and liver enzyme activity tests indicate n-RTX treatment is safe in NHPs. As this nanocapsule platform can be universally applied to other therapeutic mAbs, it holds great promise for extending mAb therapy to poorly accessible body compartments.

中文翻译：

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使用非人类灵长类动物中的定时释放纳米胶囊增强了利妥昔单抗向脑和淋巴结的递送。

肿瘤转移到中枢神经系统（CNS）和淋巴结（LNs）是有效治疗的主要障碍。治疗性单克隆抗体（mAb）彻底改变了肿瘤的治疗方法。然而，由于静脉注射后渗透到CNS和LN的效率低下，它们治疗转移性肿瘤（尤其是CNS和LN转移）的疗效很差。我们最近报道了通过将抗CD20 mAb利妥昔单抗（RTX）封装在含有胆碱和乙酰胆碱受体类似物的聚合物薄壳内，将mAb有效递送至CNS的方法。这种封装的RTX（称为n-RTX）在免疫异种移植的人源化小鼠模型中使用免疫缺陷小鼠作为人类造血干/祖细胞和胎儿胸腺的受体，比天然RTX更有效地消除了淋巴瘤细胞。重要的是，n-RTX对中枢神经系统转移具有明显的抗肿瘤作用，而天然RTX则无法显示。作为迈向该技术未来临床翻译的重要一步，我们进一步分析了n-RTX在具有免疫能力的动物，大鼠和非人类灵长类动物（NHP）中的特性。我们的结果表明，与在大鼠和NHP中注射天然RTX相比，单次静脉内注射n-RTX分别导致CNS中RTX的水平高10倍，而LTX中LN的水平高2-3倍。此外，我们证明了使用n-RTX的NHP淋巴器官中的递送增强和有效的B细胞耗竭。此外，详细的血液学分析和肝酶活性测试表明，n-RTX治疗在NHP中是安全的。由于这种纳米胶囊平台可以普遍应用于其他治疗性单克隆抗体，