Intraperitoneal Delivery of Targeted Nanoparticles for Metastatic Ovarian Cancer

描述(申请人提供)：该项目的长期目标是使用含有治疗性放射性核素的纳米颗粒治疗转移性卵巢癌，并将研究结果从动物模型转化为人类卵巢癌。这项拟议工作的总体假设是，肿瘤靶向纳米颗粒中包含的稳定同位素可以通过中子捕获过程激活为放射性同位素。由此产生的放射治疗纳米粒随后可以被腹膜内注射，以向转移性卵巢肿瘤提供有效的吸收辐射剂量。预计这将改善治疗反应，同时降低毒性。建议的放射治疗纳米粒子将通过稳定的Ho原子(165Ho)的中子激活而产生，这些原子与介孔二氧化硅纳米粒子(MSN)的基质一起包含，MSN是一种经得起长时间中子照射的耐用载体。这些纳米粒子的中子照射产生的放射性核素166Ho通过发射高能贝塔粒子而衰变，这些粒子具有辐射组织扩散范围，能够将吸收的辐射剂量传递到肿瘤，足以导致肿瘤死亡。此外，这些MSN的表面将被叶酸功能化，叶酸是卵巢肿瘤的靶向配体。在制备MSN后使其具有放射性，为医务人员和患者提供了最大限度的安全性，并允许遵守当前的良好制造规范(CGMP)并在照射前对稳定的纳米颗粒进行详细表征。初步研究表明，非靶向166HO-MSN的主要肿瘤蓄积和显著改善卵巢肿瘤荷瘤小鼠的存活率。目前的项目集中在向转移性卵巢肿瘤和肿瘤组织的核心组织注射靶向放射治疗纳米粒。其具体目的是优化与MSN相关的靶向配体，并评估纳米颗粒在肿瘤中的渗透性。我们假设，靶向的166HO-MSN将由于其特定的亲和力而与肿瘤表面强烈结合，并且辐射将通过诱导肿瘤表面的凋亡来促进166HO-MSN在肿瘤深层的渗透。体外细胞模型将被用来证实MSN与肿瘤细胞之间的靶向效应和表面相互作用。这一结果将得到靶向纳米颗粒在动物和人类肿瘤组织中积累和渗透的测量支持。这些测量将用于剂量计算，以确定166HO-MSN的最佳剂量。这项工作产生的数据将弥合将动物研究结果转化为人类的差距。这种方法还为治疗方案的设计提供了灵活性。通过关注这些临床相关因素以及制造和验证过程，这些创新将使这种靶向放射性核素疗法更容易进入临床研究阶段和 更快地将这项工作转化为临床实践。

DESCRIPTION (provided by applicant): The long-term goal of this project is to use nanoparticles containing a therapeutic radionuclide to treat metastatic ovarian cancer and to translate the research findings from animal models to ovarian cancer in humans. The overall hypothesis of the proposed work is that a stable isotope contained within tumor-targeted nanoparticles can be activated to a radioisotope by a neutron-capture process. The resulting radiotherapeutic nanoparticles can be subsequently administered intraperitoneally to deliver efficacious absorbed radiation doses to metastatic ovarian tumors. This is expected to improve therapeutic responses while lowering toxicity. The proposed radiotherapeutic nanoparticles will be produced by the neutron activation of stable Holmium atoms (165Ho) that are contained with the matrix of mesoporous silica nanoparticles (MSNs), a durable carrier that withstand long neutron-irradiation times. The radionuclide produced by neutron irradiation of these nanoparticles, 166Ho, decays by the emission of high-energy beta particles that have a radiation tissue diffusion range capable of delivering absorbed radiation doses to the tumors sufficient to result in their death. Furthermore, the surface of these MSNs will be functionalized with folate, a targeting ligand for ovarian tumors. Making the MSNs radioactive after they have been prepared provides maximum safety for the medical staff and patients, and allows compliance with current Good Manufacturing Practices (cGMP) and detailed characterization of the stable nanoparticles prior to irradiation. Preliminary studies demonstrated predominant tumor accumulation of non-targeted 166Ho-MSNs and significant improvement in survival in ovarian tumor- bearing mice. The current project is focused on the delivery of targeted-radiotherapeutic nanoparticles after intraperitoneal administration to metastatic ovarian tumors and the core of tumor tissues. The specific aims are to optimize targeting ligands associated with the MSNs and to assess the penetration of nanoparticles in tumors. We hypothesize that targeted 166Ho-MSNs will avidly bind to the surface of the tumors due to their specific affinity, and that the radiation will promote the penetration of the 166Ho-MSNs deep within the tumor by inducing apoptosis of the surface tumor. In vitro cell models will be employed to confirm the targeting effect and surface interaction between MSNs and tumor cells. The results will be supported by measurements of targeted nanoparticle accumulation and penetration into tumors in animals and human tumor tissues. These measurements will be used for dosimetry calculations for determination of optimal doses of 166Ho-MSNs. The data generated by this work will bridge the gaps in translating the results of animal studies to humans. This approach also offers flexibility in the design of treatment regimens. By paying attention to these clinicall relevant factors as well as to manufacturing and validation processes, these innovations will make it easier for this targeted radionuclide therapy to reach the clinical investigation stage and more rapidly translate this work into clinical practice.