Intraperitoneal Delivery of Targeted Nanoparticles for Metastatic Ovarian Cancer

描述（由申请人提供）：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，并将动物模型的研究结果转化为人类卵巢癌。这项工作的总体假设是，肿瘤靶向纳米颗粒中含有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。所得的放射性纳米颗粒可以随后腹膜内施用以将有效吸收的放射剂量递送至转移性卵巢肿瘤。这有望改善治疗反应，同时降低毒性。所提出的放射性纳米颗粒将通过稳定的钬原子（165 Ho）的中子活化来产生，这些钬原子包含在介孔二氧化硅纳米颗粒（MSNs）的基质中，MSNs是一种耐用的载体，可以承受长时间的中子照射。这些纳米粒子的中子辐照产生的放射性核素166 Ho通过发射高能β粒子而衰变，所述高能β粒子具有能够将吸收的辐射剂量递送到肿瘤足以导致其死亡的辐射组织扩散范围。此外，这些MSN的表面将用叶酸（卵巢肿瘤的靶向配体）功能化。在制备后使MSN具有放射性为医务人员和患者提供了最大的安全性，并允许符合当前的良好生产规范（cGMP）和在辐照前对稳定的纳米颗粒进行详细表征。初步研究证明了非靶向166 Ho-MSN的主要肿瘤积累和携带卵巢肿瘤的小鼠的存活率的显著改善。目前的项目集中在腹膜内给药后转移性卵巢肿瘤和肿瘤组织的核心靶向放射性纳米颗粒的递送。具体目标是优化与MSN相关的靶向配体，并评估纳米颗粒在肿瘤中的渗透。我们假设靶向的166 Ho-MSN由于其特异性亲和力而与肿瘤表面强烈结合，并且辐射将通过诱导表面肿瘤的凋亡来促进166 Ho-MSN在肿瘤深处的渗透。将采用体外细胞模型来证实MSN与肿瘤细胞之间的靶向作用和表面相互作用。这些结果将得到靶向纳米颗粒积聚和渗透到动物和人肿瘤组织中的测量结果的支持。这些测量结果将用于确定166 Ho-MSN最佳剂量的剂量学计算。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治疗更容易进入临床研究阶段， 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.