Image-guided radiation-induced permeability (IGRIP) for IGDD

 描述（由申请人提供）：虽然通过增强的渗透性和保留（EPR）效应将药物被动递送至转移性肿瘤具有明确的临床意义，但对肿瘤相对于正常组织的选择性不令人满意，特别是对于基因治疗。实现图像引导药物递送（IGDD）将是减少脱靶效应的有价值的策略。在这里，我们打算利用图像引导放射（IGRT）作为一种手段，以靶向非病毒基因治疗载体的肿瘤。值得注意的是，图像引导放射治疗已经在治疗发生远处转移性疾病的前列腺癌患者中发挥了既定作用。这里，磁共振（MR）和/或计算机断层扫描（CT）成像用于允许精确瞄准转移的辐射，允许向肿瘤递送消融剂量，同时对周围正常组织引起最小的损伤。重要的是，IGRT中使用的辐射剂量不仅可以杀死癌细胞，还可以改变肿瘤微环境，导致肿瘤血管通透性增加。我们使用MR肿瘤成像、X-RAD 225 Cx图像引导小动物放射设备中的机载CT图像融合以及治疗计划对小鼠转移性前列腺癌的IGRT进行建模，以向肿瘤提供精确照射。我们的研究揭示了受照射肿瘤的血管通透性增加，并证明了大分子成像剂的快速积累和长期保留，我们将这种效应命名为图像引导辐射诱导通透性（IGRIP）。我们利用IGRIP通过将纳米颗粒靶向肿瘤来实现图像引导药物递送的新方法。在这里，我们将进一步研究和优化IGRIP作为IGDD的工具，并将这种方法应用于肿瘤靶向的基因治疗。我们将开发一类新的非病毒载体纳米颗粒核酸载体，其在循环中保持稳定并通过IGRIP有效递送。作为一个模型的翻译，我们将评估IGRIP的图像引导传递基因导向酶前药治疗，并评估这作为一种策略，以加强辐射的影响。然后，为了翻译个性化的图像引导基因治疗，我们将评估IGRIP作为一种工具，用于提供RNAi敲除和CRISPR核酸酶敲除靶向癌基因和DNA修复因子。我们希望能够实现一种新的方法，其中使用放射来驱动基因治疗转移灶，作为通过实现持久的局部和全身控制来改善治疗结果的途径。

 DESCRIPTION (provided by applicant): While passive delivery of drugs to metastatic tumors via the enhanced permeability and retention (EPR) effect has clear clinical significance, the selectivity for tumor versus normal tissue is unsatisfactory, particularly for gene therapies. Enabling image-guided drug delivery (IGDD) would be a valuable strategy to decrease off target effects. Here, we intend to leverage image-guided radiation (IGRT) as a means to target non-viral gene therapy vectors to tumors. Significantly, image-guided radiotherapy already has an established role in treating prostate cancer patients who have developed distant metastatic disease. Here, magnetic resonance (MR) and/or computed tomography (CT) imaging is used to allow precise aiming of radiation to the metastasis, allowing delivery of ablative doses to the tumor while inducing minimal damage to surrounding normal tissue. Importantly, the radiation doses used in IGRT not only kill cancer cells but also alter the tumor microenvironment, leading to increased permeability of tumor blood vessels. We have modeled IGRT of metastatic prostate cancer in mice using MR tumor imaging, image fusion with the on-board CT in the X-RAD 225Cx image-guided small animal radiation device, and treatment planning to deliver precision irradiation to the tumor. Our studies reveal increased vascular permeability in the irradiated tumors, and demonstrate both rapid accumulation and long-term retention of macromolecular imaging agents, an effect that we have named image-guided radiation-induced permeability (IGRIP). We have leveraged IGRIP to enable a novel approach to image-guided drug delivery by targeting nanoparticles to tumors. Here, we will further study and optimize IGRIP as a tool for IGDD and apply this approach to enable tumor-targeted delivery of gene therapy. We will develop a new class of non-viral vector nanoparticle nucleic acid carriers that remain stable in circulation and are delivered efficiently by IGRIP. As a model for translation, we will evaluate IGRIP for image-guided delivery of gene-directed enzyme-prodrug therapy and evaluate this as a strategy to potentiate the effects of radiation. Then, toward translation of personalized image-guided gene therapy, we will evaluate IGRIP as a tool to deliver RNAi for knock-downs and CRISPR nuclease for knock outs targeting oncogenes and DNA repair factors. We hope to enable a new approach wherein radiation is used to drive gene therapy into metastases as a route to improving treatment outcomes by achieving durable local and systemic control.