Optimized ultrasound-enhanced immunotherapy

 描述（由申请人提供）：我们开发了温度敏感的纳米颗粒，其中药物在中性pH值下被隔离在晶体中，并被封装在具有低熔点的脂质壳中。在温度介导的释放之后，晶体溶解在肿瘤或溶酶体中。通过将这些颗粒与超声相结合，大部分药物被递送到肿瘤中而没有全身毒性，并且我们正在以现有药物不可能实现的方案实现局部疾病的完全反应。将这种治疗与免疫佐剂结合，我们观察到强大的全身抗肿瘤反应。我们在这里专注于开发用于实际临床前研究的图像引导递送技术，并应用该技术优化温度敏感颗粒，超声和免疫佐剂的组合。在该应用中，结合了图像引导以控制或评估声照射区域（实时超声成像）、达到的温度（实时超声测温）和释放的药物（治疗完成后的MRI成像）。在初步数据中，我们证明了在存在导致组织压缩的面内和面外运动和应变的情况下，能够以5 Hz的帧速率创建准确且可重复的温度图，并具有高信噪比。通过这种方法：1）药物不需要通过增强的渗透性和保留效应累积;相反，它在肿瘤脉管系统中释放; 2）取决于释放区域的大小和活化时间，累积可以是典型的癌症纳米治疗剂的100倍或更多; 3）释放的药物被快速内化; 4）药物在血管空间中的释放瞬时增强血管渗透性，促进额外药物、血浆和一些红细胞的释放; 5）重复应用该技术导致具有增强的抗肿瘤M1表型的巨噬细胞浸润; 6）该技术与免疫佐剂有效结合，产生非常强的全身抗癌作用。为了转化为有效的疗法，我们需要使用精心控制的条件来优化多个组件。现在需要集成的成像和治疗系统，因为必须估计温度并且利用集成的控制回路来控制超声（如在MR引导的聚焦US（MRgFUS）中所做的）。这样的系统将最大化帧速率，因为治疗和成像光束不能同时发射，并且集成系统将最大化组合的帧速率。我们将把这项技术应用于乳腺癌和膀胱癌的系统性三模态（药物，超声和免疫治疗）研究。我们的具体目标是：创建多频率成像/治疗阵列，优化超声测温，以在包括组织运动的现实场景中提供实时反馈，并评估超声引导药物输送到有和没有免疫佐剂的啮齿动物模型。在这里组装的团队是唯一有资格开发图像引导治疗，包括PI（超声成像和治疗），道格拉斯斯蒂芬斯（超声换能器），Imasonics，拉尔夫德维尔白色（UCD癌症中心主任）和威廉墨菲（癌症免疫学家）。

 DESCRIPTION (provided by applicant): We have developed temperature-sensitive nanoparticles in which a drug is sequestered in a crystal at neutral pH and encapsulated in a lipid shell with a low melting point. After temperature-mediated release, the crystal is dissolved in a tumor or lysosome. By combining these particles with ultrasound, a large fraction of drug is delivered into tumors without systemic toxicity and we are achieving a complete response in local disease in a protocol that is not possible with existing agents. Combining this treatment with an immune adjuvant, we observe a powerful systemic anti-tumor response. We focus here on developing the image-guided delivery technology for practical pre-clinical studies and applying this technology to optimize the combination of temperature sensitive particles, ultrasound and immune adjuvants. Within this application, image-guidance is incorporated to control or assess the region of insonation (real-time ultrasound imaging), the temperature achieved (real-time ultrasound thermometry), and the drug released (MRI imaging after the completion of treatment). In preliminary data, we demonstrate the ability to create accurate and repeatable temperature maps at a 5 Hz frame rate with a high signal to noise ratio in the presence of in plane and out of plane motion and strain that results in tissue compression. With this approach: 1) the drug does not need to accumulate via the enhanced permeability and retention effect; instead it is released in the tumor vasculature; 2) depending on the size of the region of release and the time of activation, accumulation can be 100 fold or more greater than typical cancer nanotherapeutics; 3) the released drug is rapidly internalized; 4) the release of the drug in the vascular space transiently enhances vascular permeability facilitating the release of additional drug, plasma and some red blood cells; 5) repeated application of this technique results in infiltration of macrophages with an enhanced anti-tumor M1 phenotype; 6) the technique is effectively combined with immune adjuvants to create a very strong systemic anti-cancer effect. In order to translate an effective therapy, we need to optimize the multiple components using carefully-controlled conditions. An integrated imaging and therapy system is now required in that temperature must be estimated and ultrasound controlled with an integrated control loop (as is done in MR-guided focused US (MRgFUS)). Such a system will maximize the frame rate since the therapeutic and imaging beams cannot be simultaneously fired and the integrated system will maximize the combined frame rate. We will apply this technology in the systematic tri-modality (drug, ultrasound, and immunotherapy) studies of breast and bladder cancer. Our specific aims are to: create a multi-frequency imaging/therapy array, optimize ultrasound thermometry for real-time feedback in a realistic scenario that includes tissue motion and evaluate ultrasound-guided drug delivery to rodent models with and without an immune adjuvant. The team assembled here is uniquely qualified to develop image-guided therapy, including the PI (ultrasound imaging and therapy), Douglas Stephens (ultrasound transducers), Imasonics, Ralph De Vere White (UCD Cancer Center Director) and William Murphy (cancer immunologist).