Drug eluting injectable biomaterials for next generation chemoembolization

摘要 肝细胞癌是最常见的一种肝癌，是世界范围内的主要公共卫生问题 令人担忧的是，它通常在治疗选择有限的晚期被发现。根据 世界卫生组织，每年新增约75万例肝细胞癌病例，导致70万人死亡 全世界。虽然从历史上看，全身化疗一直是癌症治疗的基石，但无法 实现对肿瘤的均匀给药、对非癌肝脏的副作用和全身副作用 在开发治疗肝癌的新疗法方面进展有限。最近，小说 免疫治疗药物(免疫检查点抑制物(ICI)、CAR-T细胞、溶瘤病毒) 已开发，但由于系统性副作用和难以传递到Solid，它们的使用仍然受到限制 肿瘤。尽管经导管动脉化疗栓塞术(TACE)，一种使用X射线进行的程序 引导导管将化疗与栓塞珠耦合输送到血管中，这些血管灌流 肝肿瘤在肝癌治疗中已显示出成功，但由于肝肿瘤的栓塞效率较低 珠子不容易被输送到下游的微血管系统，以实现均匀的缺血和 化疗快递。在这里，我们提出了一种变革性的技术，它使用基于导管的局部定位 提供X射线可见生物工程材料的方法，即下一代TACE，以诱导更多 肿瘤微血管内有效的缺血细胞死亡与有效的化疗和 提供免疫治疗服务。我们的目标是将TACE与化疗和免疫治疗(例如ICIS)相结合 以增强抗肿瘤免疫反应。维持甚至增强炎性 化疗后的反应可能会在局部治疗的帮助下改善肿瘤的消退 ICI快递。为了实现这一目标，我们将把阿霉素(DOX)和/ICI(α-PD1，α-PDL1，α-CTLA-4)混合在一个 可注射剪切稀释水凝胶(STH)，以加强肿瘤消融。我们假设STH，一种半固体 由明胶和纳米硅酸盐组成的胶状栓塞剂将达到更有效的治疗效果。 血管内栓塞术可以到达比目前的TACE微珠小到50微米的血管。 同时，DOX/ICI传递将被用于局部消融肝癌细胞。我们的初步数据 展示了令人兴奋的结果，显示了我们使用导管合成和传递STH的能力，以释放 来自STH的可控药物，以及体外和兔肝癌模型。在目标1中，我们将优化STH 有效血管内化疗栓塞术的组合物。在目标2中，我们将开发新型药物洗脱 血管内免疫化疗栓塞术。在目标3中，我们将评估体内性能 是DESTH的。

Abstract Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a major worldwide public health concern because it is often detected at advanced stages where treatment options are limited. According to the World Health Organization, each year there are ~750,000 new HCC cases resulting in 700,000 deaths worldwide. While historically systemic chemotherapy has been the cornerstone to cancer treatment, inability to achieve uniform drug delivery to tumors, collateral toxicity to the non-cancerous liver and systemic side-effects have limited progress in the development of novel therapies for liver cancer. Recently, novel immunotherapeutic agents (immune checkpoint inhibitors (ICI), CAR-T cells, oncolytic virus) have been developed, but there are still limitations to their use due to systemic side effects and difficulty to deliver to solid tumors. Although transcatheter arterial chemoembolization (TACE), a procedure performed using an X-ray guided catheter to deliver chemotherapy coupled to embolization beads into the blood vessels that perfuse the liver tumor has shown success in liver cancer management, the embolization efficiency is relatively low as the beads cannot be readily delivered into downstream microvasculature to achieve uniform ischemia and chemotherapy delivery. Here we propose a transformative technology that uses a catheter-based locoregional approach to deliver X-ray visible bioengineered biomaterial, i.e. next-generation TACE, to induce a more efficient ischemic cell death within the tumor microvasculature coupled with efficient chemo- and immunotherapy delivery. We aim to combine TACE with both chemo- and immuno-therapeutics (e.g. ICIs) in order to enhance the anti-tumor immune response. Maintaining and even enhancing the inflammatory response induced after chemotherapy may potentially yield improved tumor regression assisted by localized ICI delivery. To achieve this goal we will mix doxorubicin (DOX) and / ICI (α-PD1, α-PDL1, α-CTLA-4) within an injectable shear-thinning hydrogel (STH) to enhance tumor ablation. We hypothesize that STH, a semi-solid gel like embolic material, which is composed of gelatin and nanosilicate, will achieve more efficient endovascular embolization reaching vessels as small as 50 microns than the current TACE beads. Simultaneously, DOX/ICI delivery will be used to locally ablate the liver cancer cells. Our preliminary data demonstrates exciting results showing our ability to synthesize and deliver STHs using catheters, to release drugs controllably from STHs, as well as in vitro and rabbit liver cancer models. In Aim 1, we will optimize STH compositions for effective endovascular chemoembolization. In Aim 2, we will develop the novel drug-eluting STH (DESTH) for endovascular Immuno-chemoembolization. In Aim 3 we will evaluate the in vivo performance of the DESTH.