Drug eluting injectable biomaterials for next generation chemoembolization

摘要 肝细胞癌（HCC）是最常见的肝癌类型，是世界范围内的主要公共卫生问题 这是一个令人担忧的问题，因为它通常在治疗选择有限的晚期被发现。根据 世界卫生组织，每年有约750，000例新发HCC病例，导致700，000例死亡 国际吧虽然在历史上全身化疗一直是癌症治疗的基石，但无法治疗癌症。 实现均匀的药物递送至肿瘤、对非癌性肝脏的副作用和全身副作用 在肝癌新疗法的开发方面进展有限。最近，小说 免疫抑制剂（免疫检查点抑制剂（ICI）、CAR-T细胞、溶瘤病毒）已经被 开发，但由于全身副作用和难以输送到固体，其使用仍然存在局限性 肿瘤的虽然经导管动脉化疗栓塞术（TACE）是一种使用X射线进行的手术， 引导导管将与栓塞珠偶联的化疗递送到灌注血管的血管中。 肝肿瘤在肝癌治疗中已显示出成功，但栓塞效率相对较低， 珠不能容易地递送到下游微脉管系统中以实现均匀的局部缺血 化疗药物在这里，我们提出了一种变革性的技术，使用基于导管的局部区域 输送X射线可见生物工程生物材料的方法，即下一代TACE，以诱导更多的 肿瘤微血管系统内的有效缺血性细胞死亡与有效的化疗和 免疫疗法递送。我们的目标是将联合收割机TACE与化疗和免疫治疗（如ICI）相结合， 以增强抗肿瘤免疫应答。维持甚至增强了 化疗后诱导的反应可能会通过局部化疗辅助改善肿瘤消退。 ICI递送。为了实现这一目标，我们将多柔比星（DOX）和ICI（α-PD 1，α-PDL 1，α-CTLA-4）混合， 可注射剪切稀化水凝胶（STH）以增强肿瘤消融。我们假设STH，一种半固体 由明胶和纳米硅酸盐组成的凝胶状栓塞材料， 血管内栓塞达到比当前TACE珠小50微米的血管。 同时，DOX/ICI递送将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输送STH的能力， 药物可控地从STH，以及在体外和兔肝癌模型。在目标1中，我们将优化STH 用于有效血管内化疗栓塞的组合物。在目标2中，我们将开发新的药物洗脱 STH（DESTH）用于血管内免疫化疗栓塞。在目标3中，我们将评估体内性能 的沙漠。

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.