Injectable Implants for Increased Tumor Treatment Volume Using Pressure Driven Diffusion

 描述（由申请人提供）：肝癌发病率在美国和世界范围内呈上升趋势。由于大多数肝脏恶性肿瘤患者不适合进行侵入性手术切除，因此对替代疗法的需求很大。局部、微创、图像引导的方法，如肿瘤消融术，在与有效的化疗相结合时，为肝癌患者提供了有希望的结果。不幸的是，大多数化疗方案与高全身毒性相关，因此当需要微创方法时不是理想的策略。在这些情况下，局部可注射药物递送系统提供了全身治疗的替代方案，因为它们可以在图像引导下施用，并且可以将释放的药物的大部分直接集中在肿瘤侧，避免全身副作用。因此，我们研究的总体目标是开发一种有效的局部超声引导平台药物递送系统，用于治疗实体瘤，可以通过利用现有的介入放射学技术进行管理，监测和控制。在这个较大的项目范围内，关键因素之一是开发将携带药物的适当基础基质。这种基质需要是生物相容的和可注射的，并且还能够在延长的时间内携带大量的药物。此外，从递送系统释放的药物需要克服大多数可植入化疗系统所面临的有限穿透距离问题。因此，拟议项目的目标是设计和评价符合上述设计标准的新型注射给药系统。所提出的系统将包含一种独特的聚合物，通过使用可逆的高亲和力分子相互作用，可将阿霉素的释放速率延长至临床治疗速率。该聚合物还能够使用压力驱动药物扩散的独特概念来增强药物渗透到肿瘤组织中。最小侵入性、治疗释放速率和增加的扩散的协同组合应导致在肿瘤治疗中显著更有效的系统。这项工作将在 三个目标。首先，将合成和表征这些基于亲和性的聚合物的可注射制剂。然后，这些聚合物将进行评估和优化的压力诱导的阿霉素释放在一个新的体外组织模仿体模。最后，在最后一个目标中，将在原位野生型大鼠HCC模型中对前两个目标中开发的最佳植入物制剂（在最高穿透距离下具有有效浓度）进行体内测试。基于所获得的数据设计的可注射局部给药制剂将更有效地治疗肝脏肿瘤，并可能成为原发性肝细胞癌以及转移引起的继发性肝癌微创治疗转变的驱动力。

 DESCRIPTION (provided by applicant): Liver cancer incidence is on the rise in the United States and worldwide. Since the majority of patients with hepatic malignancies are not candidates for invasive surgical resection, there is a strong demand for alternative therapies. Local, minimally invasive, image-guided approaches such as tumor ablation offer promising outcomes for liver cancer patients, when combined with effective chemotherapy. Unfortunately most chemotherapeutic regimens are associated with high systemic toxicities and thus are not the ideal strategy when a minimally invasive approach is desired. Local, injectable drug delivery systems offer an alternative to systemic therapy in these cases, since they can be administered under image guidance, and can focus the bulk of released drug directly at the tumor side avoiding systemic side effects. Accordingly, the overarching goal of our research is to develop an effective local, ultrasound-guided platform drug delivery system for treatment of solid tumors that can be administered, monitored, and controlled by utilizing existing interventional radiology techniques. Within the scope of this larger project, one of the crucial elements is development of the appropriate base matrix that will carry the drug. This matrix needs to be biocompatible and injectable and yet be able to carry a high amount of drug for an extended time. In addition, the drug released from the delivery system needs to overcome the limited penetration distance problem faced by most implantable chemotherapy systems. The goal of the proposed project is thus to engineer and evaluate a new injectable delivery system that meet the above design criteria. The proposed system will incorporate a unique polymer shown to prolong the release rate of doxorubicin to clinically therapeutic rates, through use of reversible, high-affinity molecular interactions. The polymer is also capable of enhancing drug penetration into tumor tissue using a unique concept of pressure-driven drug diffusion. The synergistic combination of minimal invasiveness, therapeutic release rates, and increased diffusion should result in a system that is significantly more effective in treatment of tumors. The work will be carried out in three aims. First an injectable formulation of these affinity-based polymers will be synthesized and characterized. These polymers will then be evaluated and optimized for pressure-induced doxorubicin release in a novel in vitro tissue mimicking phantom. Finally, in this last aim, the optimal implant formulation, developed in the first two aims with the effective concentration at the highest penetration distance, will be tested in vivo in an orthotopic wildtype rat model of HCC. The injectable local drug delivery formulations designed based on the acquired data will be more effective in treatment of liver tumors and could be the driving force behind a shift in minimally invasive management of primary hepatocellular carcinomas as well as secondary liver cancers resulting from metastasis.