Injectable Implants for Increased Tumor Treatment Volume Using Pressure Driven Diffusion

 描述(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，如果与有效的化疗相结合，对肝癌患者来说是有希望的结果。不幸的是，大多数化疗方案都与高全身毒性有关，因此当需要微创方法时，不是理想的策略。在这些病例中，局部注射给药系统提供了系统治疗的替代方案，因为它们可以在图像指导下给药，并且可以将大部分释放的药物直接集中在肿瘤侧，避免全身副作用。因此，我们研究的首要目标是开发一种有效的局部超声引导平台给药系统，用于实体肿瘤的治疗，该系统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。在这个更大的项目范围内，关键因素之一是开发将携带该药物的适当碱基基质。这种基质需要是生物相容的和可注射的，但又能够在较长时间内携带大量药物。此外，从输送系统释放的药物需要克服大多数植入型化疗系统面临的有限渗透距离的问题。因此，拟议项目的目标是设计和评估一种符合上述设计标准的新的可注射输送系统。建议的系统将结合一种独特的聚合物，通过使用可逆的、高亲和力的分子相互作用，将阿霉素的释放速率延长到临床治疗率。该聚合物还能够利用压力驱动的药物扩散的独特概念来增强药物对肿瘤组织的渗透。最小侵袭性、治疗性释放率和扩散增加的协同组合应该会导致一个在治疗肿瘤方面明显更有效的系统。这项工作将在 三个目标。首先，将合成和表征这些基于亲和力的聚合物的可注射配方。然后，这些聚合物将在一种新型的体外组织模拟体模中进行评估和优化，以用于压力诱导的阿霉素释放。最后，在最后一个目标中，在前两个目标中开发的具有最高穿透距离的有效浓度的最佳植入配方将在原位野生型肝癌大鼠模型中进行体内测试。根据获得的数据设计的可注射局部给药配方将在治疗肝肿瘤方面更有效，并可能成为推动原发肝细胞癌和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.