Injectable Implants for Increased Tumor Treatment Volume Using Pressure Driven Diffusion

利用压力驱动扩散增加肿瘤治疗量的注射植入物

基本信息

批准号：
9130018
负责人：
Christopher Hernandez
金额：
$ 3.28万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2017-12-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9130018
关键词：
Accounting Address Advanced Development Adverse effects Affinity Alternative Therapies Area Beryllium Binding Biocompatible Cancer Etiology Cancer Patient Cell Death Characteristics Complex Cyclodextrins Data Development Diffusion Doxorubicin Drug Carriers Drug Controls Drug Delivery Systems Drug Implants Drug Kinetics Drug Regulations Engineering Environment Evaluation Excision Formulation Glycolic-Lactic Acid Polyester Goals Hepatic Hybrids Implant In Situ In Vitro Incidence Injectable Injection of therapeutic agent Interventional radiology Intravenous Left Liver Liver neoplasms Malignant Neoplasms Malignant neoplasm of liver Measures Mediating Metastatic Neoplasm to the Liver Modeling Molecular Weight Monitor Nature Neoplasm Metastasis Nodule Normal tissue morphology Operative Surgical Procedures Outcome Palliative Care Patients Penetration Perfusion Permeability Pharmaceutical Preparations Phase Polymers Population Precipitation Primary carcinoma of the liver cells Procedures Property Rattus Regimen Research Side Solid Solid Neoplasm Spatial Distribution Staging Swelling System Systemic Therapy Techniques Technology Testing Therapeutic Time Tissues Translations Tumor Tissue Ultrasonography United States Unresectable Water Work aqueous base biodegradable polymer chemotherapeutic agent chemotherapy clinical practice clinically relevant crosslink curative treatments design driving force drug distribution effective therapy fluorescence imaging image guided improved in vivo insight local drug delivery meetings minimally invasive mortality novel patient population polyacrylamide polyacrylamide hydrogels pressure public health relevance response systemic toxicity tissue phantom treatment strategy tumor tumor ablation uptake

项目摘要

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.

描述（由适用提供）：肝癌事件在美国和全球范围内正在增加。由于大多数肝脏恶性肿瘤的患者不是侵入性手术切除的候选者，因此对替代疗法的需求很大。与有效的化学疗法结合使用时，局部，微创，图像引导的方法（例如肿瘤消融）为肝癌患者提供了预期。不幸的是，大多数化学治疗方案都与高系统性毒性相关，因此当需要一种微创方法时，这并不是理想的策略。在这些情况下，局部可注射的药物输送系统可以替代全身治疗，因为它们可以根据图像指导进行管理，并且可以直接将大部分释放药物聚焦在肿瘤侧，以避免全身副作用。根据上述研究，我们研究的总体目标是开发一种有效的局部超声引导的平台药物输送系统，用于治疗可以通过使用现有的介入放射学技术来管理，监测和控制的实体瘤。在这个较大的项目范围内，关键要素之一是开发适合携带该药物的基本基质。该基质需要具有生物相容性和可注射量，但可以长时间携带大量药物。此外，从输送系统中释放的药物需要克服大多数可植入的化学疗法系统所面临的有限的穿透距离问题。因此，该项目的目标是设计和评估符合上述设计标准的新型可注射式输送系统。提出的系统将通过使用可逆的高亲和力分子相互作用来融合一种独特的聚合物，以延长阿霉素的释放速率到临床治疗率。该聚合物还能够使用压力驱动的药物差异概念来增强药物渗透到肿瘤组织中。最小侵入性，治疗释放率和扩散增加的协同组合应导致一个在治疗肿瘤治疗的系统。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注射公式。然后，将评估这些聚合物并在模仿幻影的新型体外组织中评估并优化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最佳植入式配方在最高穿透距离处有效浓度，将在HCC的原位野生型大鼠模型中在体内进行测试。基于获得的数据设计的可注射局部药物输送公式将在治疗肝肿瘤方面更有效，并且可能是对原发性肝细胞癌的最小侵入性管理以及由转移导致的二级肝癌的驱动力。