Tunable Temporal Drug Release for Optimized Synergistic Combination Therapy of Glioblastoma

可调节的时间药物释放，用于优化胶质母细胞瘤的协同联合治疗

基本信息

批准号：
10449370
负责人：
Kristy M Ainslie
金额：
$ 34.91万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10449370
关键词：
Abbreviations Affect Area Area Under Curve Blood Blood - brain barrier anatomy Blood capillaries Brain Carmustine Cell Membrane Permeability Cerebrospinal Fluid Cessation of life Chemotherapy and/or radiation Chemotherapy-Oncologic Procedure Clinic Clinical Combined Modality Therapy Contralateral DNA Sequence Alteration Data Dextrans Dose Dose-Limiting Doxorubicin Drug Combinations Drug Delivery Systems Drug Formulations Drug Kinetics Drug usage Excision Genetic Genetic Engineering Genetically Engineered Mouse Genotype Gliadel Glioblastoma Glycolates Histopathology Hydrophobicity Immunohistochemistry Implant In Vitro Individual Intravenous Isopropanol Kinetics Lead Left Location Malignant Neoplasms Malignant neoplasm of brain Maximum Tolerated Dose Modeling Molecular Target Morphology Mus Mutation Nature Nude Mice Operative Surgical Procedures Outcome Paclitaxel Pathologic Patients Penetration Pharmaceutical Preparations Polyesters Polymers Primary Brain Neoplasms Property Radiation Recurrence Residual Cancers Resistance Role SDZ RAD Solubility Surface Surgically-Created Resection Cavity TNF-related apoptosis-inducing ligand Therapeutic Thinness Tight Junctions Time Toxic effect Translating Tumor Cell Invasion Tumor Tissue Xenograft procedure anticancer research base biodegradable polymer bioluminescence imaging blood treatment brain tissue cancer cell cancer invasiveness cancer therapy chemotherapeutic agent chemotherapy controlled release cytotoxic drug release kinetics flexibility improved in vivo indexing interstitial mTOR Inhibitor mortality mouse model nanofiber neural implant novel poly(lactic acid)polycaprolactone precision oncology rate of change scaffold standard of care success targeted treatment temozolomide tumor tumor growth

项目摘要

ABSTRACT Glioblastoma’s (GBM) invasive nature is part of the reason this primary brain tumor results in near 100% mortality. Even with surgical resection, radiation, and chemotherapy, the median survival remains of only 12-15 months. Tumor invasion make complete surgical resection difficult leading to local recurrence within 2 centimeters of the original tumor in 90-95% of patients. Most systemically delivered chemotherapy agents are ineffective against GBM because they cannot reach the brain at therapeutic concentrations due to the blood- brain barrier. The blood-brain barrier is a highly selective and semi-permeable membrane that separates the circulating blood from the brain tissues as a protective mechanism. The capillaries that line the blood brain barrier have especially restrictive tight-junctions that significantly reduce permeation of systemically administered chemotherapeutics to brain tissues. A promising strategy to avoid the blood-brain barrier and reduce dose- limiting toxicities observed with systemic delivery is to administer drugs directly to the brain by implanting them within the cavity left after GBM resection. One way to achieve this it to load drug into a biodegradable polymer which allows for controlled temporal release of drug as the polymer degrades. Gliadel®, a biodegradable polymeric wafer that delivers carmustine into the resection cavity, is a clinical example of this type of therapy, and increased patient survival by 10-18 weeks. However, the use of more efficacious drugs, facilitated by recent advancement in cancer genotyping, could greatly improve the success of interstitial therapy. This could lead to personalized chemotherapeutic selection where one or more drugs can be co-administered based on a patient’s tumor-specific genetic mutations. In addition, our preliminary data suggests that the release rate of drugs from the polymer can greatly affect outcomes. Drug release rate can be controlled via polymer degradation rate as well as formulation of the drug within the polymer. We hypothesize that more potent chemotherapies loaded into biodegradable polymers tailored for optimal drug release rate would generate a platform that could be translated to the clinics to improved GBM therapy.

抽象的胶质母细胞瘤（GBM）侵入性性质是这种原发性脑肿瘤的一部分，导致接近100％死亡。即使进行手术切除，放射线和化学疗法，中位生存期仍然仅为12-15 月份。肿瘤侵袭使完整的手术切除难以在2中导致局部复发 90-95％的患者的原始肿瘤的厘米。大多数系统地递送的化学疗法剂是对GBM无效，因为由于血液而无法以治疗浓度到达大脑脑屏障。血脑屏障是一种高度选择性和半渗透的膜，可分开从脑组织中循环血液作为保护机制。排在血脑屏障的毛细血管具有特别限制性的紧密连接，可显着减少系统管理的渗透化学疗法对脑组织。避免血脑屏障并减少剂量的有前途的策略 - 通过全身性传递观察到的限制毒性是通过植入将药物直接施用给大脑在GBM切除后剩下的腔内。实现这一目标的一种方法，将药物加载到可生物降解的聚合物中 Gliadel®，可生物降解将carmustine输送到切除腔中的聚合物晶片是这种类型疗法的临床例子，并增加患者的生存率10-18周。但是，使用更有效的药物，由最近制备癌症基因分型的进步可以大大改善间质治疗的成功。这可能会导致个性化的化学治疗选择，其中一种或多种药物可以根据患者的共同管理肿瘤特异性遗传突变。此外，我们的初步数据表明，药物的释放率聚合物会极大地影响结果。药物释放率可以通过聚合物降解率来控制以及在聚合物中制定药物。我们假设将更多的潜在化学疗法加载到适合最佳药物释放率的可生物降解聚合物将产生一个可以翻译的平台前往诊所改善GBM治疗。