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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：
10675073
负责人：
Kristy M Ainslie
金额：
$ 34.3万
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/10675073
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-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 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 Predisposition Primary Brain Neoplasms Property Radiation Radiation therapy Recurrence Recurrent tumor 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 biodegradable polymer bioluminescence imaging blood-brain barrier crossing brain tissue cancer cell cancer invasiveness cancer therapy chemotherapeutic agent chemotherapy controlled release cytotoxic drug release kinetics fabrication 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 cancer therapy 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) 的侵袭性是这种原发性脑肿瘤导致近 100% 致死率的部分原因死亡。即使进行手术切除、放疗和化疗，中位生存期仍仅为 12-15 几个月。肿瘤侵犯使得手术难以完全切除，导致2年内局部复发 90-95%的患者的原始肿瘤缩小到厘米。大多数全身递送的化疗药物是对 GBM 无效，因为它们无法以治疗浓度到达大脑，因为血液脑屏障。血脑屏障是一种高度选择性的半透膜，可将脑细胞与脑细胞分开。从脑组织循环血液作为一种保护机制。血脑屏障内的毛细血管具有特别限制性的紧密连接，可显着减少全身给药的渗透对脑组织进行化疗。一种避免血脑屏障并减少剂量的有前途的策略通过全身给药观察到的限制毒性是将药物直接植入大脑 GBM切除后留下的空腔内。实现这一目标的一种方法是将药物装载到可生物降解的聚合物中当聚合物降解时，它可以控制药物的暂时释放。 Gliadel®，一种可生物降解的将卡莫司汀输送到切除腔内的聚合物晶片是此类疗法的临床示例，并将患者的生存期延长 10-18 周。然而，在最近的研究的推动下，更有效的药物的使用癌症基因分型的进步可以大大提高间质治疗的成功率。这可能会导致个性化化疗选择，可以根据患者的情况联合使用一种或多种药物肿瘤特异性基因突变。此外，我们的初步数据表明，药物的释放速率聚合物可以极大地影响结果。药物释放速率可以通过聚合物降解速率来控制：以及聚合物内药物的配方。我们假设更有效的化疗药物被加载到为最佳药物释放速率量身定制的生物可降解聚合物将产生一个可以转化的平台到诊所改进 GBM 治疗。