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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.

摘要