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Principal Investigator: Kristy M Ainslie
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $332,114
Funding agency: National Cancer Institute
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.
Terms: <14-Hydroxydaunomycin><2-Propanol><APO2 Ligand><Abbreviations><Abscission><Adriamycine><Affect><Anzatax><Apo-2 Ligand><Area><Area Under Curve><Asotax><Athymic Mice><Athymic Nude Mouse><BBB crossing><BCNU><Bis-Chloronitrosourea><Blood><Blood - brain barrier anatomy><Blood Reticuloendothelial System><Blood capillaries><Blood-Brain Barrier><Brain><Brain Cancer><Brain Nervous System><Bristaxol><Cancer Treatment><Cancers><Carmustine><Cell Membrane Permeability><Cerebrospinal Fluid><Cessation of life><Chemotherapy Protocol><Chemotherapy Regimen><Chemotherapy-Oncologic Procedure><Clinic><Clinical><Combination Chemotherapy Regimen><Combined Modality Therapy><Contralateral><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Death><Dextrans><Dose><Dose Limiting><Doxorubicin><Doxorubicina><Drug Combinations><Drug Delivery><Drug Delivery Systems><Drug Formulations><Drug Kinetics><Drug usage><Drugs><Encephalon><Excision><Extirpation><FIVB><GEM model><GEMM model><Genetic><Genetic Alteration><Genetic Change><Genetic Engineering><Genetic Engineering Biotechnology><Genetic Engineering Molecular Biology><Genetic defect><Genetic mutation><Genetically Engineered Mouse><Genotype><Gliadel><Glioblastoma><Glycolates><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Hemato-Encephalic Barrier><Heterograft><Heterologous Transplantation><Histopathology><Hydrophobicity><Hydroxyl Daunorubicin><Hydroxyldaunorubicin><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Implant><In Vitro><Individual><Intrasurgical Resection Cavity><Intravenous><Isopropanol><Isopropyl Alcohol><Kinetics><Leanness><Left><Location><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Brain><Malignant neoplasm of brain><Maximal Tolerated Dose><Maximally Tolerated Dose><Maximum Tolerated Dose><Medication><Mice><Mice Mammals><Modeling><Molecular Target><Morphology><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutation><Nature><Nude Mice><Occluding Junctions><Operative Procedures><Operative Surgical Procedures><Outcome><Paclitaxel><Paclitaxel (Taxol)><Pathologic><Patients><Penetration><Pharmaceutical Preparations><Pharmacokinetics><Polyesters><Polymers><Praxel><Predisposition><Primary Brain Neoplasms><Primary Brain Tumors><Property><Quimioterapia><Radiation><Radiation therapy><Radiotherapeutics><Radiotherapy><Recombinant DNA Technology><Recurrence><Recurrent><Recurrent Neoplasm><Recurrent tumor><Removal><Resection Cavity><Residual Cancers><Resistance><Role><Rubbing Alcohol><SDZ RAD><Sequence Alteration><Solubility><Surface><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Surgically-Created Cystic Resection Cavity><Surgically-Created Resection Cavity><Susceptibility><TNF-Related Apoptosis Inducing Ligand TRAIL><TNF-related apoptosis-inducing ligand><TNFSF10 Protein><TRAIL Protein><Taxol><Taxol A><Taxol Konzentrat><Temodal><Temodar><Therapeutic><Thinness><Tight Junctions><Time><Toxic effect><Toxicities><Translating><Tumor Cell Invasion><Tumor Invasion><Tumor Necrosis Factor Ligand Superfamily Member 10><Tumor Tissue><Xenograft><Xenograft procedure><Xenotransplantation><Zonula Occludens><anti-cancer research><anti-cancer therapy><biodegradable polymer><bioluminescence imaging><bioluminescent imaging><bioresorbable polymer><bis chloroethylnitrosourea><blood-brain barrier crossing><bloodbrain barrier><bloodbrain barrier crossing><brain implant><brain tissue><cancer cell><cancer chemotherapy><cancer invasiveness><cancer research><cancer therapy><cancer-directed therapy><capillary><cerebral spinal fluid><chemotherapeutic agent><chemotherapy><combination therapy><combined modality treatment><combined treatment><controlled release><cytotoxic><degradable polymer><dextran><drug release kinetics><drug release rate><drug use><drug/agent><everolimus><fabrication><flexibility><flexible><genetically engineered><genetically engineered mouse model><genetically engineered murine model><genome mutation><genomic alteration><glioblastoma multiforme><glycolic acid><improved><in vivo><indexing><individualized cancer care><individualized oncology><interstitial><mTOR Inhibitor><malignancy><membrane permeability><methazolastone><mortality><mouse model><multi-modal therapy><multi-modal treatment><murine model><nanofiber><nanofibrous><neoplasm recurrence><neoplasm/cancer><neural implant><novel><personalized oncology><poly(lactic acid)><polycaprolactone><polylactic acid><polymer><polymeric><precision cancer care><precision cancer medicine><precision oncology><radiation treatment><rate of change><resection><resistant><scaffold><scaffolding><social role><spinal fluid><spongioblastoma multiforme><standard of care><success><surgery><targeted cancer therapy><temozolomide><treatment with radiation><tumor><tumor growth><xeno-transplant><xeno-transplantation>