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Delivery of chemotherapeutics to brain tumors

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Technology: Brain cancer is a life-threatening disease with a poor prognosis. This includes Glioblastoma Multiform (GBM), which has a standard treatment of surgical resection, radiation therapy and concurrent chemotherapy with temozolomide (TMZ). The median survival is 14 months because surgeons are unable to completely remove GBM, radiation does not completely eradicate the tumor tissue and TMZ dosing is limited by toxicity. At standard of care doses, hematologic toxicity of administered TMZ is dose limiting, implying that an increased intratumoral concentration of TMZ could be beneficial to treat GBM. MUSC has developed TMZ-loaded PEG-PE and PHC micelles as a novel treatment for GBM. The TMZ-loaded micelle is designed to increase permeation across the BBB and is conjugated to a novel moiety targeting the PDGF receptor on GBM tumors. A biocompatible coating reduces cytotoxicity and improves circulation, and a pH dependent triggered carrier releases TMZ at the site of the tumor. Data gathered suggests that the targeted micelles (PMTMZ) increase efficiency of cell killing at lower concentrations of TMZ compared to untargeted TMZ (MTMZ) and free TMZ. PMTMZ also has superior tumor accumulation compared to MTMZ in brain tumors (white dashed circle) in vivo, imaged by comparing 680 nm flourescence after the micelles were functionalized with a 680 nm flurophore.Overview: Brain cancer is a life-threatening disease with a 5-year survival rate of 33% (2005-2011), results in more than 15 thousand deaths annually and has an annual incidence of 7.27 per 100,000 people, accounting for 2% of all cancers and 21.1% of pediatric cancers. GBM occurs in 2-3 people per 100,000, with a dismal prognosis and median survival of 14 months. The standard of care therapy includes TMZ, a prodrug that is converted by pH changes in the cytoplasm of cells. This drug has been used for decades, but is unable to cure patients.  Applications: Brain cancer, Glioblastoma multiform (GBM) cancerAdvantages:  Lower toxicity, targeting GBM tumor, BBB permeation, pH dependent release, accumulation of payload at tumor siteKey Words: Cancer treatment, Brain tumor, Glioblastoma, glioma, BBB permeation, Micelle, drug delivery, temozolomide, TMZ, Imidazotetrazine, prodrug, nanoparticle, nanocarrier Publication: Miller et al. “Delivery of a drug cache to glioma cells overexpressing platelet-derived growth factor receptor using lipid nanocarriers” (2016), Nanomedicine 11:6, 581-95. Inventors: Ann-Marie Broome, Suraj Dixit, Amy-Lee BredlauPatent Status: CT application filed 2/23/18                     MUSC-FRD Technology ID: P1714

*Abstract

None

*Principal Investigation

Name: Ann-marie Broome, Associate Professor

Department: Radiology

Name: Suraj Dixit, Postdoctoral Fellow

Department: Radiology - Biomedical Imaging

Name: Amy-lee Bredlau, Assistant Professor

Department: Pediatrics

国家/地区

美国