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Title: Developing a novel strategy to treat glioblastoma : improving brain bioavailability of sorafenib with a synthetic flavonoid dimer to inhibit drug efflux in blood brain barrier
Authors: Hu, Xuesen
Degree: Ph.D.
Issue Date: 2018
Abstract: Glioblastoma (GBM) is the most common form of brain cancer with a short median survival time (around 15 months). Chemotherapy is limited to temozolomide (TMZ) and resistance occurs frequently in GBM patients. There is an urgent need to develop new chemotherapeutic agents for GBM. Sorafenib, a potent multi-kinase inhibitor (TKI), being used clinically as an anti-cancer drug for hepatocarcinoma or renal cell carcinoma patients, was more potent than TMZ in killing U87MG (glioblastoma cell line) in vitro. Phase I/II clinical trials of sorafenib, however, failed to demonstrate any therapeutic effect on GBM. One possible explanation is that blood brain barrier (BBB) keep sorafenib out of the brain. The two ATP-binding cassette (ABC) transporters expressed at the BBB, P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (ABCG2), might prevent the accumulation of sorafenib in the brain by active efflux. Here, a novel dual inhibitor of P-gp and BCRP (flavonoid dimer Ac12Az9, FD 12-9) shows extraordinary inhibitory effect on both P-gp and BCRP in in vitro assay with an EC50 of 285 nM and 0.9 nM, respectively. Using canine MDCKII-P-gp and MDCKII-GFP-BCRP cell lines to mimic the trans-epithelial efflux in the BBB, it was demonstrated that FD 12-9 can inhibit the efflux of sorafenib. Pharmacokinetic studies indicate that FD 12-9 is able to increase the accumulation level of sorafenib in the brain by more than 9-fold. Pharmacokinetic profiles of sorafenib in the brain and plasma with or without co-administered FD 12-9 were studied. No toxicity response was found in in vivo toxicity studies when 10 mg/kg of sorafenib and 10 mg/kg of FD 12-9 were co-administered at the same time. In vivo efficacy studies demonstrated that the increased brain concentration of sorafenib, after co-administration with FD 12-9, is high enough to significantly reduce the tumor size of the U87MG-RedFluc orthotopic xenograft glioblastoma model in immunocompromised mice. In addition, a TMZ-relapse model of GBM was developed by a single round of TMZ treatment in Balb/c nu nu mice. TMZ was ineffective in reducing the tumor volume in the relapse stage (34 days after initial treatment), even though the initial treatment stage seems to be completely effective. In contrast, sorafenib in combination with FD 12-9 was highly effective, suggesting that sorafenib, in combination with FD 12-9, can be used in both initial treatment as well as relapse (and TMZ-resistant) case of GBM. In summary, we have discovered a new approach to potentially treat glioblastoma by using a combination of FD 12-9 and sorafenib.
Subjects: Hong Kong Polytechnic University -- Dissertations
Glioblastoma multiforme
Brain -- Cancer
Pages: xvi, 137 pages : color illustrations
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