Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, USA.
Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, USA.
J Control Release. 2020 Jul 10;323:282-292. doi: 10.1016/j.jconrel.2020.04.028. Epub 2020 Apr 23.
Glioblastoma (GBM) is a highly aggressive and heterogeneous form of brain cancer. Genotypic and phenotypic heterogeneity drives drug resistance and tumor recurrence. Combination chemotherapy could overcome drug resistance; however, GBM's location behind the blood-brain barrier severely limits chemotherapeutic options. Interstitial therapy, delivery of chemotherapy locally to the tumor site, via a biodegradable polymer implant can overcome the blood-brain barrier and increase the range of drugs available for therapy. Ideal drug candidates for interstitial therapy are those that are potent against GBM and work in combination with both standard-of-care therapy and new precision medicine targets. Herein we evaluated paclitaxel for interstitial therapy, investigating the effect of combination with both temozolomide, a clinical standard-of-care chemotherapy for GBM, and everolimus, a mammalian target of rapamycin (mTOR) inhibitor that modulates aberrant signaling present in >80% of GBM patients. Tested against a panel of GBM cell lines in vitro, paclitaxel was found to be effective at nanomolar concentrations, complement therapy with temozolomide, and synergize strongly with everolimus. The strong synergism seen with paclitaxel and everolimus was then explored in vivo. Paclitaxel and everolimus were separately formulated into fibrous scaffolds composed of acetalated dextran, a biodegradable polymer with tunable degradation rates, for implantation in the brain. Acetalated dextran degradation rates were tailored to attain matching release kinetics (~3% per day) of both paclitaxel and everolimus to maintain a fixed combination ratio of the two drugs. Combination interstitial therapy of both paclitaxel and everolimus significantly reduced GBM growth and improved progression free survival in two clinically relevant orthotopic models of GBM resection and recurrence. This work illustrates the advantages of synchronized interstitial therapy of paclitaxel and everolimus for post-surgical tumor control of GBM.
胶质母细胞瘤（GBM）是一种高度侵袭性和异质性的脑癌。基因型和表型的异质性导致了药物耐药和肿瘤复发。联合化疗可以克服药物耐药性；然而，GBM 位于血脑屏障后面，严重限制了化疗选择。间质治疗，通过可生物降解聚合物植入物将化疗药物局部递送到肿瘤部位，可以克服血脑屏障并增加可用于治疗的药物范围。间质治疗的理想药物候选物是那些对 GBM 有效的药物，并与标准治疗和新的精准医学靶点联合使用。在此，我们评估了紫杉醇用于间质治疗，研究了与替莫唑胺（GBM 的临床标准治疗化疗药物）和依维莫司（一种调节存在于 >80%GBM 患者中的异常信号的哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂）联合使用的效果。在体外对一组 GBM 细胞系进行测试，发现紫杉醇在纳摩尔浓度下有效，与替莫唑胺互补治疗，并与依维莫司强烈协同。然后在体内探索了紫杉醇和依维莫司之间的强烈协同作用。紫杉醇和依维莫司分别被制成由乙酰化葡聚糖组成的纤维支架，乙酰化葡聚糖是一种具有可调节降解率的可生物降解聚合物，用于植入大脑。乙酰化葡聚糖的降解率被调整为实现紫杉醇和依维莫司的释放动力学匹配（每天约 3%），以保持两种药物的固定组合比例。紫杉醇和依维莫司的联合间质治疗显著减少了 GBM 的生长，并改善了两种临床相关的 GBM 切除和复发的无进展生存期。这项工作说明了紫杉醇和依维莫司同步间质治疗在 GBM 手术后肿瘤控制中的优势。
