Tunable Temporal Drug Release for Optimized Synergistic Combination Therapy of Glioblastoma

摘要 胶质母细胞瘤(GBM)的侵袭性是这种原发脑瘤导致近100% 死亡率。即使经过手术切除、放射治疗和化疗，中位存活率也只有12-15 月份。肿瘤的侵袭使手术难以完全切除，导致局部复发 90-95%的患者肿瘤原发部位为厘米。大多数系统输送的化疗药物是 对GBM无效，因为它们不能在治疗浓度下到达大脑，因为血液- 大脑屏障。血脑屏障是一种高度选择性和半渗透性的膜，将 从脑组织循环血液作为一种保护机制。排列在血脑屏障上的毛细血管 有特别严格的紧密连接，显著减少系统管理的渗透 化疗药物对脑组织的影响。一种有希望的策略，可以避开血脑屏障，减少剂量- 限制全身给药的毒性是通过植入药物直接给药到大脑 在基底膜切除后留下的空洞内。实现这一目标的一种方法是将药物装载到可生物降解的聚合物中 这允许在聚合物降解时控制药物的时间释放。可生物降解的Garia del® 将卡莫司汀输送到切除腔中的聚合物晶片是这种类型治疗的临床例子， 并使患者存活时间延长10-18周。然而，使用更有效的药物，在最近的推动下 肿瘤基因分型的进展，可以极大地提高间质治疗的成功率。这可能会导致 个性化化疗选择，可根据患者的情况联合使用一种或多种药物 肿瘤特有的基因突变。此外，我们的初步数据表明，药物从 这种聚合物会极大地影响结果。药物释放速度可以通过聚合物降解速度来控制，如 以及聚合物内药物的配方。我们假设更有效的化疗药物 为最佳药物释放速率量身定做的可生物降解聚合物将产生一个可翻译的平台 到临床，以改进GBM治疗。

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.