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性脑肿瘤导致近100%死亡的部分原因。 mortality.即使采用手术切除、放疗和化疗，中位生存率仍只有12-15 个月肿瘤浸润使完全手术切除困难，导致局部复发， 在90-95%的患者中，原始肿瘤的直径为30厘米。大多数全身递送的化疗剂是 对GBM无效，因为它们不能以治疗浓度到达大脑， 脑屏障血脑屏障是一种高度选择性的半渗透膜， 从脑组织循环血液作为保护机制。排列在血脑屏障上的毛细血管 具有特别限制性的紧密连接， 化疗药物对脑组织的影响一个有希望的策略，以避免血脑屏障和减少剂量- 全身给药观察到的有限毒性是通过植入药物直接将其施用到脑中 在GBM切除后留下的空腔内。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暂时释放。Gliadel®，一种可生物降解 将卡莫司汀递送到切除腔中的聚合物薄片，是这种类型治疗的临床实例， 并使患者存活时间延长10-18周。然而，最近的研究促进了更有效药物的使用， 癌症基因分型的进展，可以大大提高间质治疗的成功率。这可能导致 个性化化疗选择，其中一种或多种药物可以基于患者的 肿瘤特异性基因突变。此外，我们的初步数据表明，药物从 聚合物可以极大地影响结果。药物释放速率可以通过聚合物降解速率来控制， 以及药物在聚合物内的制剂。我们假设，更有效的化疗加载到 为最佳药物释放速率定制的可生物降解聚合物将产生一个平台， 来改善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.