Controlled Release of Multiple Drugs from Electrospun Fiber Membranes in the Local Treatment of Glioblastoma

摘要多形性胶质母细胞瘤是最具侵袭性的脑肿瘤，复发率高达90%。 中位生存期(15个月)。因为基底膜复发大多发生在原发灶周围约2厘米内 局部扩散治疗对于显著延长中位生存期应该是非常有效的。 目前，卡莫司汀(双-氯乙基-亚硝脲-BCNU)载药盘(格列德尔®)提供当地药物 输送，植入肿瘤切除后形成的空腔内。然而，也有一些限制，包括 有效缓解期短(~5-7天)且因僵硬而与切除腔不相符， 不可延展的聚合物圆盘形式。这项提案的长期目标是开发改进的方法，以 用于治疗GBM的受控、局部给药。此应用程序的目标是调查使用 将复杂的多层纤维膜作为药物输送的最佳载体。中环 这笔赠款的假设是，基于成功的初步动物试验数据(存活150天)， 由同轴电纺形成的芯鞘纤维可以提供优异的药物释放轮廓 受控的初始释放和延长的长期给药。核心-鞘光纤结构还借出了 由于其由两个或多个单独的成分组成，其本身可能导致多次药物释放。多层 多孔膜片和袋可以提供药物分子的有计划的(编程的)释放 “鸡尾酒”疗法。 该项目包括三个具体的目标：(1)制备不同种类的芯鞘纤维膜 具有最佳机械强度、灵活性、生物兼容性和结合能力的聚合物宿主 特定的药物分子。将平面(薄的、大面积的)膜转换为3D配方(圆盘和 袋)用于外科植入。(2)研究药物从平面膜、圆盘中的释放机理 和袋，以实现可编程的长期(数月)给药。详细调查 从多层芯-鞘纤维膜片中控制双药物释放。序贯释药 最近证实使用TMZ或BCNU和阿克拉黄素(ACF)通过包埋ACF- TMZ或BCNU结合膜内的圆盘。当前抗癌药物的组合(BCNU， TMZ，紫杉醇)和潜在的新药候选(ACF，双硫仑)将被调查，以获得最多 协同联合用于局部鸡尾酒化疗。(3)证明(A)改进了对 (B)利用已建立的体内动物模型延长存活率。这 研究建议创新地使用复杂的多层纤维来控制释放 治疗基底膜的药物分子。该项目有可能带来显著的改善 通过开发一种新的给药系统来改善GBM患者的预后 生物可利用，生物相容的形式。

Glioblastoma multiforme (GBM) is the most aggressive brain tumor with > 90 % recurrence rate and short median survival time (< 15 months). Because GBM recurrence mostly occurs within ~2 cm of the original lesion, a locally diffusing treatment should be very effective to significantly extend median survival. Currently, carmustine (bis-chloroethyl-nitrosourea - BCNU) loaded discs (Gliadel®) provide local drug delivery, implanted into the cavity created after tumor resection. However, there are limitations including a short effective release period (~5-7 days) and non-conformity to the resection cavity due to stiff, unmalleable polymeric disc form. The long-term goal of this proposal is to develop improved methods for controlled, local drug delivery for treating GBM. The objective of this application is to investigate the use of complex, multi-layered fiber membranes as an optimized vehicle for drug delivery. The central hypothesis of this grant, based on successful preliminary animal trial data (with >150-day survival), is that core-sheath fibers formed by coaxial electrospinning can provide a superior drug release profile with controlled initial release and extended long term drug delivery. The core-sheath fiber construct also lends itself to multiple drug release due to its composition of two or more individual components. Multi-layered porous membrane discs and pouches can provide designed (“programmed”) release of drug molecules for “cocktail” therapy. The project consists of three specific aims: (1) Fabricate core-sheath fiber membranes with various polymer hosts for optimum mechanical strength, flexibility, biocompatibility, and ability to incorporate specific drug molecules. Transform planar (thin, large area) membranes into 3-D formulations (discs and pouches) for surgical implantation. (2) Investigate drug release mechanisms from planar membranes, discs and pouches in order to realize programmable long-term (months) drug delivery. Investigate in detail controlled dual drug release from multi-layered core-sheath fiber membrane discs. Sequential drug release was recently demonstrated using TMZ or BCNU and acriflavine (ACF) by embedding ACF-incorporated discs within TMZ or BCNU-incorporated membranes. Combinations of current anti-cancer drugs (BCNU, TMZ, paclitaxel) and potential new drug candidates (ACF, disulfiram) will be investigated to obtain the most synergistic combination for localized cocktail chemotherapy. (3) Demonstrate (a) improved inhibition of cancer cell growth in vitro and (b) extended survival rate using established in vivo animal models. This study proposes the innovative use of complex multi-layered fibers for controlled release of incorporated drug molecules for the treatment of GBM. The project has the potential to provide significant improvement in the outcome of patients with GBM by developing a novel material system for drug delivery in a bioavailable, biocompatible form.