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

多形性胶质母细胞瘤（GBM）是最具侵袭性的脑肿瘤，复发率> 90%， 中位生存期< 15个月。由于GBM复发大多发生在距离原始病灶约2厘米的范围内 局部扩散治疗应该是非常有效的，可以显著延长中位生存期。 目前，卡莫司汀（双-氯乙基-亚硝基脲- BCNU）载药盘（Gliadel®） 递送，植入肿瘤切除后产生的空腔中。然而，也有一些限制，包括 有效释放期短（约5-7天），由于僵硬， 不可延展的聚合物盘形。该提案的长期目标是开发改进的方法， 用于治疗GBM的受控的局部药物递送。本申请的目的是调查使用 复杂的多层纤维膜作为药物输送的最佳载体。中央 基于成功的初步动物试验数据（存活期>150天），这项资助的假设是， 通过同轴静电纺丝形成的芯-鞘纤维可以提供上级药物释放曲线 控制初始释放和延长的长期药物递送。芯-鞘纤维结构还提供了 由于其由两种或更多种单独组分组成，其本身具有多种药物释放。多层 多孔膜盘和袋可提供药物分子的设计（“程序化”）释放， 鸡尾酒疗法 本课题主要包括三个具体目标：（1）制备具有不同结构的芯鞘型纤维膜 聚合物主体具有最佳的机械强度、柔韧性、生物相容性和结合能力， 特定的药物分子将平面（薄的、大面积的）膜转换成3-D制剂（圆盘和 袋）用于外科植入。(2)研究平面膜、圆盘的药物释放机制 和小袋，以便实现可编程的长期（数月）药物输送。详细调查 从多层芯-鞘纤维膜盘的受控双重药物释放。序贯释药 最近使用TMZ或BCNU和acriflavine（ACF）通过包埋ACF掺入的 TMZ或BCNU掺入膜内的圆盘。目前的抗癌药物（BCNU， TMZ，紫杉醇）和潜在的新候选药物（ACF，双硫仑）将进行研究，以获得最 用于局部鸡尾酒化疗协同组合。(3)证明（a）改善的抑制 体外癌细胞生长和（B）使用建立的体内动物模型延长的存活率。这 一项研究提出了复杂的多层纤维的创新用途，用于控制释放合并的 用于治疗GBM的药物分子。该项目有可能提供重大改善 通过开发一种新的药物输送材料系统， 生物可利用的，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.