Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, United States.
Biomaterials. 2011 Apr;32(10):2532-9. doi: 10.1016/j.biomaterials.2010.12.020. Epub 2011 Jan 8.
Controlled-release drug delivery systems are capable of treating debilitating diseases, including cancer. Brain cancer, in particular glioblastoma multiforme (GBM), is an extremely invasive cancer with a dismal prognosis. The use of drugs capable of crossing the blood-brain barrier has shown modest prolongation in patient survival, but not without unsatisfactory systemic, dose-limiting toxicity. Among the reasons for this improvement include a better understanding of the challenges of delivery of effective agents directly to the brain tumor site. The combination of carmustine delivered by biodegradable polyanhydride wafers (Gliadel(®)), with the systemic alkylating agent, temozolomide, allows much higher effective doses of the drug while minimizing the systemic toxicity. We have previously shown that locally delivering these two drugs leads to further improvement in survival in experimental models. We postulated that microcapsule devices capable of releasing temozolomide would increase the therapeutic capability of this approach. A biocompatible drug delivery microcapsule device for the intracranial delivery of temozolomide is described. Drug release profiles from these microcapsules can be modulated based on the physical chemistry of the drug and the dimensions of the release orifices in these devices. The drug released from the microcapsules in these experiments was the clinically utilized chemotherapeutic agent, temozolomide. In vitro studies were performed in order to test the function, reliability, and drug release kinetics of the devices. The efficacy of the temozolomide-filled microcapsules was tested in an intracranial experimental rodent gliosarcoma model. Immunohistochemical analysis of tissue for evidence of DNA strand breaks via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed. The experimental release curves showed mass flow rates of 36 μg/h for single-orifice devices and an 88 μg/h mass flow rate for multiple-orifice devices loaded with temozolomide. In vivo efficacy results showed that localized intracranial delivery of temozolomide from microcapsule devices was capable of prolonging animal survival and may offer a novel form of treatment for brain tumors.
控释药物递送系统能够治疗多种衰弱性疾病，包括癌症。脑癌，特别是多形性胶质母细胞瘤（GBM），是一种极具侵袭性的癌症，预后极差。使用能够穿过血脑屏障的药物已显示出对患者生存时间的适度延长，但仍存在不理想的全身、剂量限制毒性。造成这种改善的原因之一是更好地理解了将有效药物直接递送到脑肿瘤部位的挑战。组合使用生物可降解聚酸酐片（Gliadel®）递送卡莫司汀和全身烷化剂替莫唑胺，可以在将药物全身毒性降至最低的同时，提高药物的有效剂量。我们之前已经表明，在实验模型中局部递送这两种药物可进一步提高生存率。我们假设能够释放替莫唑胺的微胶囊装置可以提高这种方法的治疗效果。本文描述了一种用于颅内递送替莫唑胺的生物相容性药物递送微胶囊装置。可以根据药物的物理化学性质和这些装置中释放孔的尺寸来调节这些微胶囊的药物释放曲线。这些实验中从微胶囊中释放的药物是临床使用的化疗药物替莫唑胺。进行了体外研究以测试设备的功能、可靠性和药物释放动力学。在颅内实验性啮齿动物神经胶质瘤肉瘤模型中测试了填充有替莫唑胺的微胶囊的疗效。通过末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）测定法进行了组织中 DNA 链断裂的免疫组织化学分析。实验释放曲线显示，单孔装置的质量流速为 36μg/h，多孔装置的质量流速为 88μg/h，这些装置装载了替莫唑胺。体内疗效结果表明，从微胶囊装置局部颅内递送电替莫唑胺能够延长动物的生存时间，并可能为脑肿瘤提供一种新的治疗形式。
