Upadhyay Urvashi M, Tyler Betty, Patta Yoda, Wicks Robert, Spencer Kevin, Scott Alexander, Masi Byron, Hwang Lee, Grossman Rachel, Cima Michael, Brem Henry, Langer Robert
Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA 02115;
Department of Neurosurgery, Johns Hopkins University Hospital, Baltimore, MD 21231;
Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16071-6. doi: 10.1073/pnas.1313420110. Epub 2014 Oct 27.
Metastases represent the most common brain tumors in adults. Surgical resection alone results in 45% recurrence and is usually accompanied by radiation and chemotherapy. Adequate chemotherapy delivery to the CNS is hindered by the blood-brain barrier. Efforts at delivering chemotherapy locally to gliomas have shown modest increases in survival, likely limited by the infiltrative nature of the tumor. Temozolomide (TMZ) is first-line treatment for gliomas and recurrent brain metastases. Doxorubicin (DOX) is used in treating many types of breast cancer, although its use is limited by severe cardiac toxicity. Intracranially implanted DOX and TMZ microcapsules are compared with systemic administration of the same treatments in a rodent model of breast adenocarcinoma brain metastases. Outcomes were animal survival, quantified drug exposure, and distribution of cleaved caspase 3. Intracranial delivery of TMZ and systemic DOX administration prolong survival more than intracranial DOX or systemic TMZ. Intracranial TMZ generates the more robust induction of apoptotic pathways. We postulate that these differences may be explained by distribution profiles of each drug when administered intracranially: TMZ displays a broader distribution profile than DOX. These microcapsule devices provide a safe, reliable vehicle for intracranial chemotherapy delivery and have the capacity to be efficacious and superior to systemic delivery of chemotherapy. Future work should include strategies to improve the distribution profile. These findings also have broader implications in localized drug delivery to all tissue, because the efficacy of a drug will always be limited by its ability to diffuse into surrounding tissue past its delivery source.
转移瘤是成人中最常见的脑肿瘤。仅手术切除会导致45%的复发率，且通常还需辅以放疗和化疗。血脑屏障阻碍了化疗药物充分输送至中枢神经系统。局部向胶质瘤递送化疗药物的研究显示生存期略有延长，可能受肿瘤浸润性本质的限制。替莫唑胺（TMZ）是胶质瘤和复发性脑转移瘤的一线治疗药物。阿霉素（DOX）用于治疗多种类型的乳腺癌，但其使用受到严重心脏毒性的限制。在乳腺腺癌脑转移的啮齿动物模型中，将颅内植入的DOX和TMZ微胶囊与相同治疗的全身给药进行比较。观察指标为动物生存期、定量药物暴露以及裂解的半胱天冬酶3的分布。颅内递送TMZ和全身给予DOX比颅内给予DOX或全身给予TMZ更能延长生存期。颅内给予TMZ能更有力地诱导凋亡途径。我们推测这些差异可能由每种药物颅内给药时的分布情况来解释：TMZ的分布范围比DOX更广。这些微胶囊装置为颅内化疗药物递送提供了一种安全、可靠的载体，并且有能力比化疗药物的全身递送更有效且更具优势。未来的工作应包括改善分布情况的策略。这些发现对于向所有组织进行局部药物递送也具有更广泛的意义，因为药物的疗效总是会受到其扩散到递送源周围组织能力的限制。
