A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats.
A thermal gel depot for local delivery of paclitaxel to treat experimental brain tumors in rats.
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DOI：
10.3171/2009.11.jns08162
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发表时间：
2010-08
影响因子：
4.1
通讯作者：
B. Tyler;K. Fowers;Khan W. Li;V. Recinos;J. Caplan;Alia M. Hdeib;R. Grossman;L. Basaldella;K. Bekelis;G. Pradilla;F. Legnani;H. Brem
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文献类型：
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作者：
B. Tyler;K. Fowers;Khan W. Li;V. Recinos;J. Caplan;Alia M. Hdeib;R. Grossman;L. Basaldella;K. Bekelis;G. Pradilla;F. Legnani;H. Brem
紫杉醇是一种细胞增殖抑制剂/辐射增敏剂，虽然在体外对胶质瘤有效，但在全身给药时具有较差的中枢神经系统穿透性和剂量限制性毒性。OncoGel （Re-Gel中的紫杉醇）在进入中枢神经系统时提供可控的局部紫杉醇释放。作者评价了OncoGel在颅内9L胶质瘤大鼠中的安全性和有效性。方法：安全性研究包括颅内给药增加含有1.5 （OncoGel 1.5）或6.3 (OncoGel 6.3) mg/ml紫杉醇的ReGel和OncoGel的体积。在18只fisher -344大鼠中进行了体内放射性标记生物分布研究，以确定脑内分布。疗效研究比较了对照组、仅ReGel、仅放射治疗、OncoGel 6.3或OncoGel 6.3联合放射治疗的总生存率。ReGel和OncoGel 6.3与肿瘤植入同时（第0天）或5天后（第5天）给药。第5天给予放射治疗。结果对照组和ReGel动物均在17 d内肿瘤死亡。与对照组相比，OncoGel 6.3组在第0天（中位31天，p = 0.0001）、OncoGel 6.3组在第5天（中位17天，p = 0.02）和仅放射治疗组（中位26天，p = 0.0001）的生存率均显著提高。同时接受OncoGel和放疗的动物的中位生存期最长：放疗联合OncoGel 6.3组第0天为83天，联合OncoGel 6.3组第5天为32天（p = 0.0001 vs对照组）。120天后，OncoGel第0天组37.5%的动物存活，OncoGel第6.3天联合放疗组37.5%的动物存活，OncoGel第6.3天联合放疗组12.5%的动物存活。在生物分布研究中，注射OncoGel后3周，整个同侧半球都观察到可测量的放射性，注射后3小时检测到的放射性最高。对侧半球观察到的最高放射性剂量是在第3天的时间点。结论含有6.3 mg/ml紫杉醇的OncoGel用于大鼠颅内注射是安全的，第0天给药有效。当与放疗联合使用时，联合治疗比单独使用任何一种治疗更有效，值得临床研究用于恶性胶质瘤的治疗。
OBJECT Paclitaxel, a cellular proliferation inhibitor/radiation sensitizer, while effective against gliomas in vitro, has poor CNS penetration and dose-limiting toxicities when administered systemically. OncoGel (paclitaxel in Re-Gel) provides controlled local paclitaxel release when placed into the CNS. The authors evaluated the safety and efficacy of OncoGel in rats with intracranial 9L gliosarcoma. METHODS Safety studies included intracranial delivery of increasing volumes of ReGel and OncoGel containing 1.5 (OncoGel 1.5) or 6.3 (OncoGel 6.3) mg/ml paclitaxel. An in vivo radiolabeled biodistribution study was performed in 18 Fischer-344 rats to determine intracerebral distribution. Efficacy studies compared overall survival for controls, ReGel only, radiation therapy only, OncoGel 6.3, or OncoGel 6.3 in combination with radiation therapy. ReGel and OncoGel 6.3 were delivered either simultaneously with tumor implantation (Day 0) or 5 days later (Day 5). Radiation therapy was given on Day 5. RESULTS Control and ReGel animals died of tumor within 17 days. Survival significantly increased in the Onco-Gel 6.3 group on Day 0 (median 31 days; p = 0.0001), in the OncoGel 6.3 group on Day 5 (median 17 days; p = 0.02), and in the radiation therapy-only group (median 26 days; p = 0.0001) compared with controls. Animals receiving both OncoGel and radiation therapy had the longest median survival: 83 days in the group with radiation therapy combined with OncoGel 6.3 on Day 0, and 32 days in the group combined with OncoGel 6.3 on Day 5 (p = 0.0001 vs controls). After 120 days, 37.5% of the animals in the OncoGel Day 0 group, 37.5% of animals in the OncoGel 6.3 Day 0 in combination with radiation therapy group, and 12.5% of the animals in the OncoGel 6.3 on Day 5 in combination with radiation therapy group were alive. In the biodistribution study, measurable radioactivity was observed throughout the ipsilateral hemisphere up to 3 weeks after the OncoGel injection, with the most radioactivity detected 3 hours after injection. The highest dose of radioactivity observed in the contralateral hemisphere was at the Day 3 time point. CONCLUSIONS OncoGel containing 6.3 mg/ml of paclitaxel is safe for intracranial injection in rats and effective when administered on Day 0. When combined with radiation therapy, the combination was more effective than either therapy alone and should be studied clinically for the treatment of malignant glioma.