Synthetic, implantable polymers for IUdR radiosensitization of experimental human malignant glioma.
Synthetic, implantable polymers for IUdR radiosensitization of experimental human malignant glioma.
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用于实验性人类恶性神经胶质瘤的 IUdR 放射增敏的合成植入式聚合物。
DOI：
10.1089/cbr.1999.14.187
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Williams,JA
中科院分区：
文献类型：
--
作者：
Yuan,X;Dillehay,LE;Williams,JR;Williams,JA
背景近年来，聚合物控制给药被证明能提高恶性胶质瘤患者的存活率。我们测试了IUdR通过聚合物传递对实验性脑内恶性胶质瘤的放射增敏作用。为了评估疗效，我们测定了实验性人U251胶质母细胞瘤移植瘤的体外释放、体内释放和由此产生的放射增敏作用。方法：体外测定IUdR的释放，增加(10%，30%，50%)比例的合成[(聚双(对羧基苯氧基)丙烷)：癸酸(SA)聚合物圆盘在缓冲盐水中连续孵育，并测定其上清液组分。在体内：为了比较局部和全身给药，荷瘤小鼠侧翼移植的IUdR聚合物(50%负载)处理。荷瘤小鼠(I.C.)异种移植物有I.C.对比侧翼IUdR聚合物治疗。植入聚合物后4天或8天处死小鼠，用免疫组织化学方法检测IUdR标记的肿瘤细胞百分率。为了比较放射增敏，携带I.C.的小鼠。异种移植物有I.C.结果：在体外，随着IUdR载量的增加，10%、30%和50%的IUdR聚合物释放率分别为43.7±0.1、70.0±0.2和90.2±0.2(p<；0.001 ANOVA)。在体内：对于侧翼肿瘤，同侧和对侧IUdR聚合物对时间的标记百分率相似。对于同侧IUdR聚合物，4天后肿瘤细胞标记百分比为45.8±7.0，8天后为40.6±3.9(p=NS)。对侧聚合物种植体植入后4天和8天肿瘤细胞标记百分率分别为43.9±10.1和35.9±5.2(p=NS)。对国际刑事法院来说。经颅外IUdR聚合物治疗后，肿瘤细胞标记率较低，分别为13.9±8.8和11.2±5.7。对国际刑事法院来说。有IC的肿瘤。而IUdR聚合物的标记百分率相对较高：第4天和第8天分别为34.3±4.9和35.3±4.0。对国际刑事法院来说。放射增敏：对于荷瘤的小鼠和接受侧脑IUdR聚合物治疗的小鼠，接受外束照射后的存活率显著高于接受颅内治疗的小鼠：49±8.9天比80±4.1天(p=0.03)。结论可植入的生物可降解聚合物提供了IUdR的局部可控释放，并导致了IUdR对实验性脑内恶性胶质瘤的高水平局部传递。局部递送和标记可提高放射治疗后的存活率。这项技术有望将IUdR用于人脑肿瘤的放射增敏。
BackgroundRecently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We tested the delivery of IUdR via polymers for radiosensitization of experimental intracranial human malignant glioma. To assess efficacy, we measured the in vitro release, the in vivo delivery of IUdR and the resultant radiosensitization of experimental human U251 glioblastoma xenografts.MethodsIn vitro:To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(pcarboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed.In vivo:To compare local vs. systemic delivery, mice bearing flank xenografts had intratumoral or contralateral flank IUdR polymer (50% loading) treatments. Mice bearing intracranial (i.c.) xenografts had i.c. vs. flank IUdR polymer treatments. Four or 8 days after implantation of polymers, mice were sacrificed and the percentage tumor cells that were labeled with IUdR was measured using quantitative microscopic immunohistochemistry. For comparisons of radiosensitization, mice bearing i.c. xenografts had i.c. vs. flank IUdR polymers and cranial fractionated external beam irradiation (2 Gy BID x 4 days).ResultsIn vitro:Increasing percentage loadings of IUdR resulted in higher percentages of release: 43.7 ± 0.1, 70.0 ± 0.2, and 90.2 ± 0.2 (p< 0.001 ANOVA) for the 10, 30, and 50% loadings, respectively.In vivo:For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentages labeling of the tumors vs. time. For the ipsilateral IUdR polymers, the percentages of tumor cellular labeling after 4 vs. 8 days were 45.8 ± 7.0 vs. 40.6 ± 3.9 (p = NS. For the contralateral polymer implants, the percentages tumor cellular labeling were 43.9 ± 10.1 vs. 35.9 ± 5.2 (p = NS) measured 4 vs. 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentages of tumor cellular labeling were low: 13.9 ± 8.8 and 11.2 ± 5.7 measured 4 and 8 days after implantation. For the i.c. tumors having the i.c. IUdR polymers, however, the percentages labeling were comparatively much higher: 34.3 ± 4.9 and 35.3 ± 4.0 on days 4 and 8, respectively. For the i.c. tumors, examination of the percentage cellular labeling vs. distance from the implanted IUdR polymer showed labeling was highest closest to the polymer disc.Radiosensitization:For mice bearing i. c. tumors and receiving flank vs. intracranial IUdR polymer treatments, the survival after external beam irradiation was significantly higher for the intracranial treatments: 49 + 8.9 vs. 80 + 4.1 (p = 0.03) days, respectively.ConclusionsImplantable biodegradable polymers provide the local, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. The local delivery and labeling result in improved survival following radiotherapy. This technique holds promise for the local delivery of IUdR for radiosensitization of human brain tumors.