Williams J A, Yuan X, Dillehay L E, Shastri V R, Brem H, Williams J R
Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Int J Radiat Oncol Biol Phys. 1998 Oct 1;42(3):631-9. doi: 10.1016/s0360-3016(98)00258-2.
Recently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We evaluated whether we could similarly deliver halogenated pyrimidines to experimental intracranial human malignant glioma. To address this issue we studied the in vitro release from polymers and the in vivo drug delivery of IUdR to experimental human U251 glioblastoma xenografts.
In vitro: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed. In vivo: To compare local versus 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. versus 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.
In 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 versus time. For the ipsilateral IUdR polymers, the percentage of tumor cellular labeling after 4 days versus 8 days was 45.8 +/- 7.0 versus 40.6 +/- 3.9 (p = NS). For the contralateral polymer implants, the percentage of tumor cellular labeling were 43.9 +/- 10.1 versus 35.9 +/- 5.2 (p = NS) measured 4 days versus 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentage of tumor cellular labeling was 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 percentage labeling was 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 versus distance from the implanted IUdR polymer showed that labeling was highest closest to the polymer disc.
Synthetic, implantable biodegradable polymers provide the local, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. This technique holds promise for the local delivery of IUdR for radiosensitization of human brain tumors.
最近，化疗药物的聚合物控释已被证明可提高恶性胶质瘤患者的生存率。我们评估了是否能以类似方式将卤代嘧啶递送至实验性颅内人类恶性胶质瘤。为解决此问题，我们研究了聚合物的体外释放以及碘苷（IUdR）对实验性人类U251胶质母细胞瘤异种移植瘤的体内给药情况。
体外：为测定释放情况，将合成的[聚（双（对羧基苯氧基）丙烷）（PCPP）：癸二酸（SA）]聚合物圆片中碘苷比例递增（10%、30%、50%）后，依次在缓冲盐水中孵育，并对上清液进行检测。体内：为比较局部给药与全身给药，对侧腹异种移植瘤小鼠进行瘤内或对侧腹碘苷聚合物（50%载药量）治疗。对颅内（i.c.）异种移植瘤小鼠进行颅内与侧腹碘苷聚合物治疗。聚合物植入4或8天后，处死小鼠，使用定量显微免疫组织化学法测定标记有碘苷的肿瘤细胞百分比。
体外：碘苷载药量百分比增加导致释放百分比升高：10%、30%和50%载药量时分别为43.7 + 0.1、70.0 + 0.2和90.2 + 0.2（方差分析，p < 0.001）。体内：对于侧腹肿瘤，同侧和对侧碘苷聚合物随时间推移均使肿瘤标记百分比同样高。对于同侧碘苷聚合物，4天和8天后肿瘤细胞标记百分比分别为45.8 +/- 7.0和40.6 +/- 3.9（无显著性差异）。对于对侧聚合物植入，植入后4天和8天测定的肿瘤细胞标记百分比分别为43.9 +/- 10.1和35.9 +/- 5.2（无显著性差异）。对于用颅外碘苷聚合物治疗的颅内肿瘤，植入后4天和8天测定的肿瘤细胞标记百分比很低：分别为13.9 +/- 8.8和11.2 +/- 5.7。然而，对于接受颅内碘苷聚合物治疗的颅内肿瘤，标记百分比相对高得多：第4天和第8天分别为34.3 +/- 4.9和35.3 +/- 4.0。对于颅内肿瘤，检查肿瘤细胞标记百分比与距植入碘苷聚合物的距离，结果显示距聚合物圆片最近处标记最高。
合成的、可植入的生物可降解聚合物可实现碘苷的局部控释，并使碘苷高效局部递送至实验性颅内人类恶性胶质瘤。该技术有望用于局部递送碘苷以对人类脑肿瘤进行放射增敏。
