In vivo anti-tumor effect of dual release of cisplatin and adriamycin from biodegradable gelatin hydrogel
In vivo anti-tumor effect of dual release of cisplatin and adriamycin from biodegradable gelatin hydrogel
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DOI：
10.1016/j.jconrel.2004.11.014
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发表时间：
2005-03-02
影响因子：
10.8
通讯作者：
Fujii, S
中科院分区：
文献类型：
--
作者：
Konishi, M;Tabata, Y;Fujii, S
本论文的目的是研究顺铂(CDDP)和阿霉素(ADM)从生物可降解水凝胶中双释放的体内抗肿瘤作用。用不同浓度的戊二醛对明胶进行化学交联，制备了不同水分含量的水凝胶。将CDDP、ADM或其混合物(CDDP+ADM)的水溶液浸渍到冻干水凝胶中，然后风干得到含有相应药物的干燥水凝胶。无论水凝胶的水分含量如何，在37℃的磷酸盐缓冲盐水溶液(PBS)中，8-20%的CDDP和60-80%的ADM在最初的6℃内从水凝胶中释放出来，此后几乎没有观察到释放。CDDP+ADM水凝胶对荷Meth-AR-1肿瘤细胞的小鼠肿瘤生长抑制和生存期的影响明显高于其他药物。联合效应分析表明，CDDP+ADM水凝胶对CDDP和ADM具有协同作用，而溶液形式则表现为拮抗作用。CDDP和ADM在肿瘤组织中的浓度在给药后14天内维持在较高水平。CDDP体内滞留时间与水凝胶滞留时间基本一致，而ADM释药较快，随后缓释14d。应用含有CDDP+ADM的水凝胶，小鼠的身体和血液生化参数没有明显的变化。我们认为CDDP和ADM的双重缓释通过跨组织传递协同增强了其体内的抗肿瘤作用。(C)2004爱思唯尔B.V.保留所有权利。
The objective of this paper is to investigate the in vivo anti-tumor effect by dual release of cisplatin (CDDP) and adriamycin (ADM) from a biodegradable hydrogel. Hydrogels with different water contents were prepared through the chemical crosslinking of gelatin by various concentrations of glutaraldehyde. Aqueous solution of CDDP, ADM or their mixture (CDDP+ADM) was impregnated into the freeze-dried hydrogel, followed by air-drying to obtain the dried hydrogel incorporating the corresponding drug. Irrespective of the hydrogel water content, 8-20% of CDDP incorporated and 60-80% of ADM was released from the hydrogel in the phosphate-buffered saline solution (PBS) at 37 degrees C within the initial 6 It and thereafter little release was observed. When intratumorally applied into mice carrying a mass of Meth-AR-1 tumor cells, the hydrogel incorporating CDDP+ADM showed significant higher anti-tumor effect on the tumor growth suppression and on survival period than other drug applications. Combination effect assay revealed that the hydrogel incorporating CDDP+ADM showed a synergistic effect between the CDDP and ADM, while the solution form showed antagonistic. The concentration of CDDP and ADM in the tumor tissue maintained at higher levels over 14 days after application. The time course of in vivo CDDP retention was in a good accordance with that of hydrogel remaining, whereas ADM was released faster, followed by the sustained release for 14 days. No practically problematic change in the mouse body and blood biochemical parameters was observed by application of the hydrogel incorporating CDDP+ADM. We conclude that dual sustained release of CDDP and ADM attached to the tumor synergistically enhanced their in vivo anti-tumor effect through the trans-tissue delivery. (c) 2004 Elsevier B.V. All rights reserved.