Konishi Mitsunaga, Tabata Yasuhiko, Kariya Masatoshi, Hosseinkhani Hossein, Suzuki Ayako, Fukuhara Ken, Mandai Masaki, Takakura Kenji, Fujii Shingo
Department of Gynecology and Obstetrics, Faculty of Medicine, Kyoto University, 54 Kawara-cho Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.
J Control Release. 2005 Mar 2;103(1):7-19. doi: 10.1016/j.jconrel.2004.11.014. Epub 2004 Dec 15.
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 h 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.
本文的目的是研究顺铂（CDDP）和阿霉素（ADM）从可生物降解水凝胶中双重释放的体内抗肿瘤效果。通过用不同浓度的戊二醛对明胶进行化学交联制备了具有不同含水量的水凝胶。将CDDP、ADM或它们的混合物（CDDP+ADM）的水溶液浸渍到冻干的水凝胶中，然后风干以获得包含相应药物的干水凝胶。无论水凝胶的含水量如何，在37℃的磷酸盐缓冲盐水溶液（PBS）中，最初6小时内有8-20%的CDDP和60-80%的ADM从水凝胶中释放出来，此后释放量很少。当瘤内应用于携带Meth-AR-1肿瘤细胞团的小鼠时，包含CDDP+ADM的水凝胶对肿瘤生长抑制和生存期的抗肿瘤效果明显高于其他药物应用。联合效应分析表明，包含CDDP+ADM的水凝胶在CDDP和ADM之间显示出协同效应，而溶液形式则显示出拮抗作用。应用后14天内，肿瘤组织中CDDP和ADM的浓度维持在较高水平。体内CDDP保留的时间进程与水凝胶残留的时间进程非常一致，而ADM释放得更快，随后持续释放14天。应用包含CDDP+ADM的水凝胶后，未观察到小鼠身体和血液生化参数有实际问题的变化。我们得出结论，附着于肿瘤的CDDP和ADM的双重持续释放通过跨组织递送协同增强了它们的体内抗肿瘤效果。
