Liposome-loaded thermo-sensitive hydrogel for stabilization of SN-38 via intratumoral injection: optimization, characterization, and antitumor activity
Liposome-loaded thermo-sensitive hydrogel for stabilization of SN-38 via intratumoral injection: optimization, characterization, and antitumor activity
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DOI：
10.1080/10837450.2017.1391287
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发表时间：
2018-01-01
影响因子：
3.4
通讯作者：
Wang, Shujun
中科院分区：
文献类型：
--
作者：
Bai, Ruixue;Deng, Xueqing;Wang, Shujun
7-乙基-10-羟基喜树碱(SN-38)临床应用的主要挑战是在生理条件下在活性内酯形式(SN-38A)和非活性羧酸盐形式(SN-38I)之间的简单转换以及它的低溶解度。本研究旨在研制一种可用于局部化疗的酸性SN-38脂质体(SN-38-Lip-Gel)温敏水凝胶系统，并评价其抗肿瘤活性及其在荷瘤小鼠体内的组织分布。对SN-38I和SN-38A在不同pH条件下的结构转化研究表明，酸性溶液对SN-38I和SN-38A的转化有抑制作用。也就是说，低pH值的制剂对于稳定SN-38的内酯形式是必不可少的。SN-38-Lip-Gel的凝胶化时间(GT)为25/37℃，其粒径与SN-38-Lip相近。SN-38-Lip-Gel体外释药速度慢于SN-38-Lip。SN-38-Lip-Gel具有pH依赖性的稳定性，SN-38A的残留率随pH的升高而降低。体内实验表明，在相同药物剂量下，SN-38-Lip-Gel具有较好的抗肿瘤效果和较低的全身毒性。结论：SN-38-Lip-Gel可通过稳定内酯形式、延长药物释放、提供较高的局部药物浓度和降低全身毒性来提高SN-38的有效利用。
Main challenges of the clinical use of 7-ethyl-10-hydroxycamptothecin (SN-38) are its facile transition between the active lactone form (SN-38A) and the inactive carboxylate form (SN-38I) under physiological conditions and its low solubility. The purpose of this study was to develop a thermo-sensitive hydrogel system with acidic SN-38 liposomes (SN-38-Lip-Gel) for local chemotherapy to solve these problems and to evaluate its antitumor activity and tissue distribution in tumor-bearing mice. A study of structural conversion between SN-38I and SN-38A under various pH conditions indicated that acidic solution could inhibit the conversion. Namely, a preparation with low pH was essential to stabilize lactone form of SN-38. SN-38-Lip-Gel had an appropriate gelation time (GT) at 25/37 degrees C. The particle size of SN-38-Lip-Gel was similar to that of SN-38-Lip. SN-38-Lip-Gel showed a slower release than SN-38-Lip in vitro. SN-38-Lip-Gel suggested pH-dependent stability, the percentage of SN-38A remaining decreased along with the increasing pH. In vivo studies SN-38-Lip-Gel showed better antitumor efficacy and lower systemic toxicity compared with other groups at the same drug dose. In conclusion, SN-38-Lip-Gel could improve the effective use of SN-38 by stabilizing the lactone form, extending the drug release, providing a high local drug concentration, and reducing systemic toxicity.