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一种去除接枝胆固醇的两亲性高分子材料中DMAP中间体的方法
  • ISSN号:1006-2858
  • 期刊名称:《沈阳药科大学学报》
  • 时间:0
  • 分类:R943[医药卫生—药剂学;医药卫生—药学]
  • 作者机构:[1]沈阳药科大学药学院,辽宁沈阳110016, [2]苏州科伦药物研究有限公司,江苏苏州215000
  • 相关基金:国家自然科学基金资助项目(81373334);沈阳药科大学科研专项基金资助项目(QNJJ2014507)
中文摘要:

本文合成了4种不同链长的唾液酸(SA)脂肪胺衍生物,并将其修饰于脂质体表面,制备空白脂质体(blank liposomes modified with sialic acid derivatives,BLK-Sn L,n=18,16,14,12)和马来酸匹杉琼脂质体(pixantrone maleate liposomes modified with sialic acid derivatives,Pix-Sn L,n=18,16,14,12)进行急性毒性和药效学研究,以期筛选出具有良好肿瘤相关巨噬细胞(TAM)靶向性的材料。急性毒性实验结果显示,SA衍生物的自身毒性与链长呈正相关,其所修饰的空白脂质体药效学实验结果表明,除BLK-S14L具有一定的肿瘤抑制作用外,其他空白脂质体几乎无抑瘤效果,BLK-S16L甚至促进了肿瘤增长。Pix-Sn L药效学实验结果表明,肿瘤抑制作用由强到弱依次为Pix-S18L〉Pix-S14L〉Pix-S12L〉Pix-S16L。由于SA-十八胺偶联物(SA-18)与脂质体结合较为牢固,在转运过程中不易脱落,TAM靶向性好,故其所修饰的脂质体毒性较低,对机体正常组织及免疫器官损伤较小,抗肿瘤效果最好。令人惊喜的是,该制剂组中50%小鼠出现了肿瘤脱落及伤口愈合现象。综上,SA-18为所述唾液酸脂肪胺衍生物中最具潜力的TAM靶向材料,可用于后续TAM靶向机制探讨和TAM靶向药物制剂的研发。

英文摘要:

A large number of experimental and clinical data indicates that tumor-associated macrophages(TAMs) were involved in the whole process of tumor growth, invasion and metastasis. Like macrophages in other tissues, TAMs originate from blood monocytes, which are recruited to the tumor tissues by cytokines and then differentiated into TAMs. It is interesting that the monocytes overexpress siglec receptor in their surface, which has a high binding specificity to sialic acid(SA). From this point of view, we hypothesize that if SA was used as a ligand in the surfaces of drug delivery systems, SA would enhance the targeting efficiency to monocytes, and thus to achieve a higher specificity to TAMs. In our previous study, an SA derivative of SA-octadecylamine(SA-18) was synthesized and was found to enhance cytotoxicity on TAMs in vitro. The chain length is a critical factor for SA efficiency in liposomes and it has a significant influence on the TAM targeting effects of the carriers. So in this study, four kinds of different chain length of SA fatty amine derivatives were synthesized, including SA-18, SA-hexadecylamine(SA-16), SA-tetradecylamine(SA-14) and SA-dodecylamine(SA-12), and were modified on the surfaces of blank liposomes(BLK-Sn L, n = 18, 16, 14, 12) and pixantrone maleate-loaded liposomes(Pix-Sn L, n = 18, 16, 14, 12). TAM targeting effects of these SA derivatives were evaluated by acute toxicity and antitumor efficacy in vivo. The results of acute toxicity experiments showed that the toxicities of the SA derivatives deceased gradually with the reduction in the length of lipophilic chain. The in vivo antitumor efficacies of SA-modified blank liposomes showed that these blank formulations had no effect on the tumor inhibition except BLK-S14L(61.4% ± 18.8%), and BLK-S16 L even promoted the tumor growth(-31.7% ± 13.1%, the 18 th day). The in vivo antitumor efficacies of SA-modified Pix liposomes showed that the tumor inhibition effects were Pix-S18L(97.4% ± 2.1%) 〉 Pi

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期刊信息
  • 《沈阳药科大学学报》
  • 中国科技核心期刊
  • 主管单位:辽宁省教育厅
  • 主办单位:沈阳药科大学
  • 主编:毕开顺
  • 地址:沈阳市文化路103号
  • 邮编:110016
  • 邮箱:syyd@chinajournal.net.cn
  • 电话:024-23986082 23994540
  • 国际标准刊号:ISSN:1006-2858
  • 国内统一刊号:ISSN:21-1349/R
  • 邮发代号:
  • 获奖情况:
  • 国内外数据库收录:
  • 美国化学文摘(网络版),日本日本科学技术振兴机构数据库,中国中国科技核心期刊,中国北大核心期刊(2004版),中国北大核心期刊(2008版),中国北大核心期刊(2011版),中国北大核心期刊(2014版),英国英国皇家化学学会文摘
  • 被引量:17272