Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines.
Polymeric nanogels containing the triphosphate form of cytotoxic nucleoside analogues show antitumor activity against breast and colorectal cancer cell lines.
复制标题
DOI：
10.1158/1535-7163.mct-08-0616
复制
发表时间：
2008-10
影响因子：
5.7
通讯作者：
Vinogradov SV
中科院分区：
文献类型：
--
作者：
Galmarini CM;Warren G;Kohli E;Zeman A;Mitin A;Vinogradov SV
抗癌NA的治疗效率强烈依赖于它们的细胞内积累和转化为5 '-三磷酸。由于活性NATP由于不稳定而不能直接给药，我们在这里提出了一种将这些活性药物纳米包封以有效递送至肿瘤的策略。通过自组装程序制备包封在可生物降解的PEG-或F127-cl-PEI纳米凝胶网络（分别为NGC和NGM）中的阿糖胞苷（araCTP）、吉西他滨（dFdCTP）和阿糖胞苷（FdUTP）的5 '-三磷酸盐的稳定冻干制剂。在乳腺癌和结直肠癌细胞系中分析了这些纳米制剂的细胞渗透、体外细胞毒性和药物诱导的细胞周期扰动。通过共聚焦显微镜和细胞裂解物的直接HPLC分析研究了细胞积累和从纳米凝胶释放NATP。在人乳腺癌MCF 7异种移植动物模型中评价dFdCTP-纳米制剂的抗增殖作用。纳米包封的araCTP、dFdCTP和FdUTP表现出与NA相似的细胞毒性和细胞周期扰动。没有药物的纳米凝胶显示出非常低的细胞毒性，尽管NGM比NGC毒性更大。NATP纳米制剂治疗诱导细胞内游离药物浓度快速增加。在人乳腺癌MCF 7异种移植动物模型中，静脉内dFdCTP-纳米凝胶在抑制肿瘤生长方面与游离吉西他滨相比以低四倍的施用药物剂量同样有效。封装在纳米凝胶中的NA的活性三磷酸盐在体外表现出类似的细胞毒性和细胞周期扰动，与母体药物相比，在低得多的剂量下更快的细胞积累和相等的体内肿瘤生长抑制活性，说明了它们用于癌症化疗的治疗潜力。
The therapeutic efficiency of anticancer NA strongly depends on their intracellular accumulation and conversion into 5’-triphosphates. Since active NATP cannot be directly administrated due to instability, we present here a strategy of nanoencapsulation of these active drugs for efficient delivery to tumors. Stable lyophilized formulations of 5’-triphosphates of cytarabine (araCTP), gemcitabine (dFdCTP) and floxuridine (FdUTP) encapsulated in biodegradable PEG- or F127-cl-PEI nanogel networks (NGC and NGM, respectively) were prepared by a self-assembly procedure. Cellular penetration, in vitro cytotoxicity and drug-induced cell cycle perturbations of these nanoformulations were analyzed in breast and colorectal cancer cell lines. Cellular accumulation and NATP release from nanogel was studied by confocal microscopy and direct HPLC analysis of cellular lysates. Antiproliferative effect of dFdCTP-nanoformulations was evaluated in human breast carcinoma MCF7 xenograft animal model. Nanoencapsulated araCTP, dFdCTP and FdUTP demonstrated similar to NA cytotoxicity and cell cycle perturbations. Nanogels without drugs showed very low cytotoxicity, although NGM was more toxic than NGC. Treatment by NATP nanoformulations induced fast increase of free intracellular drug concentration. In human breast carcinoma MCF7 xenograft animal model, intravenous dFdCTP-nanogel was equally effective in inhibiting tumor growth at four times lower administered drug dose compared to free gemcitabine. Active triphosphates of NA encapsulated in nanogels exhibit similar cytotoxicity and cell cycle perturbations in vitro, faster cell accumulation and equal tumor growth inhibitory activity in vivo at much lower dose compared to parental drugs, illustrating their therapeutic potential for cancer chemotherapy.