CN113274398B - 一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 - Google Patents
一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用。所述纳米自组装材料是在室温下将mPEG‑SS‑PEI‑DSPE长链与阿霉素和DNA配体的混合物在水溶液中搅拌,随后将糖葡萄糖转运蛋白抑制剂BAY‑876溶解在三氯甲烷中,上述体系中,边超声边加热,冻干得到结构为BAY‑876@(mPEG‑SS‑PEI‑DSPE‑Dox‑Duplex)纳米自组装材料,可以很好的抑制肿瘤细胞的糖代谢。本发明采用一步法合成,该纳米材料可以很好的释放Dox和BAY‑876,分别作用于肿瘤细胞的DNA和葡萄糖转运蛋白,抑制肿瘤细胞的能量代谢,限制肿瘤细胞生长、繁殖。
Description
技术领域
本发明是涉及一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用,属于生物材料研究领域。
背景技术
根据全球癌症统计数据分析,截至到2018年,全球新增癌症确诊病例已经远超1800 万,其中死亡人数更是高达960万,而且亚洲的死亡人数更是占了其中的70%,令人触目惊心。目前临床上针对肿瘤的治疗手段主要包括外科手术,放射性治疗(放疗)以及药物治疗(化疗)三大传统肿瘤治疗手段。虽然这些治疗方式已经广泛应用于临床肿瘤治疗,但是手术治疗切除不干净,导致肿瘤复发转移,化疗引起的肿瘤耐药性,放疗对周边正常组织无差别的伤害性,已经无法满足现代肿瘤治疗的需求。与传统肿瘤治疗方式相比,新兴的纳米医学表现出了更强的特异性强和更丰富的功能性以及更小的副作用。但是面对种类繁多,微环境复杂多变的实体肿瘤(包括弱酸性,氧气匮乏,高活性氧浓度,多种过表达酶以及还原性微环境等等),纳米药物呈现出的治疗效果也往往不尽人意。如肿瘤乏氧导致的氧依赖型治疗效率低下,光穿透力较弱导致的光敏型治疗效率低下,光热治疗引起的炎症因子升高导致的肿瘤复发等等,以上种种的原因导致肿瘤治疗不彻底,易复发、易转移。
葡萄糖作为自然界分布最广且最为重要的一种单糖,是活细胞的能量来源和新陈代谢中间产物,即生物的主要供能物质,也是人体热能最主要的来源。普通食物在被人体内消化后,主要以葡萄糖的形式被吸收利用。葡萄糖能够在细胞中参与细胞的呼吸作用,迅速被氧化并释放ATP,供给细胞的各项生理活动。此外,葡萄糖与脂类形成的糖脂是组成细胞膜与神经组织的成分,与蛋白质结合成糖蛋白可构成抗体、某些酶和激素等具有重要生物活性的物质。因此,合理的控制肿瘤细胞内的葡萄糖就可以限制肿瘤细胞的生长和增殖。
Zhang等(ACS Nano 2017,11,1419-1431)将葡萄糖转运蛋白1的抑制剂双氯芬酸包覆在金棒外面,运送到肿瘤细胞内,用于抑制葡萄糖转运蛋白1的活性,限制肿瘤细胞的能量代谢,同时利用金棒的光热作用,对肿瘤实施光热治疗。在多种治疗方式下,可以很好的杀死肿瘤细胞。Wei等(J.Mater.Chem.B,2018,6,2078--2088)将Cu2+和一种Zn2+的光敏剂组成有机金属骨架化合物,递送到肿瘤细胞内,利用Cu2+和ATP的亲和作用,减少肿瘤细胞内ATP的含量,限制其能量代谢,使肿瘤细胞的耐受性降低,从而增强光动力治疗效果,成功杀灭了肿瘤细胞。
发明内容
本发明目的是,提供一种抑制肿瘤细胞糖代谢的纳米自组装材料及其制备方法和应用。
本发明采用的技术方案是:
一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,包括以下步骤:
S1、在室温下将阿霉素和DNA配体混合,得到混合物Dox-Duplex,再将 mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex加入到去离子水中,在水溶液体系中搅拌均匀,超声10-30分钟,得到mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液;
S2、随后将葡萄糖转运蛋白抑制剂BAY-876溶解在三氯甲烷中,缓慢滴入到步骤(1)所得mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液体系中,边超声边加热,保持温度不超过50摄氏度,直到液体变得澄清透明,再离心冻干,最终得到结构为 BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)的纳米自组装材料。
进一步的,步骤S1所述阿霉素和DNA配体混合摩尔比为1:2。
进一步的,步骤S1所述DNA配体的碱基序列为5'-ACC TGG GGG AGT ATT GCG GAGGAA GGT-3'和5'-ACC TTC CTC CGC AAT ACT CCC CCA GGT-3'。
进一步的,所述加入的mPEG-SS-PEI-DSPE,Dox-Duplex和BAY-876质量比为 1~5:1:1。
进一步的,步骤S1所述mPEG-SS-PEI-DSPE结构为聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺,其中聚乙二醇分子量是2000,聚乙烯亚胺分子量是1800。
进一步的,步骤S1所述加入到去离子水中的mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex的摩尔比为1:1。
进一步的,步骤S2所述三氯甲烷和步骤S1所述去离子水体积比为1:10~20。
进一步的,步骤S1所述mPEG-SS-PEI-DSPE和去离子水的投料比为1mg:1~5mL。
根据上述方法制备的结构为BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)的纳米自组装材料中,阿霉素和DNA配体的混合物通过静电作用与mPEG-SS-PEI-DSPE长链中的聚乙烯亚胺吸附在一起,BAY-876与二硬脂酰基磷脂酰乙醇胺结合,存储在纳米自组装材料中心。
所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料纳米自组装材料在肿瘤治疗中应用,所述纳米自组装材料用于抑制肿瘤的葡萄糖代谢和ATP产生,以限制肿瘤细胞生长和增殖
有益效果:本发明提供的一种抑制肿瘤细胞糖代谢的纳米自组装材料纳米自组装材料及其制备方法和应用具有如下优点:
(1)本发明所述的纳米自组装材料制备方法简单,制备工艺简单高效,反应可以一步进行到底,减少了很多繁琐的合成步骤,合成方法简单明了。
(2)本发明所制备纳米自组装材料可以较好的响应肿瘤的微环境,释放出Dox和BAY-876,对正常组织细胞无伤害。
(3)本发明所制备纳米自组装材料可以很好的抑制肿瘤的葡萄糖代谢和ATP产生,限制肿瘤细胞生长和增殖。
附图说明
图1为本发明的纳米自组装材料制备方法流程图。
图2为本发明的纳米自组装材料的透射电镜(TEM)图。
图3为本发明的纳米自组装材料的粒径分布图。
图4为本发明的纳米自组装材料对肿瘤细胞葡萄糖摄取和ATP合成的抑制作用示意图。
具体实施方式
下面结合附图和实施例对本发明作进一步详细描述。总体上一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法包括有以下步骤:
S1、mPEG-SS-PEI-DSPE-Dox-Duplex纳米体系构建:在室温下将阿霉素和DNA配体混合,DNA配体的碱基序列为5'-ACC TGG GGG AGT ATT GCG GAG GAA GGT-3' 和5'-ACCTTC CTC CGC AAT ACT CCC CCA GGT-3',混合摩尔比为1:2,得到混合物 Dox-Duplex,再将mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex加入到去离子水中; mPEG-SS-PEI-DSPE结构为聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺, PEG分子量是2000,PEI分子量是1800,摩尔比为1:1,在水溶液体系中搅拌均匀,超声10-30分钟,得到mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液;其中,加入的 mPEG-SS-PEI-DSPE和Dox-Duplex质量比为1~5:1;所述mPEG-SS-PEI-DSPE和去离子水的投料比为1mg:1~5mL。
S2、随后将葡萄糖转运蛋白抑制剂BAY-876溶解在三氯甲烷中,缓慢滴入到步骤S1所得mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液中,边超声边加热,直到液体变得澄清透明,再离心冻干最终得到BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料;其中,加入的BAY-876和步骤S1中Dox-Duplex的质量比为1:1;所述三氯甲烷和步骤S1所述去离子水体积比为1:10~20。
实施例:
BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料制备方法(具体过程如图1所示):
S1、在室温下将阿霉素和DNA配体混合,得到混合物Dox-Duplex,称取50mg mPEG-SS-PEI-DSPE分散在50mL去离子水中,随后加入10mgDox-Duplex继续超声20 分钟。
S2、然后将5mgBAY-876溶解在5mL三氯甲烷中,缓慢滴入上述溶液中,边搅拌边超声,直到液体变得澄清透明为止,再离心冻干得到 BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料。
上述实施例中制备的BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料的透射电镜透如图2所示,可以很明显的观察到纳米材料形状规则,均一,最粒径在20nm 左右。
上述实施例中制备的BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料的粒径分布图如图3所示,可以明显地观察到纳米材料呈单分散,水合粒径在50-60纳米左右。
上述实施例中制备的BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)纳米自组装材料对肿瘤细胞(4T1细胞,小鼠乳腺癌细胞)葡萄糖摄取和ATP合成的抑制作用如图4所示,在72小时内,肿瘤细胞的葡萄糖摄取含量和ATP合成含量持续下降,表明纳米粒子对肿瘤的能量代谢有着优异的抑制作用。
Claims (9)
1.一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,包括以下步骤:
S1、在室温下将阿霉素和DNA配体混合,得到混合物Dox-Duplex,再将mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex加入到去离子水中,在水溶液体系中搅拌均匀,超声10-30分钟,得到聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液;
所述DNA配体的碱基序列为5'-ACC TGG GGG AGT ATT GCG GAG GAA GGT-3'和5'-ACCTTC CTC CGC AAT ACT CCC CCA GGT-3';
S2、随后将葡萄糖转运蛋白抑制剂BAY-876溶解在三氯甲烷中,缓慢滴入到步骤S1所得mPEG-SS-PEI-DSPE-Dox-Duplex的水溶液体系中,边超声边加热,保持温度不超过50摄氏度,直到液体变得澄清透明,再离心冻干,最终得到结构为BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex)的纳米自组装材料。
2.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,步骤S1所述阿霉素和DNA配体混合的摩尔比为1:2。
3.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,所述加入的mPEG-SS-PEI-DSPE,Dox-Duplex和BAY-876质量比为1~5:1:1。
4.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,步骤S1所述mPEG-SS-PEI-DSPE结构为聚乙二醇-双硫键-聚乙烯亚胺-二硬脂酰基磷脂酰乙醇胺,其中聚乙二醇分子量是2000,聚乙烯亚胺分子量是1800。
5.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,步骤S1所述加入到去离子水中的mPEG-SS-PEI-DSPE长链与混合物Dox-Duplex的摩尔比为1:1。
6.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,步骤S2所述三氯甲烷和步骤S1所述去离子水体积比为1:10~20。
7.根据权利要求1所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料的制备方法,其特征在于,步骤S1所述mPEG-SS-PEI-DSPE和去离子水的投料比为1mg:1~5mL。
8.根据权利要求1~7任一所述方法制备的抑制肿瘤细胞糖代谢的纳米自组装材料,其特征在于,所述纳米自组装材料结构为BAY-876@(mPEG-SS-PEI-DSPE-Dox-Duplex),其中阿霉素和DNA配体的混合物通过静电作用与mPEG-SS-PEI-DSPE长链中的聚乙烯亚胺吸附在一起,BAY-876与二硬脂酰基磷脂酰乙醇胺结合,存储在纳米自组装材料中心。
9.根据权利要求8所述的一种抑制肿瘤细胞糖代谢的纳米自组装材料在制备治疗肿瘤的药物中应用,其特征在于,所述纳米自组装材料用于抑制肿瘤的葡萄糖代谢和ATP产生,以限制肿瘤细胞生长和增殖。
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