CN114177310A - 基于多肽-稀土纳米晶的多功能抗癌纳米材料及其制备方法 - Google Patents
基于多肽-稀土纳米晶的多功能抗癌纳米材料及其制备方法 Download PDFInfo
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Abstract
本发明公开一种基于多肽‑稀土纳米晶的多功能抗癌纳米材料,其特征在于,它是一种多肽包载药物阿霉素和NaYF4:Yb3+,Er3+纳米晶的亲水性纳米微球;其中,P13肽的疏水端以非共价键形式和药物阿霉素、NaYF4:Yb3+,Er3+纳米晶结合,形成疏水核心;P13肽的亲水端作为靶向端形成亲水的外壳。本发明以多肽作为载体包载药物阿霉素,同时以包载NaYF4:Yb3+,Er3+纳米晶的方式,将药物抑制和PDT法结合杀死肿瘤细胞。本发明以协同治疗的方式产生了显著的超加法(1+1>2)效果,比任何单一疗法显著性增强;同时,多模态相结合的治疗方式,还能有效地克服肿瘤的多药耐药性;除此以外,解决了多肽自身无荧光特性导致载药体系无法荧光追踪的缺点。
Description
技术领域
本发明涉及纳米材料,具体地,涉及一种基于多肽-稀土纳米晶的多功能抗癌纳米材料及其制备方法。
背景技术
基于纳米载体的肿瘤单模态治疗能够取得一定的治疗效果,但是,肿瘤的复杂性、多样性和异质性使得单一的治疗形式往往不能完全根除肿瘤。因此,目前临床研究的趋势己由单一治疗逐渐转向联合治疗以提高治疗效果。
在多功能材料治疗疾病的研究中,上转换纳米发光材料以其能够吸收NIR光并将其转化为光、热的特点备受研究人员的青睐。在众多的上转换材料中,光子转换能力较高的当属六方NaYF4:Yb3+,Er3+纳米晶。虽然NaYF4:Yb3+,Er3+纳米晶修饰载药体系治疗肿瘤的功能性研究已有很多报道,但NaYF4:Yb3+,Er3+纳米晶的光热效应和多肽载药联用对载药体系的形态结构以及生物学效应等方面的影响还没有人做过系统的研究。
发明内容
本发明所要解决的技术问题是针对上述现有技术存在的不足而提供一种多功能抗癌载药纳米材料及其制备方法。该多功能抗癌载药纳米材料具有优异的光热效应、载药能力、靶向作用和缓释作用。
本发明为解决上述提出的问题所采用的技术方案为:
一种基于多肽-稀土纳米晶的多功能抗癌纳米材料,其是一种多肽包载药物阿霉素(DOX)和NaYF4:Yb3+,Er3+纳米晶的亲水性纳米微球;其中,多肽的疏水端以非共价键形式和药物阿霉素、NaYF4:Yb3+,Er3+纳米晶结合,形成疏水核心;多肽的亲水端作为靶向端形成亲水的外壳。
按上述方案,该多功能抗癌纳米材料中,NaYF4:Yb3+,Er3+纳米晶和阿霉素、多肽之间的质量比为1:(1-5):(20-30);多肽采用P13肽等。
本发明所述基于多肽-稀土纳米晶的多功能抗癌纳米材料的制备方法,首先将NaYF4:Yb3+,Er3+纳米晶和药物DOX分别溶解在有机溶剂中,分别得到NaYF4:Yb3+,Er3+纳米晶的有机溶液和药物DOX的有机溶液;接着将NaYF4:Yb3+,Er3+纳米晶的有机溶液和药物DOX的有机溶液混合,再滴加P13肽水溶液,在20-40℃反应3-20min后透析;透析所得溶液经离心收集上清液,冷冻干燥后,得到基于多肽-稀土纳米晶的多功能抗癌纳米材料。
上述制备方法中,所述NaYF4:Yb3+,Er3+纳米晶为六方相晶体,粒径小于20nm,Y3+/Yb3+/Er3+三者的摩尔比为(22-35):1:(2-4)。
上述制备方法中,溶解药物DOX的有机溶剂选自N,N-二甲基甲酰胺(DMF)、二氯甲烷(DCM)等中的至少一种;溶解NaYF4:Yb3+,Er3+纳米晶的有机溶剂选自甲醇(MeOH)、乙醇(ET)、二甲基亚砜(DMSO)等中的至少一种。
上述制备方法中,NaYF4:Yb3+,Er3+纳米晶的有机溶液的浓度为0.5-1mg/mL,药物DOX的有机溶液的浓度为1-4mg/mL,P13肽水溶液的浓度为3-6mg/mL;NaYF4:Yb3+,Er3+纳米晶和药物DOX、P13肽之间的质量比为1:(1-5):(20-30)。
上述制备方法中,所述透析的条件为:透析液选择去离子水、PBS缓冲液或超纯水,透析温度为25-30℃,透析时间为12-24h,透析袋的截留分子量为1000-3500Da。
上述制备方法中,所述NaYF4:Yb3+,Er3+纳米晶的制备方法包括如下步骤:
1)根据NaYF4:Yb3+,Er3+纳米晶中Y、Yb、Er、Na元素的化学计量比,按Y3+/Yb3+/Er3+的摩尔比为(22-35):1:(2-4)称取Y2O3、Yb2O3、Er2O3并用硝酸溶解后,加入络合剂、水和NaOH,得到储备液,pH在8-10范围内;其中,Y离子的浓度为0.44-0.66mmol/mL、Yb离子的浓度为0.015-0.025mmol/mL、Er离子的浓度在0.04-0.065mmol/mL,Na离子的浓度为1.25-1.5mmol/mL;络合剂跟总稀土离子之间的摩尔比为(0.9-1):1;
2)将所述储备液中加入乙二醇、表面活性剂和氢氟酸得到白色乳状胶体;然后再加入硝酸,在180-200℃反应18-22h,所得固体产物经洗涤干燥,即NaYF4:Yb3+,Er3+纳米晶。
进一步地,络合稳定剂以选自乙二胺四乙酸二钠(EDTA二钠)、2-噻吩甲酰三氟丙酮(TTA)、乙二胺四乙酸四钠盐(EDTA四钠)等中的至少一种;表面活性剂以选自十六烷基三甲基溴化铵(CTAB)、己基三甲基溴化铵(HTAB)等中的至少一种。
进一步地,步骤1)中,先加入络合稳定剂均匀后,然后再加水;步骤2)中,先加入表面活性剂混合均匀后,加入乙二醇,再滴加氢氟酸。其中,乙二醇可以采用甲醇、异丁醇等替换。
进一步地,步骤2)中,储备液与乙二醇、表面活性剂之间的比例为(8-10)mL:(20-30)mL:(0.4-0.6)g;氢氟酸所含F离子与储备液中稀土离子总量之间的摩尔比为(8-12):1;硝酸采用浓度为10%的稀硝酸,0.5-0.7g稀土原料粉末大约加入10%的稀硝酸5-7mL,将粉色粉末状稀土原料搅拌反应成澄清透明溶液体系为止。
本发明以多肽作为载体包载药物阿霉素,同时以包载NaYF4:Yb3+,Er3+纳米晶的方式,将药物抑制和PDT法结合杀死肿瘤细胞。本发明提供的基于多肽-稀土纳米晶的多功能抗癌纳米材料具有靶向药用治疗和光热治疗作用以协同治疗的方式产生了显著的超加法(1+1>2)效果,比任何单一疗法显著性增强;同时,多模态相结合的治疗方式,还能有效地克服肿瘤的多药耐药性;除此以外,解决了多肽自身无荧光特性导致载药体系无法荧光追踪的缺点。
与现有技术相比,本发明提供的基于多肽-稀土纳米晶的多功能抗癌纳米材料具有靶向药用治疗和光热治疗作用,并且利用非共价结合制备出载药颗粒P13@NaYF4:Yb3+,Er3+-DOX,具有很多优势:
(1)具有良好的pH响应性:在偏酸性环境中具有良好的pH响应能力,这意味着在与肿瘤微环境相关的微酸性环境下,P13肽具有很好的pH响应能力,便于参与代谢循环、能调节生物体内系统和生物体细胞间的生理功能;
(2)靶向作用强:对4T1细胞等多种癌细胞都具有明显的主动识别结合的作用,提高疗效,降低副作用;
(3)提高对肿瘤细胞的抑制率:该材料具有良好的光热效应,在980nm照射下,可以很好的通过光热治疗途径杀死肿瘤细胞,同时,当材料进入细胞核后,可以定点释放药物DOX,达到药物治疗的效果,两种治疗手段结合,大大提高了对肿瘤细胞的抑制率;
(4)提高纳米微球(本发明所述多功能抗癌纳米材料)的纯度:在制备方法中,先通过非共价结合和共价结合两种方式制备出功能化肽链P13@NaYF4:Yb3+,Er3+,并且包载DOX,再进一步用透析法将未包载上的游离药物和残留有机溶剂除去,具有粒径大小更加均一、对细胞毒副作用更加降低的优势,并且具有操作步骤简单、操作条件温和和原料易得,产率高,纯度高的优点。
综上可知,本发明提供的具有靶向药用治疗和光热治疗作用的抗癌纳米复合材料在生物体内高效靶向识别癌细胞,具有优异的光热效应、载药能力、靶向作用和pH响应作用。
附图说明
图1是本发明提供的基于多肽-稀土纳米晶的多功能抗癌纳米材料的制备原理图以及进入肿瘤细胞释放药物示意图;
图2是实施例所采用的P13的MS和HPLC质谱图;
图3是实施例所采用的P13的酸碱缓冲图;
图4是实施例所制备的NaYF4:Yb3+,Er3+的能谱图;
图5是实施例所制备的NaYF4:Yb3+,Er3+的扫描电镜图;
图6是实施例1的P13@NaYF4:Yb3+,Er3+-DOX光热效应分析图;
图7是实施例1中P13@NaYF4:Yb3+,Er3+-DOX的细胞毒性图;
图8是实施例1中P13@NaYF4:Yb3+,Er3+-DOX的细胞凋亡图。
具体实施方式
为了更好地理解本发明,下面结合实施例进一步阐明本发明的内容,但本发明不仅仅局限于下面的实施例。
以下实施例中,P13肽可参考ZL 2018 1 0692478.3制备,具体结构式如下所示:
其制备方法包括如下步骤:
a、首先,在DCM(15mL,每次3分钟)中溶胀2-cl树脂(1.03mmol/g,1.0g)。通过将DIEA(1.5mL)加入含有Fmoc-Asp(OtBu)-OH(0.55g),HOBT(0.45g)和DIC(1.5mL)的DMF(15mL)溶液来制备偶联溶液。将偶联溶液加入到树脂中并反应1.5小时,Kaiser试验显示完全偶联。然后用甲醇和DCM封闭未反应的活性氯基团,反应时间为30min。用DMF洗涤数次后,用20%的哌啶脱去肽链氨基端上的Fmoc,反应时间为20min。Kaiser试验显示NH2存在暴露。树脂用DMF(15mL,每次3min)洗涤。
b、用DMF充分洗涤后,可投入下一个氨基酸,直到P13肽的最后一个氨基酸Fmoc-Ala-OH。最后,通过与DMF中的20%哌啶(20mL,30min)混合除去偶联化合物中的保护基,并用CH3OH(20mL,每次5min)洗涤。通过用三氟乙酸(TFA)和水(V/V为95:5)摇动树脂2小时,从树脂上切割和侧链去保护,通过在冷乙醚中沉淀得到粗产物。
c、制备的P13粗产物用水溶解后,经0.45μm滤膜过滤后,通过RP-HPLC纯化P13。色谱条件为:C18柱(Gemini-NX),110A,20μL,4.6*250mm柱,洗脱液A:0.1%TFA/100%乙腈,洗脱液B:0.1%TFA/100%H2O(V/V),梯度洗脱20%B→80%B,20min,流速为1.0mL·min-1,检测波长λ=220nm。纯化后P13溶液冻干(FD-1C50,冷冻干燥机)成白色粉末。
下述实施例中,NaYF4:Yb3+,Er3+纳米晶的制备方法包括如下步骤:
a、取0.5g Y2O3,0.035g Yb2O3,0.08g Er2O3置于烧杯中,加入5-7mL 10%HNO3加热蒸干多余水分,加入1.36gEDTA,5mL超纯水搅拌溶解,然后加入约0.5gNaOH至溶液澄清,调节pH值至8.5,加水定容至8mL,作为储备液。
b、上述8mL储备液在搅拌条件下(HJ-4A,磁力搅拌器)加入0.4g CTAB,25mL乙二醇,再逐滴加入1.0mL氢氟酸(F+摩尔量为0.0575mol,Y3+/Yb3+/Er3+的摩尔比约为25:1:2.4)得到白色乳状胶体。
c、将白色乳状胶体中再加入5.5mL HNO3(浓度为10%),搅拌均匀后,转移到50mL带聚四氟乙烯内衬的反应釜(型号)中,195℃反应24h。
d、将反应釜取出后冷却至室温,弃上清液体,釜底的固体用热水冲洗到烧杯中,超声5min,然后静置数分钟,待固体沉淀至杯底后,将上层液体倒掉,再加热水超声,重复三次。然后加乙醇超声分散,并以4800r/min的转速离心2min,所得固体置于70℃烘箱中干燥10h,固体粉末即为NaYF4:Yb3+,Er3+纳米晶。所得纳米晶中稀土掺杂量为0.0044molY3+、0.0000178molYb3+、0.00042molEr3+,形态为六方相晶体,粒径小于20nm,产量约为200mg。
实施例1
一种多功能抗癌纳米材料,具体制备方法包括如下步骤:
a、在避光条件下,将1mL三乙胺和10mg DOX·HCL加入5mL DMF中,然后在20℃下放入磁力搅拌器中,在1000r/min下,接触反应1h,最后冷冻干燥(温度为-80℃,压力为999Pa,干燥时间为12h)以制得DOX;
b、在同一转速下,将4mg/mL DOX有机溶液(有机溶剂为DMF,体积为1mL)中加入1mg/mL NaYF4:Yb3+,Er3+有机溶液(有机溶剂为DMF,体积为1mL),反应时间15min,得到约2mL的DOX和NaYF4:Yb3+,Er3+混合DMF有机溶液;
c、在超声条件下,用0.34mm规格针头的注射器将5mL P13水溶液(6mg/mL,滴加时间为15s)进2mL DOX和NaYF4:Yb3+,Er3+混合DMF有机溶液中,室温反应20min,在磁力搅拌器上进行搅拌透析,选用MWCO1000的透析袋,1000mL去离子水透析,透析温度为25℃,透析24h,透析后冻干,制得具有靶向药用治疗和光热治疗作用的抗癌纳米复合材料NaYF4:Yb3+,Er3+@P13-DOX,冷冻干燥后备用。
性能测试
1)对实施例中使用的P13肽进行MS(质谱)和HPLC(高效液相色谱)检测,具体结果见图2。由图2可知,P13的保留时间为10.638min,纯度约为96.5751%。在其质谱图中,[M+H]+=1381.70,与理论值相符,合成的产物为目的产物P13。
2)对实施例中使用的P13肽进行酸碱缓冲能力检测,具体结果见图3。由图3可知,空白组NaCl溶液的酸碱滴定结果表明,加入270μL HCl后,溶液pH迅速降低,无缓冲能力。相较于NaCl溶液,在滴加270μL HCl后,P13溶液的pH并无明显降低的趋势,并且其pH分布表明在pH 6.0和4.0之间的偏酸性环境中具有良好的pH响应能力,这意味着在与肿瘤微环境相关的微酸性环境下,P13肽具有很好的pH响应能力。
3)对实施例中使用的NaYF4:Yb3+,Er3+纳米晶进行EDS能谱检测,具体结果见图4。由图4可知,纳米晶为规则的六方相晶体,组成元素均匀分布。
4)对实施例1制得的载药材料NaYF4:Yb3+,Er3+@P13-DOX进行SEM检测,具体结果见图5,由图可知所制得的NaYF4:Yb3+,Er3+@P13-DOX为纳米级微球,大小均匀。
5)对实施例1制得的载药材料NaYF4:Yb3+,Er3+@P13-DOX进行光热效应检测,具体结果见图6,由图可知所制得的NaYF4:Yb3+,Er3+@P13-DOX在近红外光808nm照射下,5min内,NaYF4:Yb3+,Er3+@P13-DOX纳米微球的温度可以从25℃迅速上升至55℃,说明稀土材料NaYF4:Yb3+,Er3+的掺入可以很好赋予载药微球光热效应,从而使该粒子在靶向载药的光热疗法中有着良好的运用前景。
6)无论是P13-DOX还是NaYF4:Yb3+,Er3+@P13-DOX纳米微球对肿瘤细胞均具有明显的杀伤作用和浓度依赖性。结果如图7所示,P13-DOX和NaYF4:Yb3+,Er3+@P13-DOX在浓度为200μg/mL时,细胞存活率分别为82.8%±5.33%和63.78%±1.93%;在浓度为12.5μg/mL时,细胞存活率分别为52.58%±5.17%和35.33%±2.96%。说明在同等浓度时,相较于可见光450nm照射作用,用近红外光808nm照射下,药物对癌细胞的抑制率更高。说明NaYF4:Yb3 +,Er3+的引入可以有效提高药物的药效。
7)为了更好的分析NaYF4:Yb3+,Er3+@P13-DOX在诱导细胞凋亡方面的效果,分别使用不同浓度(0、50、200、400μg/mL)药物作用4T1细胞,结果如图8所示。根据凋亡结果发现,NaYF4:Yb3+,Er3+@P13-DOX在50μg/mL时的细胞凋亡率为4.65%,200μg/mL时为11.19%,400μg/mL时为28.55%。
以上所述仅是本发明的优选实施方式,应当指出,对于本领域的普通技术人员来说,在不脱离本发明创造构思的前提下,还可以做出若干改进和变换,这些都属于本发明的保护范围。
Claims (10)
1.一种基于多肽-稀土纳米晶的多功能抗癌纳米材料,其特征在于,它是一种多肽包载药物阿霉素和NaYF4:Yb3+,Er3+纳米晶的亲水性纳米微球;其中,多肽的疏水端以非共价键形式和药物阿霉素、NaYF4:Yb3+,Er3+纳米晶结合,形成疏水核心;多肽的亲水端作为靶向端形成亲水的外壳。
2.一种基于多肽-稀土纳米晶的多功能抗癌纳米材料,其特征在于,NaYF4:Yb3+,Er3+纳米晶和阿霉素、多肽之间的质量比为1:1-5:20-30;多肽采用P13肽。
3.一种基于多肽-稀土纳米晶的多功能抗癌纳米材料的制备方法,其特征在于,首先将NaYF4:Yb3+,Er3+纳米晶和药物DOX分别溶解在有机溶剂中,分别得到NaYF4:Yb3+,Er3+纳米晶的有机溶液和药物DOX的有机溶液;接着将NaYF4:Yb3+,Er3+纳米晶的有机溶液和药物DOX的有机溶液混合,再滴加P13肽水溶液,在20-40℃反应3-20min后透析;透析所得溶液经离心收集上清液,冷冻干燥后,得到基于多肽-稀土纳米晶的多功能抗癌纳米材料。
4.根据权利要求3所述的多功能抗癌纳米材料的制备方法,其特征在于,所述NaYF4:Yb3 +,Er3+纳米晶为六方相晶体,粒径小于20nm,Y3+/Yb3+/Er3+的摩尔比为22-35:1:2-4。
5.根据权利要求3所述的多功能抗癌纳米材料的制备方法,其特征在于,溶解药物DOX的有机溶剂选自N,N-二甲基甲酰胺、二氯甲烷中的至少一种;溶解NaYF4:Yb3+,Er3+纳米晶的有机溶剂选自甲醇、乙醇、二甲基亚砜、N,N-二甲基甲酰胺中的至少一种。
6.根据权利要求3所述的多功能抗癌纳米材料的制备方法,其特征在于,NaYF4:Yb3+,Er3 +纳米晶的有机溶液的浓度为0.5-1mg/mL,药物DOX的有机溶液的浓度为1-4mg/mL,P13肽水溶液的浓度为3-6mg/mL;NaYF4:Yb3+,Er3+纳米晶和药物DOX、P13肽之间的质量比为1:1-5:20-30。
7.根据权利要求3所述的多功能抗癌纳米材料的制备方法,其特征在于,所述透析的条件为:透析液选择去离子水、PBS缓冲液或超纯水,透析温度为25-30℃,透析时间为12-24h,透析袋的截留分子量为1000-3500Da。
8.根据权利要求3所述的多功能抗癌纳米材料的制备方法,其特征在于,所述NaYF4:Yb3 +,Er3+纳米晶的制备方法包括如下步骤:
1)根据NaYF4:Yb3+,Er3+纳米晶中Y、Yb、Er、Na元素的化学计量比,按Y3+/Yb3+/Er3+的摩尔比为22-35:1:2-4称取Y2O3、Yb2O3、Er2O3并用硝酸溶解后,加入络合剂、水和NaOH,得到储备液,pH在8-10范围内;其中,Y离子的浓度为0.44-0.66mmol/mL、Yb离子的浓度为0.015-0.025mmol/mL、Er离子的浓度在0.04-0.065mmol/mL,Na离子的浓度为1.25-1.5mmol/mL;络合剂跟总稀土离子之间的摩尔比为0.9-1:1;
2)将所述储备液中加入乙二醇、表面活性剂和氢氟酸得到白色乳状胶体;然后再加入硝酸,在180-200℃反应18-22h,所得固体产物经洗涤干燥,即NaYF4:Yb3+,Er3+纳米晶。
9.根据权利要求8所述的多功能抗癌纳米材料的制备方法,其特征在于,储备液与乙二醇、表面活性剂之间的比例为8-10mL:20-30mL:0.4-0.6g;氢氟酸所含F离子与储备液中稀土离子总量之间的摩尔比为8-12:1。
10.根据权利要求8所述的多功能抗癌纳米材料的制备方法,其特征在于,络合稳定剂以选自乙二胺四乙酸二钠、2-噻吩甲酰三氟丙酮、乙二胺四乙酸四钠盐中的至少一种;表面活性剂以选自十六烷基三甲基溴化铵、己基三甲基溴化铵中的至少一种。
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