CN112472683A - 一种纳米诊疗剂及其制备方法与应用 - Google Patents
一种纳米诊疗剂及其制备方法与应用 Download PDFInfo
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Abstract
本发明公开了一种纳米诊疗剂及其制备方法与应用,所述纳米诊疗剂包括:纳米颗粒,所述纳米颗粒包括活性氧响应的小分子前药的内核,以两亲性聚合物包覆在所述内核表面形成的外壳。本发明所述纳米诊疗剂是由小分子前药和两亲性聚合物在水中沉积形成,纳米颗粒成分简单,稳定性好,具有肿瘤响应的成像和治疗效果,在肿瘤的诊断与治疗领域具有良好的应用前景。
Description
技术领域
本发明涉及医用纳米材料领域,尤其涉及一种纳米诊疗剂及其制备方法与应用。
背景技术
在过去的几十年中,癌症治疗取得了长足的进步。未来实现精准医疗是癌症治疗的重要发展趋势,然而实现这一目标仍具有挑战性。目前癌症治疗的主要方法仍是采用保守的化学治疗方法,但该方法通常具有快速的血液清除,产生耐药性和严重的副作用等问题。为了减轻副作用并提高对癌细胞的治疗选择性,人们提出了前药的概念。前药通常指那些可以在体内经酶或非酶的刺激转化而释放出活性药物而发挥药效的化合物,这些化合物通常由药物分子经过一定的化学结构修饰后得到,并且在体外展现无活性或活性较小。
目前,在前药的常见设计上,通常是将活性药物包封在可响应的聚合物载体中或通过可响应的链接基团将药物链接到聚合物侧链上,从而实现药物的最佳的药代动力学和药效学特性。然而,大多数已开发的体系常常面临着低载药量和药物过早释放的问题,同时其高分子结构的复杂性可能会阻碍其临床进一步转化。
发明内容
鉴于上述现有技术的不足,本发明的目的在于提供一种纳米诊疗剂及其制备方法与应用,解决肿瘤响应的纳米诊疗剂的低载药量和药物过早释放的问题。
第一方面,本发明实施例提供一种纳米诊疗剂,其中,纳米颗粒,所述纳米颗粒包括活性氧响应的小分子前药的内核,以两亲性聚合物包覆在所述内核表面形成的外壳。
可选地,所述的纳米诊疗剂,其中,所述两亲性聚合物选自普朗尼克、磷脂聚乙二醇、聚乙二醇-聚乳酸中的一种。
可选地,所述的纳米诊疗剂,其中,所述活性氧响应的小分子前药,包含以下结构:
可选地,所述的纳米诊疗剂,其中,所述纳米诊疗剂的粒径为5-100nm。
可选地,所述的纳米诊疗剂,其中,聚合物和前药的质量比例为1:1-200:1。
第二方面,本发明实施例提供一种纳米诊疗剂的制备方法,其中,包括步骤:
将所述两亲性聚合物和所述活性氧响应的小分子前药分散在溶剂中,得到混合液;
向所述混合液中加入水溶液,得到所述纳米诊疗剂。
可选地,所述的纳米诊疗剂的制备方法,其中,所述溶剂选自二甲基亚砜、四氢呋喃、乙腈、N,N-二甲基甲酰胺、乙醇、甲醇中的一种或多种。
可选地,所述的纳米诊疗剂的制备方法,其中,所述水溶液选自磷酸缓冲溶液,生理盐水,蒸馏水中的一种。
可选地,所述的纳米诊疗剂的制备方法,其中,所述溶剂和所述水溶液的体积比为1:10000-1:1。
第三方面,本发明实施例提供一种纳米诊疗剂在制备肿瘤荧光成像和/或肿瘤的生长抑制剂中的应用。
有益效果:本发明实施例提供一种纳米诊疗剂,所述纳米诊疗剂能够同时实现肿瘤的光动力治疗和化学治疗;本发明所述纳米诊疗剂能实现肿瘤的荧光成像。
附图说明
图1为采用高效液相色谱图谱分析HRC溶液,HRC溶液在光照8分钟后,HRC溶液与500mM H2O2孵育1小时和喜树碱溶液的结果;
图2为通过动态激光散射分析的HRC@F127的水合粒径尺寸分布图;
图3为HCT116细胞和L929细胞与5μM HRC@F127一起孵育不同时间后的相对荧光强度(I/I0)图,其中,I0为细胞背景荧光;
图4为通过MTT试验测定评估细胞活力,HCT116和L929细胞与不同浓度的HRC@F127孵育48小时;
图5为通过MTT试验测定评估细胞活力,HCT116和L929细胞与不同浓度的HRC@F127孵育48小时并在第24小时的时间点用671nm光照射(光强度=15mW/cm2)处理5分钟;
图6为在注射药物后的选定时间点对小鼠肿瘤区域的荧光强度的测量结果;
图7为注射药物72小时采集的荷瘤小鼠的主要器官和肿瘤的荧光信号对比,其中一组小鼠注射HRC@F127(n=3),另一组小鼠注射HPPH@F127(n=3);主要器官为心、肝、脾、肺、肾。
图8为经过各种治疗方案的小鼠的相对肿瘤生长曲线;
图9为经过各种治疗方案的小鼠的存活曲线。
具体实施方式
本发明提供一种纳米诊疗剂及其制备方法与应用,为使本发明的目的、技术方案及效果更加清楚、明确,以下对本发明进一步详细说明。应当理解,此处所描述的具体实施例仅用以解释本发明,并不用于限定本发明。
除非另有定义,本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施方式的目的,不是旨在于限制本发明。
本发明实施例提供一种纳米诊疗剂,其中,包括:纳米颗粒,所述纳米颗粒包括活性氧响应的小分子前药的内核,以两亲性聚合物包覆在所述内核表面形成的外壳。
在本实施例中,通过所述两亲性聚合物,可以提高药物的负载率,具有较高的载药量,颗粒稳定性。具有活性氧响应的小分子前药,在具有活性氧水平高的肿瘤细胞中被激活并释放出响应的活性药物和光敏剂,可同时实现肿瘤的选择性荧光成像,提高成像的对比度,以及对肿瘤的选择性的化疗与光动力治疗相结合的联合治疗效果,减少副作用。
在本实施例中,所述两亲性聚合物包括但不限于普朗尼克(Pluronic F127)、磷脂聚乙二醇(DSPE-PEG)、聚乙二醇-聚乳酸(PEG-PLA)。所述的活性氧响应的小分子前药选自由抗癌药物和光敏剂通过活性氧响应链接基团链接而形成的分子组合。所述小分子前药是指小分子药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。其中,抗癌药物可以选自已批准或正在进行临床实验的化学药物和光敏剂药物。所述活性氧响应的小分子前药,可以包含以下结构:
在本实施例的一种实施方式中,所述纳米诊疗剂的粒径可以为5nm至10nm,10nm至20nm,20nm至30nm,30nm至40nm,40nm至60nm,60nm至80nm,80nm至100nm。纳米诊疗剂的粒径在该粒径范围内能够被动靶向蓄积到肿瘤部位。
在本实施例的一种实施方式中,所述两亲性聚合物和所述活性氧响应的小分子前药的质量比为1:1-200:1。在该比例范围内可以实现高药物装载效率。
基于相同的发明构思,本发明实施例提供一种纳米诊疗剂的制备方法,所述方法包括步骤:
S10、将所述两亲性聚合物和所述活性氧响应的小分子前药分散在溶剂中,得到混合液;
S20、向所述混合液中加入水溶液,得到所述纳米诊疗剂。
在本实施例中,所述两亲性聚合物可以选自Pluronic F127、DSPE-PEG、PEG-PLA。活性氧响应的小分子前药可以是由市售CPT和HPPH合成的异二聚体前药HRC。其中,所述CPT为一种疏水性抗肿瘤药物,作用于DNA拓扑异构酶I,是一种广谱的抗肿瘤药物,用于治疗胃癌,结肠癌,白血病及非小细胞肺癌等。HPPH,全称2-((1′-正己氧基)乙基)-2-二乙烯基-焦脱镁叶绿酸(a),英文名2-((’-n-hexyloxy)ethyl)-2-divinyl-pyropheophorbide-a),是一种新型肿瘤光动力治疗(PDT)药物—光敏剂。
在本实施例中,所述溶剂包括但不限于二甲基亚砜、四氢呋喃、乙腈、N,N-二甲基甲酰胺、乙醇、甲醇等。所述水溶液包括但不限于磷酸缓冲溶液,生理盐水,蒸馏水等。
在本实施例的一种实施方式中,所述溶剂和所述水溶液的体积比为1:10000-1:1。在该比例范围内药物可以全部溶解。
基于相同的发明构思,本发明实施例还提供一种纳米诊疗剂在制备肿瘤荧光成像和/或肿瘤的生长抑制剂中的应用。
在本实施例中,可以通过静脉注射将纳米诊疗剂注射到实验动物体内,并在一定时间内如(0至48小时)对肿瘤区域实施光照,观察到可以对肿瘤的生长产生抑制作用。
下面通过具体的实施例对本发明的技术方案做进一步的解释说明。
实施例1
一种活性氧响应的异二聚体前药的合成和表征
首先,通过两步反应路线,由市售CPT和HPPH合成异二聚体前药HRC。在BF3Et2O(110mmol,13ml)的催化下,由巯基乙酸甲酯(70mmol,6.26ml)和丙酮(34mmol,2.55ml)缩合合成化合物1的前体(产率:90%)。1H NMR(300MHz,MeOD)3.718(6H,s),3.463(4H,s),1.603(6H,s)。将化合物1的前体(1g)溶于无水四氢呋喃(150mL)中并在冰水浴中冷却,然后将LiAlH4(1.52g,40.1mmol)缓慢加入反应混合物中。30分钟后,将混合物缓慢加热至回流并保持2个小时。然后加入水(1mL)淬灭反应。过滤混合物,并通过旋转蒸发仪将滤液中的溶剂蒸发。通过二氧化硅柱色谱法纯化得到呈黄色液体化合物1(产率:98%)。1H NMR(300MHz,CDCl3)3.67(4H,t,J=6Hz),3.54(2H,s),2.75(4H,t,J=6Hz),1.53(6H,s)。在40mL无水二氯甲烷中搅拌溶解(S)-(+)-喜树碱(CPT)(348mg,1mmol)和对二甲胺基吡啶(240mg,2mmol),并在氮气保护下在冰浴中冷却。将三光气固体(100mg,0.33mmol)加入到混合物中,并将反应混合物在室温下搅拌30分钟。随后,向反应混合物中加入化合物1(800mg,4mmol),并搅拌过夜。反应结束后,旋转蒸发仪除去溶剂。粗产物经柱色谱纯化,得到化合物2(产率:80%),为浅白色固体。1H NMR(300MHz,MeOD)8.42(1H,s),8.24(1H,d,J=8.4Hz),7.95(1H,d,J=8.1Hz),7.85(1H,t,J=7.7Hz),7.69(1H,t,J=7.5Hz),7.39(1H,s),5.70(1H,d,J=17.4Hz),5.42–5.29(3H,m),4.23(2H,t,J=7.0Hz),3.70(2H,t,J=6.0Hz),2.86–2.74(4H,m),2.28–2.03(2H,m),1.47(6H,s),0.93(3H,t,J=7.5Hz)。将HPPH(12.6mg,0.02mmol),化合物2(14mg,0.025mmol),对二甲胺基吡啶(0.6mg,0.5 0.005mmol)和EDC·HCl(9mg,0.05mmol)溶解于5mL二氯甲烷中并在室温下搅拌24小时,然后混合物通过旋转蒸发仪浓缩,并通过硅胶柱使用乙酸乙酯/己烷作为洗脱剂纯化。产率:70%。1H NMR(300MHz,CDCl3)9.75(1H,d,J=8.1Hz),9.46(1H,s),8.36(1H,d,J=9.7Hz),7.89(1H,t,J=10Hz),7.55-7.47(2H,m),7.28-7.20(3H,m),7.12(1H,d,J=9.6Hz),5.98–5.93(1H,m),5.73(1H,d,J=17.1Hz),5.43–5.25(1H,m),5.23-5.02(2H,m),4.87–4.61(2H,m),4.48–4.12(6H,m),3.80–3.60(6H,m),3.39(3H,d,J=4.8Hz),3.33(3H,s),2.93–2.76(4H,m),2.50–2.07(6H,m),1.95–1.65(10H,m),1.53(6H,s),1.36–1.20(8H,m),1.01-0.78(6H,m),–1.86(1H,d,J=14.4Hz)。ESI-MS m/z[M+]计算值:1188.5064,实际值为[M+H+]:1189.5490。
通过用H2O2或光照射处理制备得到的HRC,然后用高效液相色谱(HPLC)分析反应结果,如图1,经过处理后,在10.65分钟出现一个峰,该峰与CPT的洗脱时间相同,表明药物有活性药物CPT的释放。同时,在24.1min时HRC的峰值明显下降,表明活性氧有效切断了HRC中的链接基团。
实施例2
基于异二聚体前药的纳米诊疗剂的制备和表征
通过纳米沉淀的方法,将HRC和F127溶解于少量的DMSO中,然后加入适量水,则自发形成纳米颗粒HRC@F127纳米颗粒,在HRC:F127=0.2的进料重量比,该纳米颗粒具有约23nm的水合粒径(图2),得到的纳米颗粒具有超过95%的高负载效率。当进料比更改为0.1或0.4时,获得具有相似尺寸的纳米颗粒。所得的HRC@F127纳米颗粒具有稳定性,一周后没有发现明显的沉淀和明显的尺寸变化。相比之下,通过相同方法获得的CPT@F127纳米颗粒的尺寸大于200nm,并且不稳定,在数小时内发生沉淀。同时CPT和HPPH的载药效率只有55%76%。我们进一步研究了这些纳米颗粒的药物释放。在48小时后,HRC@F127仍保留了近98%的HRC,其泄漏百分比(2%),相比于CPT(75%)和HPPH(24%)小得多。
上述结果说明,所制备得到的纳米诊疗剂是基于活性氧响应的异二聚体前药与两亲性聚合物形成的纳米颗粒。所述的纳米诊疗剂有效的提高药物在两亲性聚合物载体的负载率,具有较高的载药量,颗粒稳定性,和降低药物的过早泄露问题,有利于减少副作用。
进一步地,上述制备工艺相对简单、操作方便,不需要复杂昂贵的设备,易于实现工业化生产。
实施例3
纳米诊疗剂应用于选择性癌细胞成像和治疗
选用具有高内源性活性氧水平的癌细胞(HCT116细胞)和具有高内源性活性氧水平低的正常细胞(小鼠成纤维细胞系L929)两种细胞系来进行试验。将HRC@F127与细胞一起孵育24小时后进行荧光成像分析。如图3所示,结果表明相同孵育时间下,HCT116细胞显示出比L929更高的荧光强度,表明HRC@F127在癌细胞较高的活性氧水平的作用下,被激活并释放出更多的HPPH,产生更强的荧光。
同时,通过3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑(MTT)方法评估细胞活性的试验结果表明(图4),在无光照的情况中,HRC@F127对活性氧水平高的HCT116细胞表现出更高的细胞毒性:在20uM的浓度下,HCT116细胞的细胞存活率为37%,L929细胞的存活率为61%。这表明了HRC@F127对肿瘤细胞的选择性化学治疗的效果。在光照条件下(图5),HRC@F127对活性氧水平高的HCT116的细胞毒性进一步提高,与L929细胞之间的差异极大地增加了。在2.5uM的浓度下,HCT116细胞的细胞存活率为4.3%,L929细胞的存活率为80%。这表明了HRC@F127对肿瘤细胞的选择性光动力治疗的效果。产生这样的结果是由于癌细胞中较高的活性氧水平,激活了更多的HRC,释放出更多的HPPH和CPT,从而实现在纳米诊疗剂对癌细胞的选择性荧光成像以及化学和光动力治疗效果。
实施例4
纳米诊疗剂应用于活体肿瘤的荧光成像
选择小鼠皮下异种移植人结肠癌肿瘤模型中进行研究。活体成像结果(图6)表明,静脉内(静脉内)注射HRC@F127后,肿瘤区域的荧光强度明显随时间增长,在48h达到峰值,表明HRC@F127在肿瘤区域具有较好的蓄积能力和能够被肿瘤中的活性氧有效地激活。与HRC@F127相比,HPPH@F127表现出更慢的肿瘤点亮和更快的信号下降。这主要是因为HPPH@F127具有更快的药物泄漏导致HPPH在肿瘤区的蓄积较慢。此外,注射后72小时的主要器官的荧光成像分析表明,在肿瘤部位,HRC@F127的荧光信号远高于HPPH@F127,同时其他主要器官的荧光信号均较低(图7),表明HRC@F127对肿瘤具有高选择性,可用于指示活体肿瘤的位置。总体而言,荧光成像结果表明,HRC@F127可以有效蓄积在肿瘤部位,并有效被激活而实现对肿瘤的荧光成像。
实施例5
纳米诊疗剂应用于活体肿瘤的生长抑制
在无胸腺裸鼠上建立人结肠癌HCT116皮下异种移植肿瘤模型用于评估纳米诊疗剂的肿瘤治疗效果。荷瘤小鼠被随机分为7组(n=5/组),并按以下方案进行治疗:G1(注射PBS),G2(注射PBS+激光照射),G3(注射HRC@F127),G4(注射CPT@F127),G5(注射HPPH@F127+激光照射)和G6(注射HRC@F127+激光照射)。治疗在第一天和第三天分两次进行。对于有激光照射的实验组,在每次药物注射后24h,用671nm激光在肿瘤区域照射(10分钟,100mW/cm2)。每隔一天用游标卡尺测量肿瘤体积,同时监测小鼠的体重,并按照公式V=AB2/2计算肿瘤体积(Tumor volume),其中A是肿瘤的长径,B是肿瘤的短径(mm)。每次测量结果均通过处理前的起始肿瘤体积归一化。实验结果见图8。
如图8所示,无论有或没有激光照射,注射PBS的小鼠的肿瘤均呈现快速生长。无光照下,在第16天,注射HRC@F127对小鼠的肿瘤生长具有明显的抑制效果,与注射CPT的抑制效果相似,表明HRC@F127对肿瘤起到化学治疗的效果。在激光照射下,注射HRC@F127对肿瘤生长的抑制效果进一步提高,显著高于G5(注射HPPH@F127+激光照射)。该结果表明在光照下,HRC@F127对肿瘤起到了化学治疗和光动力治疗的协同治疗的效果。同时,由于具有良好的肿瘤抑制效果,G6(注射HRC@F127+激光照射)的小鼠生存时间明显高于其他组(图9)。
综上所述,本发明提供一种纳米诊疗剂,所述纳米诊疗剂包括:纳米颗粒,所述纳米颗粒包括活性氧响应的小分子前药的内核,以两亲性聚合物包覆在所述内核表面形成的外壳。通过所述两亲性聚合物,可以提高药物的负载率,具有较高的载药量,颗粒稳定性。所述的纳米诊疗剂可在具有活性氧水平高的肿瘤细胞中被激活并释放出响应的活性药物和光敏剂,可同时实现肿瘤的选择性荧光成像,提高成像的对比度,以及对肿瘤的选择性的化疗与光动力治疗相结合的联合治疗效果,减少副作用。对活体肿瘤的生长具有显著的抑制作用,提高荷瘤小鼠的生存时间。在肿瘤的诊断与治疗领域将具有良好的应用前景。
应当理解的是,本发明的应用不限于上述的举例,对本领域普通技术人员来说,可以根据上述说明加以改进或变换,所有这些改进和变换都应属于本发明所附权利要求的保护范围。
Claims (10)
1.一种纳米诊疗剂,其特征在于,包括:纳米颗粒,所述纳米颗粒包括活性氧响应的小分子前药的内核,以两亲性聚合物包覆在所述内核表面形成的外壳。
2.根据权利要求1所述的纳米诊疗剂,其特征在于,所述两亲性聚合物选自普朗尼克、磷脂聚乙二醇、聚乙二醇-聚乳酸中的一种。
4.根据权利要求1-3任一所述的纳米诊疗剂,其特征在于,所述纳米诊疗剂的粒径为5-100nm。
5.根据权利要求1-3任一所述的纳米诊疗剂,其特征在于,所述两亲性聚合物和所述活性氧响应的小分子前药的质量比为1:1-200:1。
6.一种如权利要求1所述的纳米诊疗剂的制备方法,其特征在于,包括:
将所述两亲性聚合物和所述活性氧响应的小分子前药分散在溶剂中,得到混合液;
向所述混合液中加入水溶液,得到所述纳米诊疗剂。
7.根据权利要求6所述的纳米诊疗剂的制备方法,其特征在于,所述溶剂选自二甲基亚砜、四氢呋喃、乙腈、N,N-二甲基甲酰胺、乙醇、甲醇中的一种或多种。
8.根据权利要求6所述的纳米诊疗剂的制备方法,其特征在于,所述水溶液选自磷酸缓冲溶液,生理盐水,蒸馏水中的一种。
9.根据权利要求6所述的纳米诊疗剂的制备方法,其特征在于,所述溶剂和所述水溶液的体积比为1:10000-1:1。
10.一种权利要求1-3任一所述的纳米诊疗剂在制备肿瘤荧光成像和/或肿瘤的生长抑制剂中的应用。
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