CN114569734B - 一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法 - Google Patents
一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法 Download PDFInfo
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Abstract
一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法,属于纳米粒子技术领域。本发明合成了Phenanthriplatin即Phenii,同时还开发出具有GSH响应能力的负电荷聚合物poly Poly‑2‑HD‑co‑HPMDA,并通过共价结合将Phenii键合在poly Poly‑2‑HD‑co‑HPMDA高分子的支链上,形成表面带负电的纳米粒子(NP‑Phenii),可以很好的改善菲啶铂的毒性并提高其疗效。
Description
技术领域
本发明属于纳米粒子技术领域,尤其涉及一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法。
背景技术
传统的铂类抗癌药物(即顺铂、卡铂和奥沙利铂)是最广泛使用的化疗药物之一,并成为全世界使用的约80%的联合治疗方案的一部分。机制上,以铂(II)为基础的药物会产生细胞内的水化物种,并被认为主要结合DNA上的亲核位点,形成链内和/或链间Pt-DNA加合物1。
菲啶铂(cis-[Pt(NH3)2-(phenanthridine)Cl]NO3,phenanthriplatin)是一类基于顺铂的新型抗癌药物,在体外对铂耐药肿瘤细胞显示出良好的活性2。菲啶铂的结构与顺铂相似,但是它含有一个菲啶配体(即含氮杂环化合物)和一个氯原子在正方形平面几何上。但是因其本身带正离子电荷,这种电荷状态导致带负离子的等离子体成分迅速结合。在全身给药后,这些复合物被先天免疫系统的细胞识别和/或可能经历非特异性结合,介导快速清除,体内疗效差和显著的脱靶毒性3,4。
关于铂类药物纳米递送体系研究,这些年越来越多的研究表明,利用纳米递送体系担载铂类药物可以有效的改善铂基抗癌剂的治疗效果,特别针对铂类药物毒性和耐药问题。采用纳米递送体系治疗癌症,可以使药物进入人体之后,更大程度的蓄积到肿瘤部位,具有延长药物的血液循环时间,避免药物到达靶标之前失活和降低系统毒性的特点。这样纳米递送就可以大幅度提高铂基药物递送的靶向性,从而减少对细胞内其他健康组织的毒性副作用。纳米药物传递体系是目前热门的研究方向,也是本设计的出发点。
菲啶铂是一种阳离子型单功能铂类抗癌药物,对多种肿瘤细胞株均有良好的抗癌作用。然而,由于该药物带正电荷,容易与血浆蛋白结合,导致快速的系统清除和有害毒性,这极大地限制了其体内应用。Hao C4等合成了一种亲脂性菲铂(PhenPt(IV))前药。为了进一步降低其毒性,将带负电荷且具有还原反应性的聚合物与PhenPt(IV)组装成PhenPt(IV)NPs。与顺铂相比,PhenPt(IV)NPs对各种癌细胞株的体外杀伤能力高达30倍。此外,在体内,PhenPt(IV)NPs未发现明显的副作用。在4T1肿瘤模型中,肿瘤积累显著增强,药物疗效显著改善。综上所述,本研究为菲安铂的临床转化提供了一种有前景的策略。
参考文献:
1 Bruno,P.M.et al.A subset of platinum-containing chemotherapeuticagents kills cells by inducing ribosome biogenesis stress.Nat Med 23,461-471,doi:10.1038/nm.4291(2017).
2 Kellinger,M.W.,Park,G.Y.,Chong,J.,Lippard,S.J.& Wang,D.Effect of amonofunctional phenanthriplatin-DNA adduct on RNA polymerase IItranscriptional fidelity and translesion synthesis.J Am Chem Soc 135,13054-13061,doi:10.1021/ja405475y(2013).
3 Park,G.Y.,Wilson,J.J.,Song,Y.&Lippard,S.J.Phenanthriplatin,amonofunctional DNA-binding platinum anticancer drug candidate with unusualpotency and cellular activity profile.Proc Natl Acad Sci U S A 109,11987-11992,doi:10.1073/pnas.1207670109(2012).
4 Chen,H.et al.Delivery of Cationic Platinum Prodrugs via ReductionSensitive Polymer for Improved Chemotherapy.Small 17,e2101804,doi:10.1002/smll.202101804(2021).
发明内容
本发明设计并合成了Phenanthriplatin即Phenii,同时还开发出具有GSH响应能力的负电荷聚合物poly Poly-2-HD-co-HPMDA,并通过共价结合将Phenii键合在polyPoly-2-HD-co-HPMDA高分子的支链上,形成表面带负电的纳米粒子(NP-Phenii),可以很好的改善菲啶铂的毒性并提高其疗效。
为实现上述目的,本发明采用了以下技术方案。
(1)聚合物Poly-2-HD-co-HPMDA的合成
将2-羟乙基二硫化物(2-Hydroxyethyl disulfide,2-HD)和1,2,4,5-环己烷四甲酸二酐(1,2,4,5-Cyclohexanetetracarboxylic Dianhydride,HPMDA)置于圆底烧瓶中,然后将DMF加入到烧瓶中连续搅拌48小时;随后,为了将聚合物封端24小时,加入mPEG,通过透析并真空干燥得到负电荷聚合物(Poly-2-HD-co-HPMDA);
2-羟乙基二硫化物与1,2,4,5-环己烷四甲酸二酐的摩尔比优选为1:1,mPEG优选为mPEG2k,2-羟乙基二硫化物与mPEG的摩尔比为5:1。
(2)Phenanthriplatin即Phenii的合成
将顺铂(Cisplatin)、AgNO3分散在超干N,N-二甲基甲酰胺(DMF)中,55℃避光搅拌16h后,溶液由深黄色变为浅灰色混浊液体;过滤后,将菲啶(phenanthridine)溶解在滤液中,55℃避光搅拌16h后,旋蒸除去DMF,加入甲醇溶解,过滤除去沉淀,加无水乙醚使固体沉降收集;固体用甲醇和乙醚洗涤,最后干燥收集得到固体粉末;
顺铂(Cisplatin)、AgNO3、菲啶(phenanthridine)的摩尔比为1:0.9:0.9。
(3)Poly-2-HD-co-HPMDA-Phenii的合成
将步骤(2)Phenii、AgNO3溶解在超干DMF中,55℃避光搅拌16h后,溶液由深黄色变为浅灰色混浊液体,过滤后,将步骤(1)Poly-2-HD-co-HPMDA溶解在滤液中,在55℃下在黑暗中搅拌16小时后,通过透析去除DMF,冷冻干燥;
Phenii、AgNO3、Poly-2-HD-co-HPMDA的摩尔比为1:1:3.4。
(4)表面带负电的纳米粒子NP-Phenii的制备
将Poly-2-HD-co-HPMDA-Phenii溶于DMF中并逐滴加入蒸馏水中,在室温下搅拌10分钟,通过透析去除DMF,通过离心分离收集上清液即得到NP-Phenii。
本发明的优点:
1本方案采用双(2-羟乙基)二硫化物与1,2,4,5-环己烷四甲酸二酐共聚合成对GSH(谷胱甘肽)敏感的聚合物,该聚合物生物安全性良好,可降解。
2本方案采用上述聚合物与带正电菲啶铂药共价结合形成Poly-2-HD-co-HPMDA-Phenii,可降低菲啶铂的毒性,增强其靶向性以及有效性。
附图说明
图1、为高分子(Poly-2-HD-co-HPMDA)的合成
图2.Phenanthriplatin(Phenii)的合成
图3.Poly-2-HD-co-HPMDA-Phenii的合成
图4.poly(2-HD-co-HPMDA)-PEG在d6-DMSO中的核磁氢谱
图5.Phenii在d6-DMSO中的核磁氢谱
图6.Poly-2-HD-co-HPMDA-Phenii在d6-DMSO中的核磁氢谱
图7.NP-Phenii的制备和表征
图8.激光共聚焦用于可视化A549DDP细胞对荧光纳米粒的內吞过程。红色荧光来自纳米粒包裹的Cyanine5.5 NHS ester,蓝色荧光来自DAPI染色的细胞核,绿色荧光来自F-Action染色的细胞膜
图9.Cisplatin,Phenii以及NP-Phenii与不同细胞系作用48h时细胞存活率曲线
图10.Cisplatin,Phenii以及NP-Phenii与A549DDP细胞系作用24h时细胞凋亡图(A)和凋亡统计(B)
图11.NP-Phenii的体内分布
图12.NP-Phenii的抑瘤效果。
具体实施方式
下面结合实施例对本发明做进一步说明,但本发明并不限于以下实施例。
实施例1
1.1高分子(Poly-2-HD-co-HPMDA)的合成
将2-羟乙基二硫化物(2-Hydroxyethyl disulfide,2-HD,0.1mM,)和1,2,4,5-环己烷四甲酸二酐(1,2,4,5-Cyclohexanetetracarboxylic Dianhydride,HPMDA)(0.11mM,246.6mg)置于50mL圆底烧瓶中,然后将10mL DMF加入到烧瓶连续搅拌48小时。随后,为了将聚合物封端24小时,加入mPEG2k(0.02mmol,400mg)。通过透析并真空干燥得到负电荷聚合物(Poly-2-HD-co-HPMDA),干燥产物用1H NMR分析(图4)。
1.2 Phenanthriplatin(Phenii)的合成
将顺铂(Cisplatin,300mg,1mM)、AgNO3(153mg,0.9mM)分散在30毫升超干N,N-二甲基甲酰胺(DMF)中。55℃避光搅拌16h后,溶液由深黄色变为浅灰色混浊液体。过滤后,将菲啶(phenanthridine,153mg,0.9mmol)溶解在滤液中。55℃避光搅拌16h后,旋蒸除去DMF,加入30mL甲醇溶解,过滤除去沉淀,加无水乙醚使固体沉降收集。固体用甲醇和乙醚洗涤3次,最后干燥收集得到固体粉末,干燥产物用1H NMR分析(图5)。
1.3 Poly-2-HD-co-HPMDA-Phenii的合成
将Phenii(505.0mg,1.0mmol)、AgNO3(170mg,1.0mmol)溶解在10mL的超干DMF中。55℃避光搅拌16h后,溶液由深黄色变为浅灰色混浊液体。过滤后,将poly(2-HD-co-HPMDA)-PEG(2500mg)溶解在滤液中。在55℃下在黑暗中搅拌16小时后,通过透析去除DMF(分子截止量为3500)。冷冻干燥后,干燥的产品通过1H NMR进行分析(图6)。
1.4 NP-Phenii的制备和表征
将Poly-2-HD-co-HPMDA-Phenii(30mg)溶于1mL DMF中并逐滴加入10mL蒸馏水中,在室温下搅拌10分钟。通过透析去除DMF(分子截流量为3500),通过离心分离(3000rpm.,5min)收集上清液(NP-Phenii)。NP-Phenii的形态通过TEM(HT-7700,Hitachi,Japan)表征。NP-Phenii的尺寸由Malvern Zetasizer Nano ZS90激光粒度分析仪(Nano ZS,UK)表征。通过电感耦合等离子体质谱法(Inductively Coupled Plasma Mass Spectrometry,ICP-MS)定量测定纳米粒子中Pt的浓度。
1.5 NP-Phenii的体外细胞摄取
将Poly-2-HD-co-HPMDA-Phenii(30mg/mL)和Cyanine5.5 NHS ester(1mg)溶解在1mL DMF中,并在室温下搅拌10分钟。通过透析去除DMF(分子截止Mw=3500)。通过离心分离(5000rpm.,5min)收集上清液(NP@Cyanine5.5 NHS ester)。
通过CLSM和流式细胞术分析细胞内NP@Cyanine5.5 NHS ester检测。对于CLSM观察,将A549DDP细胞以每孔3×104个细胞的密度接种到24孔分室载玻片(ThermoScientific,USA)中,并与补充有10%FBS(1mL)的RPMI1640在37℃下孵育12小时.去除培养基后,将细胞用等价的Cyanine5.5 NHS ester浓度(10μg/mL)的NP@Cyanine5.5 NHS ester处理0.5小时、3小时和6小时,然后去除培养基,将细胞与FITC鬼笔环肽一起孵育根据制造商的协议。随后,将细胞用DAPI染色,然后用激光共聚焦显微镜(OLYMPUS FV1000-IX81,Olympus,Japan)观察。
1.6 NP-Phenii对各种癌细胞的细胞活力
利用MTT测定来检查NP-Phenii对癌细胞(BEL-7404、A549、BEL-7404DDP、A549DDP)的活力。将细胞以每孔5,000个细胞的密度接种在96孔板(Thermo Scientific,美国)中并培养12小时。细胞分别与终浓度为0.005、0.05、0.5、5、10、20、40μM Pt的Cisplatin、Phenii、NP-Phenii孵育48小时。然后,在孔中加入用RPMI1640(100μL)稀释的10%MTT。37℃培养4h后,每孔加入10%SDS(100μL),37℃培养12h。通过酶标仪(SpectraMax)在570nm(峰值吸光度)和650nm(背景吸光度)下测试孔的吸光度。细胞活力表示为测试孔和对照孔的吸光度的比率。
1.7 NP-Phenii对A549DDP细胞的细胞凋亡
将A549DDP细胞以每孔2×105个细胞的密度接种在12孔板(Thermo Scientific,美国)中并培养12小时。细胞与Cisplatin、Phenii、NP-Phenii一起孵育24小时,最终浓度为10μM的Pt。按照制造商的说明收集细胞并通过膜联蛋白V-FITC/PI细胞凋亡试剂盒染色。样品最终通过流式细胞术(Becton Dickinson and Company,USA)进行分析。
1.8体内FL成像和生物分布分析:
将Poly-2-HD-co-HPMDA-Phenii(30mg/mL)和Cyanine7.5 NHS ester(1mg)溶解在1mL DMF中,并在室温下搅拌10分钟。通过透析去除DMF(分子截止Mw=3500)。通过离心分离(5000rpm.,5min)收集上清液(NP@Cyanine7.5 NHS ester)。
LLC细胞(1×106)皮下注射到雌性C57小鼠的右臀部。当肿瘤体积达到约200mm3时,对小鼠进行静脉注射。注入NP@Cyanine7.5 NHS ester。注射后,在IVIS光谱成像系统(Spectrum CT,PerkinElmer,Ex/Em=740nm/800nm)上记录1、4、8、10、12、24小时的FL信号。对于生物分布研究,注射后24小时后处死小鼠,收获肿瘤和正常器官并成像。
1.9 LLC实体瘤的建立和治疗效果
将LLC细胞(1×106)皮下注射到雌性C57小鼠的右侧。小鼠静脉注射。当肿瘤大小达到100mm3时,分别以3.5mg Pt kg-1的剂量注射PBS、顺铂、Phenii和NP-Phenii。每隔一天记录一次肿瘤体积。
2.实验结果与讨论
2.1 NP-Phenii的制备和表征
我们首先合成了Phenanthriplatin(Phenii),如图2所示,随后通过1H NMR对其进行表征(图4)。其次,合成了具有二硫键的还原敏感聚合物poly(2-HD-co-HPMDA)-PEG,并通过1H NMR对其进行了表征(图5)。当全身给药时,带正电荷的Phenii将被免疫系统细胞识别或可能发生非特异性结合,并会迅速清除,导致显着的脱靶毒性。此后,poly-2-HD-co-HPMDA链段上的羧酸与Phenii共价形成聚合物Poly-2-HD-co-HPMDA-Phenii,Poly-2-HD-co-HPMDA-Phenii通过1H NMR表征(图6)。poly-2-HD-co-HPMDA和Poly-2-HD-co-HPMDA-Phenii本质上是两亲性的,因此可以分别自组装成纳米颗粒(NP、NP-Phenii)(图7中A)。通过动态光散射(DLS)(图7C),NP-Phenii的平均直径为63.24nm,这与TEM结果非常一致(平均直径=~40nm,图7中B)。NP和NP-Phenii的Zeta电位为-22.6±1.769mV和-5.67±0.44mV(图7中D),这表明NP-Phenii屏蔽了Phenii的正电荷。具有二硫键的Poly-2-HD-co-HPMDA-Phenii在GSH存在下很容易降解,以验证NP-Phenii在GSH存在下是否可以裂解并释放Phenii。通过电子显微镜可以观察到NP-Phenii在GSH的孵育下降解成小碎片(图7中E),DLS的结果也表明NP-Phenii的粒径在GSH的孵育下发生了显着变化(图7中F)。这表明NP-Phenii在GSH存在下被裂解。纳米粒子的解离必然伴随着药物的释放。研究表明,当NP-Phenii的条件为pH7.4时,24小时后Pt的释放量仅为33%左右。但在10mMGSH的存在下,24小时后Pt的释放量达到约86%(图7中G)。综上所述,上述结果表明,Poly-2-HD-co-HPMDA-Phenii不仅可以自组装成稳定的纳米颗粒,而且可以在GSH存在下快速降解和释放药物。
2.2细胞内吞实验
CLSM可以将纳米粒的內吞过程可视化,采用染料Cyanine5.5 NHS ester标记纳米粒,显示红光,用DAPI染细胞核,显示蓝光,用F-Action染细胞质,显示绿光,如图8所示。红色荧光显示在细胞质中,表明纳米粒确实能被细胞內吞,先绿色荧光分布在红色周围,红色荧光分布蓝色荧光四周,且没有重叠,表明纳米粒不会进入细胞核,并且二价铂是在细胞质从被释放,然后进入细胞核发挥作用。从1-7h,我们观察到红色荧光强度逐渐加强,说明纳米粒的內吞具有时间依赖性,內吞作用随着作用时间的延长而加强。
2.3细胞毒性实验
采用MTT法测定Cisplatin,Phenii以及NP-Phenii对BEL7404和BEL7404/DDP,A549和A549/DDP两对亲本株和顺铂耐药株的细胞毒性,药物作用时间为48h,实验结果如图9所示。药物浓度增大,其毒性会增强,并且对于以上两对细胞系,细胞毒性:Phenii>NP-Phenii>Cisplatin。结果可以说明纳米粒降低了Phenii的毒性,但是显著克服了Cisplatin耐药。
2.4细胞凋亡实验
探究Cisplatin,Phenii以及NP-Phenii对细胞凋亡产生的影响,我们采用AnnexinV/FITC与PI双染的方法,利用流式细胞术检测药物处理相同时间后细胞凋亡的情况。如图10显示,Q2-UL:PI阳性,Annexin V阴性,为细胞坏死;Q2-UR:PI和Annexin V双阳性,为细胞晚期凋亡;Q2-LR:PI阴性,Annexin V阳性,为细胞早期凋亡;Q2-LL:PI和Annexin V双阴性,为正常细胞。可以看出,对照组细胞大多处在左下区域,即大多为正常细胞,经过不同药物处理后,坏死、早期凋亡、晚期凋亡的细胞明显增加。在所有的处理手段中,NP-Phenii效果仅次于Phenii。图10中B更加直观反映出,NP-Phenii处理过后的细胞,凋亡比例是是高于顺铂的。这说明NP-Phenii的效果比游离Cisplatin的效果要好,显著克服了Cisplatin耐药。
2.5 NP-Phenii的体内分布
见图11.
2.6 NP-Phenii的抗肿瘤效果
最后,在患有LLC肺肿瘤的小鼠身上评估了NP-Phenii的抗癌活性。结果显示,与顺铂和NP-Phenii相比,NP-Phenii显着抑制肿瘤生长(图12中B)。顺铂(3.5mg Pt kg-1)治疗小鼠肿瘤生长抑制率仅为49.18%。然而,NP-Phenii处理的小鼠的肿瘤抑制率为80.51%。结果显示,NP-Phenii组肿瘤重量为0.49±0.3g,明显小于顺铂组(1.31±0.16g),这说明NP-Phenii具有优良的抗癌作用。
与传统的Phenanthriplatin相比较可以发现,设计出来的Poly-2-HD-co-HPMDA-Phenii可通过GSH触发释放铂药,而且可以增长Phenanthriplatin的血液循环,增强Phenanthriplatin的肿瘤靶向性,其中水分子很容易脱离,从而可以与DNA碱基一个位点发生配位。开发出具有降低响应能力的负电荷聚合物poly(2-HD-co-HPMDA)-PEG,以封装带正电荷的PhenPt(II),通过静电相互作用形成中性电荷纳米粒子(PhenPt(II)NPs),可以很好的改善毒性和提高疗效,更好的抑制DNA复制过程,使之发生凋亡。
Claims (6)
1.一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法,其特征在于,包括以下步骤:
(1)聚合物 Poly-2-HD-co-HPMDA的合成
将 2-羟乙基二硫化物和 1,2,4,5-环己烷四甲酸二酐置于圆底烧瓶中,然后将 DMF加入到 烧瓶中连续搅拌 48 小时; 随后,为了将聚合物封端24小时,加入mPEG, 通过透析并真空干燥得到负电荷聚合物Poly-2-HD-co-HPMDA;
(2)Phenanthriplatin 即Phenii的合成
将顺铂、AgNO3分散在超干 N,N-二甲基甲酰胺中,55℃避光搅拌16h后,溶液由深黄色变为浅灰色混浊液体;过滤后,将菲啶溶解在滤液中,55℃避光搅拌16h后,旋蒸除去DMF,加入甲醇溶解,过滤除去沉淀,加无水乙醚使固体沉降收集;固体用甲醇和乙醚洗涤,最后干燥收集得到固体粉末;
(3) Poly-2-HD-co-HPMDA-Phenii的合成
将 步骤(2)Phenii、AgNO3 溶解在超干 DMF中,55℃避光搅拌16h后,溶液由深黄色变为浅灰色混浊液体,过滤后,将步骤(1)Poly-2-HD-co-HPMDA溶解在滤液中,在55℃下在黑暗中搅拌16小时后,通过透析去除 DMF,冷冻干燥;
(4)表面带负电的纳米粒子NP-Phenii的制备
将Poly-2-HD-co-HPMDA-Phenii溶于DMF 中并逐滴加入蒸馏水中,在室温下搅拌 10分钟, 通过透析去除 DMF,通过离心分离收集上清液即得到NP-Phenii。
2.按照权利要求1所述的一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法,其特征在于,步骤(1)中2-羟乙基二硫化物与1,2,4,5-环己烷四甲酸二酐的摩尔比为1:1,mPEG为mPEG2k,2-羟乙基二硫化物与mPEG的摩尔比为5:1。
3.按照权利要求1所述的一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法,其特征在于,步骤(2)中顺铂、AgNO3、菲啶的摩尔比为1:0.9:0.9。
4.按照权利要求1所述的一种基于还原敏感聚合物递送阳离子铂药的纳米粒的制备方法,其特征在于,Phenii、AgNO3、Poly-2-HD-co-HPMDA的摩尔比为1:1:3.4。
5.按照权利要求1-4任一项所述的方法制备得到的纳米粒。
6.按照权利要求1-4任一项所述的方法制备得到的纳米粒在制备抗肿瘤药物中的应用。
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