CN114437357A - 一种分级释药的肿瘤高渗透聚合物及其制备方法与应用 - Google Patents
一种分级释药的肿瘤高渗透聚合物及其制备方法与应用 Download PDFInfo
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Abstract
本发明属于生物医药技术领域,具体涉及一种分级释药的肿瘤高渗透聚合物及其制备方法与应用。该聚合物由马来酰亚胺‑聚乙二醇、聚天冬氨酸‑接枝聚乙烯亚胺、聚赖氨酸‑接枝苯甲醛制成,其尺寸较小,通过各嵌段相互作用,协同达到了渗透肿瘤组织并聚集的效果;进一步负载结合抗肿瘤小分子抑制剂、抗体和小干扰RNA,可以减少胶原基质的旁分泌,增加杀伤性免疫细胞的肿瘤浸润,降低其葡萄糖量摄取量来提高肿瘤微环境的葡萄糖含量,最终达到显著改善肿瘤微环境、治疗肿瘤的效果。
Description
技术领域
本发明属于生物医药技术领域。更具体地,涉及一种分级释药的肿瘤高渗透 聚合物及其制备方法与应用。
背景技术
肿瘤间质是肿瘤组织中除肿瘤细胞外其他成分的统称,包括细胞成分(间质 细胞)和非细胞成分两大类。其中,胰腺癌具有较为丰富的肿瘤间质,这些肿瘤 间质可以促进肿瘤细胞的生长和转移,对化疗产生耐药性,并构建起物理屏障阻 碍药物进入肿瘤。胰腺癌的细胞间质主要由非肿瘤细胞构成,如:胰腺星状细胞 (PSCs)、肿瘤相关成纤维细胞、免疫细胞和血管内皮细胞等,这些细胞与肿 瘤之间相互影响,分泌细胞外基质构成物理屏障。为了治疗肿瘤疾病,中国专利 申请公开了一种肿瘤间质pH敏感型钯向树状聚合物,该聚合物可以实现药物的 肿瘤靶向递送,增加药物在肿瘤细胞内的累积,但是治疗效果有限。
研究发现,癌症中形成的肿瘤间质是造成癌症免疫抑制微环境及难以药物治 疗的主要原因:一方面,由于致密的肿瘤间质的存在,机体的免疫细胞很难浸润 到肿瘤组织,并且趋化因子1(CXCL1)基因呈高表达,促进星状细胞的活化, 促进肿瘤间质的胶原和细胞外基质形成;另一方面,由于肿瘤间质的存在,细胞 生长所需要的葡萄糖在肿瘤组织中供应不足,根据Warburg效应,肿瘤细胞主要 通过糖酵解的方式获取能量,这种方式会促进对葡萄糖的摄取和乳酸的形成,形 成了肿瘤组织中极度缺糖和酸性的微环境,而同样需要摄取葡萄糖维持正常细胞 活动发挥监控和杀伤功能的T细胞在肿瘤微环境下,免疫效果显著降低。
发明内容
本发明要解决的技术问题是克服现有肿瘤靶向聚合物无法克服肿瘤间质难 以浸润的缺陷和不足,提供一种分级释药的肿瘤高渗透聚合物。
本发明的目的是提供所述分级释药的肿瘤高渗透聚合物的制备方法。
本发明另一目的是提供所述分级释药的肿瘤高渗透聚合物在制备抗肿瘤药 物中的应用。
本发明另一目的是提供一种分级释药的肿瘤高渗透药物。
本发明上述目的通过以下技术方案实现:
一种分级释药的肿瘤高渗透聚合物,所述聚合物由马来酰亚胺-聚乙二醇 (Mal-PEG)、聚天冬氨酸-接枝聚乙烯亚胺(PAsp(-g-lPEI))、聚赖氨酸-接枝 苯甲醛(PLys(BZD))制成,为三嵌段聚合物:马来酰亚胺-聚乙二醇-聚天冬氨 酸(接枝聚乙烯亚胺)-聚赖氨酸(接枝苯甲醛)(Mal-PEG-PAsp(-g-lPEI)-PLys(BZD), 缩写MPAEB)。
进一步地,所述聚合物具有如下结构:
其中,m为6~12的整数,n为18~30的整数,p为10~12的整数。
胰腺癌是渗透性很差的高致密性实体瘤,在聚合物中引入可以键连抗体等靶 向分子的马来酰亚胺基团可以显著增强聚合物在肿瘤的富集和渗透效果;通过在 聚天冬氨酸上接枝小分子量的聚乙烯亚胺,可提高阳离子密度,增强siRNA、抗 肿瘤小分子抑制剂等的负载效果;聚赖氨酸嵌段上接枝疏水苯环(由苯甲醛通过 可响应肿瘤微环境pH(pH 6.5)断裂的亚胺键键连到聚合物载体上),当聚合 物载体自组装形成的胶束在肿瘤微环境中响应,亚胺键断裂脱去苯环后,可以由 疏水变亲水;同时,本发明所得聚合物的尺寸较小,更加有助于聚合物在瘤内实 现高效渗透。
更进一步地,所述聚天冬氨酸-接枝聚乙烯亚胺的嵌段分子量为3200~6500 Da。
进一步地,所述聚赖氨酸-接枝苯甲醛的嵌段分子量为5000~8300Da。
更进一步地,所述马来酰亚胺-聚乙二醇的嵌段中,聚乙二醇的分子量为 1800~2200Da。
另外的,本发明还提供了所述分级释药的肿瘤高渗透聚合物的制备方法,具 体包括如下步骤:
S1、炔丙胺引发L-天冬氨酸-4-苄酯-N-羧基环内酸酐(BLA-NCA)开环聚 合成炔基聚天冬氨酸(alkynyl-PBLA),再用线性聚乙烯亚胺氨解,得到炔基聚 天冬氨酸-接枝聚乙酰亚胺(alkynyl-PAsp(-g-lPEI));
S2、以3-叠氮丙胺引发N6-苄氧羰基-L-赖氨酸环内酸酐(Lys-NCA)开环聚 合成叠氮基聚赖氨酸(N3-PLL(Z)),再用三氟乙酸脱去苄基保护、接枝苯甲醛, 得到叠氮基聚赖氨酸-接枝苯甲醛(N3-PLys(BZD));
S3、通过点击化学将步骤S1、S2所得产物对接,得到聚天冬氨酸-接枝聚乙 烯亚胺-聚赖氨酸-接枝苯甲醛(PAsp(-g-lPEI)-PLys(BZD)),再将马来酰亚胺-聚 乙二醇-羧基与聚天冬氨酸的端氨基酰胺化键相连,即得终产物 (Mal-PEG-PAsp(-g-lPEI)-PLys(BZD),缩写MPAEB)。
进一步地,步骤S1、S2、S3的反应在15~40℃条件下进行。
更进一步地,步骤S1中,还需要添加无水二氯甲烷作溶剂,在氩气的保护 下以及室温条件下进行反应,所得产物需要用冷乙醚沉淀洗涤,离心收集产物;
进一步地,步骤S2中,还需要添加无水N,N-二甲基甲酰胺以及无水氯仿作 溶剂(体积比1:1),添加乙酰氯在氩气保护下以及室温条件下进行反应所得产 物需要用冷乙醚沉淀洗涤,离心收集产物。
更进一步地,步骤S3中,还需要添加二甲基亚砜以及水作为溶剂,加入硫 酸铜/五甲基二乙烯基三胺水溶液(含15μ摩尔的铜离子,摩尔比为1:1),混 合溶液在在真空条件下进行冻融循环后,在室温以及避光条件下进行反应,反应 结束后用pH=7.4的乙二胺四乙酸二钠水溶液透析除去Cu离子,冷冻干燥收集 中间产物聚天冬氨酸-接枝聚乙烯亚胺-聚赖氨酸-接枝苯甲醛;然后添加N-羟基 琥珀酰亚胺、1-乙基-(3-二甲氨基丙基)碳二酰亚胺盐酸盐以及马来酰亚胺-聚乙二 醇-羧基与中间产物在室温下混合6小时后在冷乙醇中沉淀,离心收集沉淀物后 用冷乙醇和冷乙醚洗涤3此后真空干燥得到最终产物。
另外的,本发明还提供了所述分级释药的肿瘤高渗透聚合物在制备抗肿瘤药 物中的应用。
另外的,本发明还提供了一种分级释药的肿瘤高渗透药物,其含有所述分级 释药的肿瘤高渗透聚合物、抗肿瘤小分子抑制剂、抗体和小干扰RNA。
优选地,所述抗体为抗间皮素(MSLN)抗体。当肿瘤高渗透药物给药后, MSLN抗体的靶向功能可以将负载的CXCL1 siRNA和小分子药物的药物靶向递 送到肿瘤区域,同时MSLN抗体还可以促使肿瘤细胞增加摄取药物的驱动力, 显著增加药物的渗透。
优选地,所述小干扰RNA可为CXCL1 siRNA,其可以特异性地抑制肿瘤细 胞CXCL1的分泌,改善肿瘤微环境,促进免疫细胞往肿瘤部位浸润。
优选地,所述抗肿瘤小分子抑制剂为PI3K抑制剂渥曼青霉素(WT),在 Warburg效应中,葡萄糖转运受体1(GLUT1)发挥着重要的功能,PI3K信号 通路作为调控GLUT1表达的通路之一,抑制PI3K信号可以通过抑制GLUT1的 表达来抑制肿瘤细胞葡萄糖的摄取,增加肿瘤微环境中的葡萄糖量来激活微环境 中浸润的T细胞的功能,达到杀伤肿瘤细胞的效果。因此,WT通过抑制肿瘤细 胞、巨噬细胞PI3K信号通路来抑制GLUT1的表达,从而抑制肿瘤细胞的葡萄 糖摄取,增加微环境中的葡萄糖含量,为浸润的T细胞发挥肿瘤杀伤功能提供保 障。
即,本发明构建了一种具有靶向功能的pH敏感的分级释药肿瘤高渗透药物 MSLN-siRNA/WT-NPs(M-s/W-NPs),用于联合递送CXCL1 siRNA和PI3K信 号通路抑制剂渥曼青霉素(WT)。为保证纳米载体能够高效靶向递送到胰腺癌, 在聚合物胶束外周修饰上了抗间皮素抗体,当药物尾静脉给药后,MSLN抗体的 靶向功能可以将纳米药物靶向递送到肿瘤区域,促进肿瘤细胞摄取纳米药物,同 时,纳米药物响应溶酶体的酸性环境,释放出CXCL1siRNA和PI3K抑制剂 WT。一方面,CXCL1 siRNA特异性抑制肿瘤细胞CXCL1的分泌,促进免疫细 胞往肿瘤部位浸润;另一方面,WT通过抑制肿瘤细胞PI3K信号通路来抑制 GLUT1的表达,从而抑制肿瘤细胞的葡萄糖转运过程,增加微环境中的葡萄糖 含量,为浸润的T细胞发挥肿瘤杀伤功能提供保障。
本发明具有以下有益效果:
本发明提供了一种可负载小分子药物、靶向抗体等的分级释药肿瘤高渗透聚 合物,该聚合物由马来酰亚胺-聚乙二醇、聚天冬氨酸-接枝聚乙烯亚胺、聚赖氨 酸-接枝苯甲醛制成,其尺寸较小,通过各嵌段相互作用,协同达到了渗透肿瘤 组织并聚集的效果;进一步负载结合抗肿瘤小分子抑制剂、抗体和小干扰RNA, 可以减少胶原基质的旁分泌,增加杀伤性免疫细胞的肿瘤浸润,降低其葡萄糖量 摄取量来提高肿瘤微环境的葡萄糖含量,最终达到显著改善肿瘤微环境、治疗肿 瘤的效果。
附图说明
图1为聚合物MPAEB的合成线路图。
图2为本发明实施例1步骤S1所得聚天冬氨酸嵌段产物在DMSO-d6中的 1H NMR谱图。
图3为本发明实施例1步骤S2所得聚赖氨酸嵌段产物在DMSO-d6中的1H NMR谱图。
图4为本发明实施例1步骤S3所得终产物马来酰亚胺-聚乙二醇-聚天冬氨 酸酰聚乙烯亚胺-聚赖氨酸苯甲醛亚胺MPAEB在DMSO-d6中的1H NMR谱图 (左)及预聚物的凝胶渗透色谱(GPC)曲线(右)。
图5为本发明实施例2中靶向纳米药物M-s/W-NPs以不同N/P比复合siRNA 的粒径电位变化图。
图6A为实施例2中聚合物胶束靶向纳米药物(M-s/W-NP)和非靶向抗体修饰 的纳米药物(I-s/W-NP)在pH=7.4时的粒径;图6B为实施例2中M-s/W-NP在不 同pH条件下的动态光散射DLS测定分析仪检测的粒径变化图;图6C为实施例 2中M-s/W-NP在不同pH条件下的TEM图片。
图7为本发明实施例2中靶向纳米药物M-s/W-NPs在不同pH条件下WT的 释放情况图。
图8为本发明实施例3中小动物活体成像仪拍摄尾静脉注射后离体观 察动物肿瘤和主要器官的富集情况图(左)及肿瘤切片后观察其渗透情 况图(右)。
图9为本发明实施例4中接受不同药物治疗的荷瘤小鼠肿瘤生长抑制 情况统计图,包括荷瘤小鼠肿瘤体积变化曲线(左)和荷瘤小鼠的生存 曲线(右)。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明,但实施例并不对本 发明做任何形式的限定。除非特别说明,本发明采用的试剂、方法和设备为本技 术领域常规试剂、方法和设备。
其中,靶向抗体(The anti-mesothelin antibody(ab187063),Anti-MSLN): 具有靶向效果,购自Abcam;同类型对照抗体(Isotype control,Cat#BE0090), 与靶向抗体理化性质完全相同,不同之处在于,不具有靶向效果,购自Bio X Cell (West Belgium,NH,USA)。
除非特别说明,以下实施例所用试剂和材料均为市购。
实施例1分级释药的肿瘤高渗透聚合物的制备
S1、炔基聚天冬氨酸聚乙酰亚胺alkynyl-PAsp(-g-lPEI)-NH2的合成
合成路线如下:
反应步骤如下:
在氩气的保护下,将炔丙胺(0.055g,55g/mol,1.0mmo)加入到50mL干燥 的烧瓶中后加入无水二氯甲烷(20mL)使之溶解;然后,将L-天冬氨酸-4-苄酯-N- 羧基环内酸酐BLA-NCA(2.49g,249.22g/mol,10mmol)溶解于2mL无水DMF 中,加入烧瓶中;密封后在室温下反应48h后将溶液加入到300mL冷乙醚中, 离心收集沉淀物,用冷乙醚洗涤3次,真空干燥得到产物:炔基聚天冬氨酸 alkynyl-PBLA-NH2;将alkynyl-PBLA-NH2(1.8g,1800g/mol,1.0mmol)溶于20 mL二甲基亚砜(DMSO)后加入线性聚乙酰亚胺(lPEI)(7.7g,430g/mol,18mmol, 2eq.)在氩气保护下室温下反应48h;所得溶液在去离子水中透析(透析袋截留分子量:1kDa)两天,冷冻干燥得到产物炔基聚天冬氨酸聚乙酰亚胺 alkynyl-PAsp(-g-lPEI)-NH2。
图2为步骤S1所得产物在DMSO-d6中的1H NMR谱图的核磁谱图,由上 到下依次为:炔基聚天冬氨酸alkynyl-PBLA-NH2和炔基聚天冬氨酸聚乙酰亚胺 alkynyl-PAsp(-g-1PEI)-NH2。图中标注的各基团均有相应的峰响应,说明本发明 制备得到了相应的产物。
S2、叠氮基聚赖氨酸苯甲醛亚胺N3-PLys(BZD)的合成
合成路线如下:
反应步骤如下:
在氩气保护下,将0.025g 3-叠氮丙胺(306.12g/mol,0.25mmol)和1.91g N6- 苄氧羰基-L-赖氨酸环内酸酐(Lys-NCA)(306.12g/mol,6.25mmol)溶解在30mL 无水DMF和CHCl3(v:v=1:10)中,在35℃下搅拌48h后,加入2.36g乙酰氯(78.5 g/mol,30mmol,100eq),室温下继续反应24h后,加入过量的冷乙醚,离心 收集沉淀,用冷乙醚洗涤三次,真空干燥,得到叠氮基聚赖氨酸N3-PLL(Z);将 N3-PLL(Z)(2.0g,6300g/mol,0.32mmol)溶于含30%氢溴酸的三氟乙酸溶剂(3mL) 中进行脱保护,在室温下磁力搅拌4h,加入到400mL冷乙醚中;沉淀经过滤、 乙醚洗涤三次,真空干燥;所得产物在去离子水中透析72h,冷冻干燥后得到 N3-PLys;在氮气及苯甲醛(3.7g、106.12g/mol、35mmol、5eq.)的保护下,将得 到的聚合物N3-PLys(1.2g、4100g/mol、0.29mmol.)溶解在30mL的超干DMF 溶剂中,溶液在室温下搅拌24h,然后放入截留分子量为3.5kDa的透析袋中在 甲醇里透析;透析袋中的混合物在冷乙醚(400mL)中沉淀并过滤,所得固体经乙 醚洗涤3次后真空干燥得到产物:叠氮基聚赖氨酸苯甲醛亚胺N3-PLys(BZD)。
图3为步骤S2所得产物在DMSO-d6中的1H NMR谱图的核磁谱图,由上 到下依次为:叠氮基聚赖氨酸N3-PLL(Z)、脱去苯环保护的叠氮基聚赖氨酸 N3-PLys、叠氮基聚赖氨酸苯甲醛亚胺N3-PLys(BZD)。图中标注的各基团均有相 应的峰响应,说明本发明制备得到了相应的产物。
S3、马来酰亚胺-聚乙二醇-聚天冬氨酸酰聚乙烯亚胺-聚赖氨酸苯甲醛亚胺 Mal-PEG-PAsp(-g-lPEI)-PLys(BZD)的合成
合成路线如下:
反应步骤如下:
分别将步骤S1所得alkynyl-PAsp(-g-lPEI)-NH2(0.56g,5600g/mol,0.1mmol) 和步骤S2所得N3-PLys(BZD)(0.56g,5600g/mol,0.1mmol)溶于二甲基亚砜和 水(30mL,v:v=1:1)混合溶液中,加入硫酸铜/五甲基二乙烯三胺CuSO4/PMDETA 水溶液(含15μ的铜离子,摩尔比为1:1),溶液在真空条件下经2次冻融循环脱 氧,然后加入抗坏血酸(0.15mmol);该混合物经一次冻融除氧后在室温避光条件 下搅拌反应24小时以上;反应结束后,用pH=7.4的EDTA水溶液透析3d以除 去铜离子,冷冻干燥,然后把产物溶解于二甲基亚砜和水(30mL,v:v=1:1)混合 溶液中,加入N-羟基琥珀酰亚胺(11mg,115.09g/mol,0.083mmol),1-乙基-(3- 二甲氨基丙基)碳二酰亚胺盐酸盐(19mg,191.70g/mol,0.083mmol)和马来酰亚 胺-聚乙二醇-羧基Mal-PEG2k-COOH(0.2g,2000g/mol,0.1mmol)后室温反应6h; 将所得混合溶液加入到500mL的冷乙醚中,离心收集沉淀物并用冷乙醚洗涤三 次,最后真空干燥得到产物马来酰亚胺-聚乙二醇-聚天冬氨酸酰聚乙烯亚胺-聚赖 氨酸苯甲醛亚胺(Mal-PEG-PAsp(-g-lPEI)-PLys(BZD)),缩写为MPAEB。
图4为步骤S3所得产物MPAEB在DMSO-d6中的1H NMR谱图的核磁谱 图及凝胶渗透色谱(GPC)曲线(使用凝胶渗透色谱(GPC)系统,以聚苯乙烯为 校准标准,估算了聚合物的分子量;以含1g/L溴化锂的N,N-二甲基甲酰胺为洗 脱液,流速为1.0mL/min并对聚合物的信号强度进行了归一化处理)。图4(左) 中标注的各基团均有相应的峰响应,说明本发明制备得到了相应的产物;图4(右) 预聚物的凝胶渗透色谱(GPC)曲线也能说明其含有相应的相应基团,与核磁图 相辅相成,表征反应所得产物分子量的差别。
实施例2靶向纳米药物的制备及表征
取实施例1所得聚合物MPAEB通过乳化法制备聚合物胶束靶向纳米药物。 具体步骤如下:
将3mg PI3K抑制剂渥曼青霉素(WT)溶解在1.5mL氯仿中,另取40mg MPAEB聚合物溶解在0.5mL DMSO溶剂中,然后将二者混合均匀;取20mL PBS 缓冲液于小烧杯中,在冰浴和超声的条件下缓慢滴入上述混合溶液;所得乳化液 旋蒸去掉氯仿,将得到的溶液移入透析袋(MW=14kDa)中,在PBS缓冲液中 透析4h,除去有机溶剂DMSO及游离聚合物等,加入CXCL1 siRNA,涡旋30 秒后静置半小时,使siRNA得到充分复合;将靶向抗体(Anti-MSLN)加入到 含有三(2-羰基乙基)磷盐酸盐(TCEP)的水溶液中,震荡5分钟并静置半小时, 加入到已经复合好siRNA的体系中,于4℃下孵育过夜,用滤头过滤掉大颗粒, 超滤上述滤液,浓缩后得到聚合物胶束靶向纳米药物MSLN-siRNA/WT-NPs (M-s/W-NPs)。
将上述方法中的靶向抗体(Anti-MSLN)替换为同类型对照抗体(Isotypecontrol)其他参数及方法不变,制备得到同型非靶向抗体修饰的纳米药物 I-s/W-NP,作为对照组。
用Nano ZS粒径电位仪测定靶向纳米药物M-s/W-NPs的粒径和Zeta电位, 结果参见图5。由图可见,复合物的粒径随N/P比的增大而减小,在N/P比为6 时达到86.52±5.57nm,N/P比为6时形成的复合物带弱正电荷(+1.91±0.53mV)。
采用透射电镜(TEM)对所得聚合物胶束靶向纳米药物M-s/W-NPs、非靶 向抗体修饰的纳米药物I-s/W-NP的形貌用进行表征。结果参见图6:
由图6A可见,聚合物胶束靶向纳米药物(M-s/W-NP)和非靶向抗体修饰的纳 米药物(I-s/W-NP)在pH=7.4时的水合粒径基本一致。
由图6B、6C可见,M-s/W-NP的粒径从pH 7.4时的80nm显著减小到pH 6.5 时的40nm,这意味着通过断裂肿瘤组织中的苄基亚胺键(pH 6.5),暴露的氨基 将实现更好的siRNA负载,使残余siRNA纳米颗粒变得更小;动态光散射DLS 测定分析仪检测也证实了这一点,这对残余siRNA纳米药物在瘤内渗透有很好 的辅助作用。
W-NP的制备:制备方法参考实施例2,不同之处在于,不负载靶向抗体 (Anti-MSLN)和CXCL1 siRNA,其余方法参考实施例2。
s/W-NP的制备:制备方法参考实施例2,不同之处在于,不负载靶向抗体 (Anti-MSLN),其余方法参考实施例2。
测定聚合物胶束W-NP和s/W-NP在正常生理条件(pH=7.4)和肿瘤组织 (pH=6.5)时的WT释放,结果如图7所示,在pH为7.4时,负载siRNA与否 均基本不释放WT,表明在血流和正常组织中均能有效地防止药物渗漏;而当pH 为6.5时,W-NP释放WT的速度变得非常快,6h释放了60%以上的WT,这是 由于苄基亚胺键的断裂使胶束核具有亲水性而解体,负载siRNA后的WT释放 虽然变慢,但6h内释放量仍接近50%,证明纳米体系可在肿瘤基质中实现WT 的有效释放,并且,pH为6.5时的整体效果明显pH为7.4时好。
实施例3肿瘤靶向与瘤内渗透效果
1、实验材料:实验使用鼠源胰腺癌Panc02细胞系,4~6周龄的C57BL/6小 鼠购置于广东省动物中心,所有动物操作程序均遵照中山大学“实验动物关爱和 使用指南”进行实验。所有涉及动物的实验均严格遵守《中国动物管理条例》(1988 年,2017年修订)和《中国实验动物人道待遇指南》(MOST 2006)。
靶向(M-SCR/DiR-NPs)聚合物胶束的制备:
参考实施例2中纳米药物的制备方法,将其中的PI3K抑制剂渥曼青霉素 (WT)替换为DiR碘化物(1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide;CAS号100068-60-8),将CXCL1 siRNA替换为标记了AF750荧光的空 白RNA(简称M-AF750-SCR),其余参数及制备方法参考实施例2,制备得到 靶向(M-SCR/DiR-NPs)聚合物胶束。
非靶向(I-SCR/DiR-NPs)聚合物胶束的制备:
参考实施例2中纳米药物的制备方法,将其中的PI3K抑制剂渥曼青霉素 (WT)替换为DiR碘化物(1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide;CAS号100068-60-8),将CXCL1 siRNA替换为标记了AF750荧光的空 白RNA(简称M-AF750-SCR),将靶向抗体(Anti-MSLN)替换为同类型对照 抗体(Isotype control),其余参数及制备方法参考实施例2,制备得到非靶向 (I-SCR/DiR-NPs)聚合物胶束。
2、实验方法:
原位胰腺癌动物模型建模:脱净小鼠腹部毛发,在小鼠左下腹用手术刀切出 1cm左右的缺口,暴露胰腺组织,将Panc02胰腺癌细胞悬液50μL(1×106个) 注射到小鼠胰腺部位,碘伏消毒后缝合伤口。建模5天后进行不同的给药处理, 并在第5天和第14天通过MRI检测肿瘤的大小。记录小鼠生存期用以统计生存 率。
建立胰腺癌动物模型5天后的给药处理:将靶向(M-SCR/DiR-NPs)和非靶 向(I-SCR/DiR-NPs)的聚合物胶束溶液;聚合物胶束溶液经尾静脉注射到小鼠 体内,注射24h后让小鼠安乐死,取出主要肿瘤和主要器官,用小动物活体成 像仪观察拍照。
3、实验结果
结果如图8所示,靶向聚合物胶束组给药后,肿瘤部位的荧光强度明显优于 非靶向聚合物胶束组;而且,肿瘤切片的荧光结果显示,由于聚合物载体中聚赖 氨酸嵌段上疏水苯环(由苯甲醛通过可响应肿瘤微环境pH(pH=6.5)断裂的亚 胺键键连到聚合物载体上)在聚合物载体自组装形成的胶束后,在肿瘤微环境中 苄基亚胺键响应断裂脱去苯环后,由疏水变亲水,胶束发生坍缩,从而粒径智能 变小的策略能很好地辅助纳米药物渗透。根据上述结果,说明靶向聚合物胶束可 以实现药物在小鼠原位胰腺癌的高效递送。
实施例4动物水平抑瘤效果研究
1、实验材料:
4~6周龄的C57BL/6小鼠购置于广东省动物中心,所有动物操作程序均遵照 中山大学“实验动物关爱和使用指南”进行实验。所有涉及动物的实验均严格遵守 《中国动物管理条例》(1988年,2017年修订)和《中国实验动物人道待遇指 南》(MOST 2006)。
不含WT的纳米药物Iso-WT-NPs(I-WT-NP)制备:制备方法参考实施例2, 不同之处在于,不负载PI3K抑制剂渥曼青霉素(WT),其余方法参考实施例2。
不含CXCL1 siRNA的纳米药物Iso-siRNA-NPs(I-siR-NP)制备:制备方法 参考实施例2,不同之处在于,不负载CXCL1 siRNA,其余方法参考实施例2。
同类型非靶向对照抗体修饰的纳米药物I-s/W-NP:制备方法参考实施例2, 不同之处在于,将靶向抗体(Anti-MSLN)替换为同类型非靶向对照抗体,其余 方法参考实施例2。
抗间皮素抗体修饰的纳米药物M-s/W-NP:实施例2制备所得靶向纳米药物。
2、实验方法:
胰腺癌皮下瘤动物模型建模:种瘤前,首先清洁干净小鼠毛发,将100μL含 1×106个Panc02胰腺癌细胞悬液接种于C57BL/6小鼠右腿皮下建立动物肿瘤模 型;小鼠分别于第6、9、12、15天尾静脉注射PBS、I-s/W-NP、I-siR-NP、I-WT-NP 和M-s/W-NP。电子游标卡尺测量肿瘤大小,计算肿瘤体积公式为:肿瘤体积=0.5× 长×宽2;记录小鼠生存期用以统计生存率。
3、实验结果:
结果如图9所示,药物不处理(PBS)组和I-WT-NP组肿瘤急剧生长,在第 14天的时候肿瘤体积已接近3000mm3及2000mm3;I-siR-NP组和I-s/W-NP组 处理后只观察到较弱的肿瘤抑制效果;M-s/W-NP组处理后可以显著抑制肿瘤的 生长,与第5天对比,14天的肿瘤大小没有明显增加。小鼠的生存曲线统计也 观察到相似的结果,M-s/W-NP处理后可以显著延长小鼠的生存期。
上述实施例为本发明较佳的实施方式,但本发明的实施方式并不受上述实施 例的限制,其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替 代、组合、简化,均应为等效的置换方式,都包含在本发明的保护范围之内。
Claims (10)
1.一种分级释药的肿瘤高渗透聚合物,其特征在于,所述聚合物由马来酰亚胺-聚乙二醇、聚天冬氨酸-接枝聚乙烯亚胺、聚赖氨酸-接枝苯甲醛制成。
3.根据权利要求1或2所述分级释药的肿瘤高渗透聚合物,其特征在于,所述聚天冬氨酸-接枝聚乙烯亚胺的嵌段分子量为3200~6500Da。
4.根据权利要求1或2所述分级释药的肿瘤高渗透聚合物,其特征在于,所述聚赖氨酸-接枝苯甲醛的嵌段分子量为5000~8300Da。
5.根据权利要求1或2所述分级释药的肿瘤高渗透聚合物,其特征在于,所述马来酰亚胺-聚乙二醇的嵌段中,聚乙二醇的分子量为1800~2200Da。
6.权利要求1~5任一所述分级释药的肿瘤高渗透聚合物的制备方法,其特征在于,包括如下步骤:
S1、以炔丙胺引发L-天冬氨酸-4-苄酯-N-羧基环内酸酐开环聚合成炔基聚天冬氨酸,再用线性聚乙烯亚胺氨解,得到炔基聚天冬氨酸-接枝聚乙酰亚胺;
S2、以3-叠氮丙胺引发N6-苄氧羰基-L-赖氨酸环内酸酐开环聚合成叠氮基聚赖氨酸,再用三氟乙酸脱去苄基保护、接枝苯甲醛,得到叠氮基聚赖氨酸-接枝苯甲醛;
S3、通过点击化学将步骤S1、S2所得产物对接,得到聚天冬氨酸-接枝聚乙烯亚胺-聚赖氨酸-接枝苯甲醛,再将马来酰亚胺-聚乙二醇-羧基与聚天冬氨酸的端氨基酰胺化键相连,即得。
7.根据权利要求6所述制备方法,其特征在于,步骤S1、S2、S3的反应在15~40℃条件下进行。
8.权利要求1~5任一所述分级释药的肿瘤高渗透聚合物在制备抗肿瘤药物中的应用。
9.一种分级释药的肿瘤高渗透药物,其特征在于,含有权利要求1~7任一所述分级释药的肿瘤高渗透聚合物、抗肿瘤小分子抑制剂、抗体和小干扰RNA。
10.根据权利要求9所述分级释药的肿瘤高渗透药物,其特征在于,所述抗肿瘤小分子抑制剂为PI3K抑制剂,所述抗体为抗间皮素抗体,所述小干扰RNA为CXCL1 siRNA。
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