CN110038134A - 用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统及制备方法 - Google Patents
用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统及制备方法 Download PDFInfo
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Abstract
本发明涉及一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统及制备方法。以11‑巯基十一烷酸(MUA)修饰的海藻酸钠作为骨架,通过原位矿化的方式使CaCO3和抗肿瘤药物共沉淀于海藻酸钠骨架上,并利用超声震荡的方式促使修饰后的海藻酸钠上的巯基交联从而制备出pH和氧化还原双响应纳米药物传递载体。本发明通过体内外释药、细胞毒性实验和动物实验证明,该基于CaCO3的纳米粒子具有良好的肿瘤选择性及调控肿瘤细胞内pH的能力,在杀伤肿瘤细胞的同时降低对正常细胞和机体的毒副作用。本发明提供的纳米药物传递载体有望用于肿瘤治疗,在生物医学领域有良好的应用前景。
Description
技术领域:
本发明涉及一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统及制备方法。
背景技术:
恶性肿瘤具有早期诊断困难,恶性度高,侵袭性强,患者生存期短的特点。目前,化疗是除手术外最主要的肿瘤干预手段。常见的用于肿瘤的化疗药物包括5-氟嘧啶、顺铂、紫杉醇、抗肿瘤药物的等。弱碱性药物如抗肿瘤药物的在细胞外被质子化难以进入肿瘤细胞内。此外,少量可以进入细胞的弱碱性药物被困在酸性囊泡内无法发挥药效(Fais S,DeMilito A,You H,et al.Targeting vacuolar H+-ATPases as a new strategy againstcancer[J].Cancer Research,2007,67(22):10627–10630)。最终导致肿瘤细胞对这种弱碱性药物的敏感性降低。
为了增强抗癌药物的疗效并且同时降低其副作用,大量的刺激响应型的纳米粒子被用于药物传递系统(Fenton O S,Olafson K N,Pillai P S,et al.Advances inBiomaterials for Drug Delivery[J].Advanced Materials,2018,30(29):e1705328)。在这些纳米体系中,纳米粒子本身往往扮演着惰性载体或肿瘤微环境响应载体的角色(ChenY,Yu H,Su J,et al.Tumor-Microenvironment-Adaptive Nanoparticles CodeliverPaclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer[J].Advanced Functional Materials,2016,26(33):6033–6046)。然而,不友好的肿瘤微环境(弱酸性,乏氧等)可以屏蔽或削弱药物对肿瘤细胞的攻击力,这样就导致即使药物从载体释放后,依然要面对肿瘤微环境的巨大挑战。因此,开发具备肿瘤微环境调控能力的纳米载药粒子可以作为更加有效的化疗药物递送体系。
在肿瘤细胞中,过度调节的pH形成的不利的细胞内微环境阻碍了抗癌药物的活性。不同于正常细胞的代谢方式,肿瘤细胞倾向于通过糖酵解的方式来获得能量,从而导致了肿瘤细胞内过量的乳酸堆积。为了避免酸中毒,相对于正常细胞所具有的胞外环境(pHe~7.4)和胞内环境(pHi~7.2),肿瘤细胞通过增加质子流出来达到一个偏碱性的胞内环境(PHi≥7.4),同时营造出一个偏酸性的胞外坏境(pHe=6.2-6.9)(Henning T,Kraus M,Brischwein M,et al.Relevance of tumor microenvironment for progression,therapy and drug development[J].Anti-Cancer Drugs,2004,15(1):7–14)(Reshkin SJ,Greco M R,Cardone R A.Role of pHi,and proton transporters in oncogene-driven neoplastic transformation[J].Philosophical Transactions of the RoyalSociety B:Biological Sciences,2014,369(1638)),这种自调控后的肿瘤内外环境可以促进肿瘤细胞增殖并且预防细胞的早期凋亡(Kise K,Kinugasa-Katayama Y,TakakuraN.Tumor microenvironment for cancer stem cells[J].Advanced Drug DeliveryReviews,2016,99(Pt B):197–205)。此外,大量研究已经证实细胞内碱化和细胞外酸化是恶性肿瘤的特定标志:一方面,碱性的细胞内环境可阻碍弱碱性抗肿瘤药物(如多柔比星,长春花生物碱和米托蒽醌等)插入DNA(Simon S,Roy D,Schindler M.Intracellular pHand the control of multidrug resistance[J].Proc Natl Acad Sci U S A,1994,91(3):1128–1132),并可激活肿瘤细胞中的DNA修复活性(Yuan J,Narayanan L,Rockwell S,et al.Diminished DNA repair and elevated mutagenesis in mammalian cellsexposed to hypoxia and low pH[J].Cancer Res,2000,60(16):4372–4376);另一方面,由碱性的内环境和酸性的外环境所产生的肿瘤细胞跨膜pH梯度可以抑制药物摄取并促进药物外排(De Milito A,Fais S.Proton pump inhibitors may reduce tumourresistance[J].Expert Opinion on Pharmacotherapy,2005,6(7):1049–1054)。综上所述,癌细胞中失调的pH值可促进肿瘤进展并帮助肿瘤细胞抵抗化疗(Webb B A,ChimentiM,Jacobson M P,et al.Dysregulated pH:A perfect storm for cancer progression[J].Nature Reviews Cancer,2011,11(9):671–677)。因此,降低肿瘤内环境的pH并且使肿瘤微环境正常化可以作为一种提高化疗药物对抗肿瘤能力的潜在策略。
目前,一些可以促进肿瘤细胞糖酵解速率(Hagen T,Deng L-W,Teo X-Y,etal.Utilizing hydrogen sulfide as a novel anti-cancer agent by targetingcancer glycolysis and pH imbalance[J].British Journal of Pharmacology,2014,171(18):4322–4336)或者具有pH调节蛋白靶向功能的体系被用来酸化肿瘤细胞内环境(Parks S K,Pouysségur J.Targeting pH regulating proteins for cancer therapy–Progress and limitations[J].Seminars in Cancer Biology,2017,43:66–73)。然而,多数的上述体系缺乏对肿瘤细胞的选择性,从而对机体其他部位导致不可避免的副作用和毒性。此外,由于肿瘤细胞内环境的酸性调控是多种类型蛋白的协同作用,单一的靶向某一蛋白不能有效的调控胞内酸度。
溶酶体是细胞中重要的酸性细胞器,其内储存了大量酸性内含物。与正常细胞相比,肿瘤细胞中的溶酶体,不论是从其数目,体积,乃至到酸性程度都有所增加(Altan N,Chen Y,Schindler M,et al.Defective acidification in human breast tumor cellsand implications for chemotherapy[J].J Exp Med,1998,187(10):1583–1598)。因此,一旦将溶酶体损伤,其释放出的酸性内含物进入细胞质后可以增加细胞质酸度,从而触发肿瘤细胞的凋亡(Galluzzi L,Bravo-San Pedro J M,Kroemer G.Organelle-specificinitiation of cell death[J].Nature Cell Biology,2014,16(8):728–736)。由此可以推测,溶酶体的崩解或溶酶体膜的渗透性的改变可以用作一种酸化细胞质和降低pHi的方法。此外,大量研究表明,溶酶体是癌细胞中营养物质利用和能量平衡的中心(Biswas S,Torchilin V P.Nanopreparations for organelle-specific delivery in cancer[J].Advanced Drug Delivery Reviews,2014,66:26–41)。肿瘤细胞中的异常溶酶体与肿瘤侵袭,转移,复发和预后不良密切相关(Ross K N,Ferrone C R,Zoncu R,etal.Transcriptional control of autophagy–lysosome function drives pancreaticcancer metabolism[J].Nature,2015,524(7565):361–365)。近年来,溶酶体被认为是新的抗肿瘤靶点(Saftig P,Sandhoff K.Cancer:Killing from the inside[J].Nature,2013,502(7471):312–313)。
碳酸钙纳米粒子通常被用作一种pH响应的药物载体(Qi C,Lin J,Fu L H,etal.Calcium-based biomaterials for diagnosis,treatment,and theranostics[J].Chemical Society Reviews,2018,47(2):357–403),由于其可在肿瘤细胞外酸性环境或细胞内酸性细胞器(如溶酶体)下逐渐瓦解并释放出CO2(Yuan Z,Cao Z,Yildirimer L,etal.Tumor-Triggered Controlled Drug Release from Electrospun Fibers UsingInorganic Caps for Inhibiting Cancer Relapse[J].Small,2015,11(34):4284–4291),造成体积迅速膨胀。因此,CaCO3纳米载体可以破坏溶酶体膜进而释放负载药物(Liu Z,Chen M,Zhang Q,et al.Synthesis of Hollow Biomineralized CaCO3–PolydopamineNanoparticles for Multimodal Imaging-Guided Cancer Photodynamic Therapy withReduced Skin Photosensitivity[J].Journal of the American Chemical Society,2018,140(6):2165–2178)。同时,溶酶体膜被破坏后也使得溶酶体中大量酸性内含物释放来降低细胞内pH。得益于碳酸钙良好的生物相容性,利用碳酸钙作为pH药物载体通过破坏溶酶体的方式来酸化细胞内环境,是一种有效且安全的增强弱碱性化疗药物疗效的方式。
基于此,选择碳酸钙纳米粒子作为一种pH触发的药物传递载体,其可以在肿瘤溶酶体酸性环境(pH 4.3-5.8)中分解并产生大量的二氧化碳,像“炸弹”一样迅速“炸开”溶酶体膜,使得酸性内含物和搭载的抗肿瘤药物被释放,并降低胞内pH。为了避免破坏正常细胞,在碳酸钙纳米粒中引入具有氧化还原响应性的二硫键交联的海藻酸钠(DSA),起到“安全阀”的作用。由于肿瘤细胞和正常细胞中谷胱甘肽(GSH)水平不同,DSA很容易在肿瘤细胞中被打开,但会阻止“溶酶体炸弹”破坏正常细胞。总之,这种氧化还原和pH双敏感的药物传递系统可以降低细胞内pH、增强抗肿瘤药物的功效。
CN20150426521.8公开的技术中,利用天然的海藻酸钠和多价金属盐,通过超声震荡获得pH响应性海藻酸钠纳米凝胶。该凝胶可负载多种药物用于肿瘤治疗并降低对正常细胞的毒副作用。然而,相较于游离阿霉素(IC50=0.18μg/mL),负载阿霉素的该种凝胶对肿瘤细胞Hela的IC50为0.26μg/mL,阿霉素的药效降低了44%。这表明该pH响应性海藻酸钠纳米凝胶在降低对正常细胞的毒副作用时,也削弱了阿霉素的药效,这种削弱使得该凝胶的抑瘤效果大大降低。
综上所述,如何构建一种简单有效适用于体内的纳米粒子体系,在提高抗肿瘤药物对肿瘤细胞杀伤力的同时降低对正常组织的毒副作用,是本发明致力解决的问题。
发明内容
本发明目的是提供一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统及制备方法,可以通过选择性打破肿瘤细胞pH梯度提高弱碱性化疗药物的抗肿瘤活性,降低其毒副作用,提高治疗效果,更加方便其应用于临床治疗问题。即现有的高效载药体系都具有结构复杂,制备困难的特点,极大限制了其应用,难以实现临床治疗。本发明提供一种可以治疗肿瘤的载抗肿瘤药物的纳米药物传递载体及其制备方法,制备出结构简单、疗效显著的双响应性载抗肿瘤药物的纳米粒子。
本发明提供的一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统是以11-巯基十一烷酸(MUA)修饰的海藻酸钠作为骨架,通过原位矿化的方式使碳酸钙和抗肿瘤药物共沉淀于海藻酸钠骨架上,并利用超声震荡的方式促使修饰后的海藻酸钠上的巯基交联,制备出pH和氧化还原双响应载抗肿瘤纳米药物的传递系统(载体为DSA/CC);其中,纳米药物传递系统的粒径为150nm-200nm,优选200nm。
所述的DSA/CC与抗肿瘤药物的质量比为4-25:1;可选24:1,9:1,4:1.
所述的抗肿瘤药物为弱碱性化疗药物:阿霉素,长春新碱以及其它。
含阿霉素的药物传递系统DSA/CC-DOX中,DSA/CC和阿霉素的质量比为24:1,9:1,4:1。
所述的11-巯基十一烷酸(MUA)修饰后的海藻酸钠的结构式为:
n=1800-2000之间,海藻酸钠的平均分子量为3.081×105。
本发明提供的一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统的制备方法经过以下步骤:
1)在海藻酸钠水溶液中加入高碘酸钠(NaIO4)溶液,补充加入去离子水;避光搅拌反应20-24小时后,加入无水乙醇,继续搅拌反应20-30分钟终止反应;将所得粗产物溶于去离子水中,并用丙酮进行沉淀来纯化产物;纯化3次后,用乙醇洗涤粗产物,最后抽滤得氧化海藻酸钠(OSA);
海藻酸钠与NaIO4的摩尔比为:1-2:1-2:1,优选摩尔比为:1:1。
2)室温下,乙二胺和11-巯基十一烷酸(MUA)在二氯甲烷溶剂中均匀混合,再加入4-氨基甲基吡啶,并滴加EDC·HCl,搅拌10-12小时,将反应混合物用水萃取三次,并将有机相在真空干燥箱中常温干燥,制备得到乙二胺和11-巯基十一烷酸(MUA)偶联形成的脂肪族胺;乙二胺、MUA和4-氨基甲基吡啶的摩尔比为:1:1:1;
3)将步骤1)制备的氧化海藻酸钠的加入到步骤2)的脂肪族胺无水乙醇溶液中,在惰性气体(氮、氦气)保护下搅拌5-6小时,加入NaBH4以还原席夫碱结构;然后将溶液透析后冻干,得到浅黄色固体,即为巯基化海藻酸钠(TSA);其中氧化海藻酸钠与脂肪族胺的质量比为6:5;
所述的透析条件为:7000Da透析袋,超纯水为透析介质,72小时透析,每12小时换透析液一次。
4)按计量将碳酸钠溶液、抗肿瘤药物溶液(如阿霉素)和氯化钙溶液混合,再与巯基化海藻酸钠的无水乙醇溶液混合,在避光条件下搅拌反应20-30分钟;将所得反应液置于探入式超声波探头中,超声(时间3分钟,功率50W),以此来完成对巯基的氧化交联;
5)将所得溶液装入透析袋中进行透析(透析条件为:7000Da透析袋,超纯水为透析介质,72小时透析,每12小时换透析液一次),冻干得到最终产物(例如DSA/CC-DOX)。
本发明提供了一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统及其制备方法。具体讲,在具有良好生物相容性的天然多糖——海藻酸钠上修饰11-巯基十一烷酸,通过原位矿化的方式使CaCO3和抗肿瘤药物共沉淀于海藻酸钠骨架上,并利用超声震荡的方式促使修饰后的海藻酸钠上的巯基交联从而制备出pH和氧化还原双响应纳米药物传递系统。DSA/CC传递载体实现了对弱碱性化疗药物在肿瘤细胞内的选择性释放。这是依赖于DSA/CC纳米颗粒表面二硫键交联的海藻酸钠保护层在高GSH环境的肿瘤细胞内的选择性解开,这种选择性保护了正常组织细胞,实现了将药物选择性地释放到肿瘤内这一设计目的。此外,暴露出的碳酸钙内核在溶酶体酸性环境内快速气化生成CO2,固-气转换导致的体积膨胀会快速撕裂溶酶体膜,使得大量的溶酶体酸性内涵物倾泻入胞质环境,降低了胞质环境pH。随着溶酶体破裂,纳米载体负载的抗肿瘤药物也释放到胞质环境中,这保障了抗肿瘤药物对肿瘤细胞的细胞毒性。此外,肿瘤细胞内pH的下降有利于破坏肿瘤细胞抵抗化疗药物的能力,这增强了抗肿瘤药物对肿瘤细胞的杀伤作用。在体内,该纳米载药系统也表现出良好肿瘤富集效果和治疗效果,进一步显示了DSA/CC在肿瘤治疗中良好的应用前景。
本发明的突出特点是:通过合理设计,选用生物安全性极佳的海藻酸钠和碳酸钙作为载体的响应组分,构建了肿瘤选择性的双响应性载抗肿瘤药物的纳米药物传递系统。基于纳米碳酸钙的“溶酶体炸弹”—DSA/CC(Disulfide-crosslinked Sodium Alginateloaded with Calcium Carbonate)纳米粒子,具备识别肿瘤细胞和正常肝细胞的能力,可以选择性地将抗肿瘤药物释放在高GSH的肿瘤细胞内,同时可以避免抗肿瘤药物在低GSH的正常细胞内泄漏。DSA/CC处理2小时后,抗肿瘤药物在肿瘤细胞内的浓度是正常细胞内的近8倍。该纳米碳酸钙体系能够降低胞质环境的pHi。在封闭的溶酶体内,碳酸钙可以快速撕裂溶酶体膜,这种撕裂不仅可以将负载的抗肿瘤药物释放到胞质环境中,还将大量的溶酶体内酸性内含物释放,导致肿瘤细胞的pHi由7.61下降到7.09。pHi的下降打破了肿瘤细胞树立起的两道pH梯度防线,促使抗肿瘤药物在肿瘤细胞内的富集量提高近3倍,抑瘤率较裸药提高约16%。
附图说明
图1是;DSA/CC在体外的药物释放曲线;
图2是;DSA/CC选择性在HepG2(肝癌细胞)内释放抗肿瘤药物阿霉素而避免在LO2(正常肝细胞)内释放阿霉素;
图3是;DSA/CC选择性降低HepG2(肝癌细胞)内pH值而不影响LO2(正常肝细胞)的pH值;
图4是;DSA/CC增强抗肿瘤药物阿霉素对HepG2(肿瘤细胞)的杀伤效果并削弱阿霉素对LO2(正常肝细胞)的毒副作用;
图5是;DSA/CC-DOX(含阿霉素的药物传递系统),Saline(生理盐水),DOX(抗肿瘤药物阿霉素)和DSA/CC(不含药的载体)对H22荷瘤小鼠模型的抑瘤效果;
图6是;不负载阿霉素的空载体DSA/CC和TSA/CC对HepG2(肝癌细胞)和LO2(正常肝细胞)无明显毒副作用;
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。实施例中未注明具体条件的实验方法,通常按照常规条件以及手册中所述的条件,或按照制造厂商所建议的条件;所用的通用设备、材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1:用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递载体的制备:
通过高碘酸钠还原法制备氧化海藻酸钠(OSA):称取2g海藻酸钠(C5H7O4COONa)溶于120mL去离子水中,接着加入20mL高碘酸钠(NaIO4)溶液(n(SA):n(NaIO4)=1:1),再次补充加入60mL去离子水。避光搅拌反应24小时后,加入0.7mL无水乙醇,继续搅拌反应30分钟来终止反应。将所得粗产物溶于100mL去离子水中,并用丙酮进行沉淀来纯化产物。纯化3次后,用乙醇洗涤粗产物,最后抽滤得OSA。
制备由乙二胺和11-巯基十一烷酸(C11H22O2S,MUA)偶联形成的脂肪族胺:将乙二胺(5mmol)和MUA(5mmol)溶解在20mL二氯甲烷中,逐滴加入10mL的EDC·HCl和4-氨基甲基吡啶(5mmol)的二氯甲烷溶液。室温下,避光搅拌12小时后,将反应混合物用30mL水萃取三次,并将有机相在真空干燥箱中常温干燥。
通过脂肪族胺和OSA反应制备巯基化海藻酸钠(TSA):步骤如下:将0.06g上述合成的脂肪族胺溶解在5mL无水乙醇中,并加入5mL OSA水溶液(0.01g mL-1)。将混合物在惰性气体保护下搅拌6小时后,加入0.1g NaBH4以还原席夫碱结构。接着,将溶液透析后冻干,得到浅黄色固体TSA。
取5mL TSA无水乙醇溶液,使之与碳酸钠溶液、抗肿瘤药物溶液和氯化钙溶液混合,在避光条件下磁力搅拌反应30分钟。具体操作为:
取10mg的TSA超声溶解于5mL无水乙醇中,然后加入6mL的碳酸钠溶液(100mM),搅拌混合均匀。接着,将5mL含有不同质量DOX·HCl的氯化钙(100mM)溶液逐滴滴加到上述混合液中,在避光条件下磁力搅拌反应30分钟。注:Na2CO3=63.594mg,TSA即巯基化海藻酸钠=10mg,CaCl2=55.5mg,阿霉素=1.25mg,2.5mg,5mg,10mg和20mg见表1)。
将所得反应液置于探入式超声波探头中,超声(时间3分钟,功率50W),以此来完成对巯基的氧化交联。将所得溶液装入透析袋中进行透析(透析条件为:7000Da透析袋,超纯水为透析介质,72小时透析,每12小时换透析液一次),冻干得到产物(含阿霉素的药物传递系统,DSA/CC-DOX),纳米药物传递载体为DSA/CC。
表1不同抗肿瘤药物的投料量制备的纳米粒子载抗肿瘤药物的量和包封率
。
实施例2:体外模拟纳米粒子释药行为研究:
在含有或不含有10mM GSH的磷酸盐缓冲溶液(pH 7.4和5.7)中考察DSA/CC中抗肿瘤药物的体外释放曲线。首先,将2mg DSA/CC溶解在4mL缓冲溶液中并转移至透析袋中(MW=3500Da),然后将透析袋置于装有释放介质的50mL离心管中,在37℃下进行透析。在设定的时间间隔下,取出0.2mL样品并用等体积的释放介质替换。最终,使用EnspireTM多功能酶标仪(激发480nm,发射588nm)测定样品中释放的抗肿瘤药物的量,见图1。
实施例3:细胞内抗肿瘤药物释放监测:
分采用活细胞成像系统观察抗肿瘤药物的细胞内释放。将细胞(HepG2和LO2)以1×105个细胞/孔的密度接种到玻璃皿底,加入2mL的1640培养基(10%胎牛血清+1%青霉素-链霉素),放入培养箱中孵育24小时(37℃,5%CO2)后,小心吸出培养基,PBS清洗两遍后,并用1mL含有DSA/CC的培养基(25μg mL-1)替换。然后将细胞在活细胞工作站中温育2小时,设定每10分钟拍摄一次,见图2。
实施例4:细胞内pH测定:
1)首先,进行pH标准曲线的测量。参考文献后,在不同标准pH值的KCl(130mM)缓冲溶液中,通过离子载体尼日利亚菌素(10μM)测定pHi标准曲线[112]。此外,利用BCECF-AM的pH依赖性变化的激发光谱来标定样品之间的pH变化,具体就是通过多功能酶标仪测定在485nm和395nm两处的荧光强度比率。在尼日利亚菌素存在下,细胞中的pHi与KCl缓冲液的pHi相等。根据BCECF在标准溶液中的激发光谱,可以得到一条由荧光强度比率和pH确定的标准曲线。为了获得细胞内pH标准曲线,将细胞以2×104个细胞/孔接种于96孔中。在培养箱中孵育1天后,吸走原培养基,用含有BCECF-AM的培养基(4μM)替换,并继续在培养箱中孵育30分钟。然后,用Krebs Ringer Hepes缓冲液(130mM NaCl,5mM KCl,1.2mM K2HPO4,1.2mMMgSO4,6mM葡萄糖,25mM Hepes和1mM CaCl2,pH=7.4)洗涤细胞两次。随后,向细胞中加入100μL各种pH条件下的(pH=6.0,6.5,7.0,7.5和8.0)的KCl缓冲液(130mM KCl,1mM MgCl2,15mM Hepes,15mM MES和10μM尼日利亚菌素)。孵育20分钟后,通过多功能酶标仪(发射535nm,激发350-530nm,步长=2nm)测量BCECF的激发光谱。以485nm处荧光强度与395nm处荧光强度的比值作为Y轴,KCl缓冲液的pH为X轴,绘制标准曲线。
2)为了进一步测定纳米颗粒处理后的细胞内pH的变化,将细胞以2×104个细胞/孔接种于96孔板中。在培养箱中孵育1天后,吸走上清,用含有5μg mL-1抗肿瘤药物(阿霉素),25μg mL-1TSA/CC-抗肿瘤药物(Thiolated Sodium Alginate loaded with CalciumCarbonate,抗肿瘤药物为阿霉素)或25μg mL-1DSA/CC的培养基替换,并继续放入培养箱内孵育。然后在0,2和6小时这三个不同时间点(在2小时吸走纳米颗粒并继续孵育4小时),用含有4μM BCECF-AM的培养基替换旧培养基,并继续在37℃下孵育30分钟。然后,用KrebsRinger Hepes缓冲液洗涤细胞两次。随后,向细胞中加入100μL Krebs Ringer Hepes缓冲液。孵育20分钟后,通过多功能酶标仪测量485nm和395nm的荧光强度(发射波长=535nm),并根据标准曲线计算细胞内pH,见图3。
实施例5:体外毒性测试:
将细胞以5×103细胞/孔的密度接种在96孔板中,在培养箱中孵育24小时。用PBS洗涤细胞两次,并分别加入含有游离抗肿瘤药物,非交联组TSA/CC-DOX或DSA/CC-DOX的培养基,继续孵育48小时。接着,将含有MTT的PBS溶液(20μL,5mg mL-1)加入各孔中,并将细胞继续孵育48小时。然后小心地除去培养基,并向每个孔中加入150μL DMSO。用多功能酶标仪在570nm处测量各孔的吸光度,见图4。
实施例6:体内肿瘤抑制效果考察:
1)首先,将H22细胞以腹水的形式接种到ICR小鼠中一周。然后,从这只ICR小鼠腹腔中收集含有H22细胞的腹水,用生理盐水将腹水稀释至1×107个细胞每毫升,并将0.2mL腹水稀释液注入ICR小鼠的右前肢腋下,以建立携带H22肿瘤的小鼠模型。
2)为了证实体内抗癌作用,如上所述在ICR小鼠体内建立H22肿瘤异种移植模型,等待肿瘤体积生长到约100mm3时进行抑瘤效果考察。将荷瘤小鼠随机分成4组(n=5),分别尾静脉注射200μL生理盐水,抗肿瘤药物,DSA/CC和DSA/CC,其中含有抗肿瘤药物的组中抗肿瘤药物的注射量为3.86mg kg-1,每三天给药一次,总计给药5次。此外,每隔一天记录小鼠的肿瘤大小、体重变化以及存活情况。治疗持续15天后,脱颈处死小鼠,收集每只小鼠的肿瘤,见图5。根据下式计算肿瘤体积:肿瘤体积(mm3)=0.5×长度×宽2。
实施例7:空载体的细胞毒性测试:
将细胞以5×103细胞/孔的密度接种在96孔板中,在培养箱中孵育24小时。用PBS洗涤细胞两次,并分别加入含有非交联组TSA/CC或DSA/CC的培养基,继续孵育48小时。接着,将含有MTT的PBS溶液(20μL,5mg mL-1)加入各孔中,并将细胞继续孵育48小时。然后小心地除去培养基,并向每个孔中加入150μL DMSO。用多功能酶标仪在570nm处测量各孔的吸光度,见图6。
Claims (9)
1.一种用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统,其特征在于它是以11-巯基十一烷酸修饰的海藻酸钠作为骨架,通过原位矿化的方式使碳酸钙和抗肿瘤药物共沉淀于海藻酸钠骨架上,并利用超声震荡的方式促使修饰后的海藻酸钠上的巯基交联,制备出pH和氧化还原双响应载抗肿瘤纳米药物传递系统。
2.按照权利要求1所述的纳米药物传递系统,其特征在于所述的11-巯基十一烷酸修饰后的海藻酸钠的结构式为:
, n= 1800-2000之间,海藻酸钠的平均分子量为3.081×105。
3.按照权利要求1所述的纳米药物传递系统,其特征在于所述的纳米药物传递系统的粒径为150nm-200nm ,优选200nm。
4.按照权利要求1所述的纳米药物传递系统,其特征在于纳米药物传递载体与抗肿瘤药物的质量比为4-25:1。
5.按照权利要求1所述的纳米药物传递系统,其特征在于所述的抗肿瘤药物为弱碱性化疗药物:阿霉素,长春新碱以及其它。
6.按照权利要求5所述的纳米药物传递系统,其特征在于所述的纳米药物传递载体和阿霉素的质量比为24:1, 9:1, 4:1。
7.一种权利要求1所述的用于肿瘤治疗的双响应性载抗肿瘤药物的纳米药物传递系统的制备方法,其特征在于经过以下步骤:
1)在海藻酸钠水溶液中加入高碘酸钠溶液,补充加入去离子水;避光搅拌反应20-24小时后,加入无水乙醇,继续搅拌反应20-30分钟终止反应;将所得粗产物溶于去离子水中,并用丙酮进行沉淀来纯化产物;纯化3次后,用乙醇洗涤粗产物,最后抽滤得氧化海藻酸钠;
2)室温下,乙二胺和11-巯基十一烷酸在二氯甲烷溶剂中均匀混合,再加入4-氨基甲基吡啶,并滴加EDC·HCl,搅拌10-12小时,将反应混合物用水萃取三次,并将有机相在真空干燥箱中常温干燥,制备得到乙二胺和11-巯基十一烷酸偶联形成的脂肪族胺;乙二胺、MUA和4-氨基甲基吡啶的摩尔比为:1:1:1;
3)将步骤1)制备的氧化海藻酸钠的加入到步骤2)的脂肪族胺无水乙醇溶液中,在惰性气体保护下搅拌5-6小时,加入NaBH4以还原席夫碱结构;然后将溶液透析后冻干,得到浅黄色固体,即为巯基化海藻酸钠;其中氧化海藻酸钠与脂肪族胺的质量比为6:5;
4)按计量将碳酸钠溶液、抗肿瘤药物溶液和氯化钙溶液混合,再与巯基化海藻酸钠的无水乙醇溶液混合,在避光条件下搅拌反应20-30分钟;将所得反应液置于探入式超声波探头中,超声,以此来完成对巯基的氧化交联;
5)将所得溶液装入透析袋中进行透析,冻干得到最终产物。
8.按照权利要求1所述的制备方法,其特征在于步骤1)所述的海藻酸钠与NaIO4的摩尔比为:1-2:1-2:1,优选摩尔比为:1:1。
9.按照权利要求1所述的制备方法,其特征在于所述的透析条件为:7000 Da透析袋,超纯水为透析介质,72小时透析,每12小时换透析液一次。
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