CN111643514B - 一种治疗前列腺癌药物的制备方法 - Google Patents
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Abstract
本发明涉及一种治疗前列腺癌药物的制备方法，所述的用于治疗癌症骨转移纳米药物载体由磷酸盐和氯化钙复合形成的磷酸钙、白蛋白或多糖、磷脂、胆固醇复合而成，负载的药物为siRNA和多西他赛。通过所述的一种治疗前列腺癌药物的制备方法制成的纳米药物载体可以负载siRNA和多西他赛用于前列腺癌，乳腺癌和肺癌骨转移的治疗，能够靶向富集至转移灶，在转移灶缓慢序贯释放药物，发挥多西他赛和siRNA双重协同治疗的优势，克服单一治疗的局限性，达到减毒增效作用，发挥协同杀伤肿瘤细胞的作用。
Description
技术领域
本发明涉及癌症治疗技术及其应用领域，尤其涉及一种治疗前列腺癌药物的制备方法。
背景技术
癌症产生的原因是由于异常细胞生长导致的疾病，癌细胞有可能扩散到身体的不同组织和器官。据世界卫生组织统计，全球每年有上千万人被确诊为癌症。癌症常出现骨骼转移，是进展期癌症患者死亡的主要原因。前列腺癌、乳腺癌和肺癌骨转移常引起骨骼疼痛、骨折、脊髓压迫、感染和高钙血症等症状，明显地降低了患者的生存质量。目前针对骨转移的治疗包括外科切除、放疗和化疗，但外科治疗比较局限，放疗效果较差。由于传统化疗药物在骨组织中渗透性较弱和对骨转移灶的选择性较差，化疗的治疗效果是有限的。因此，探索和寻求癌症骨转移灶新的治疗方法显得非常急迫和必要。研究表明，单一的治疗方法对癌症的治疗效果有限，而采用两种或多种治疗联合治疗常常能够取得较好的效果。
骨微环境中的间质细胞包括成骨细胞、破骨细胞、骨髓造血细胞等细胞。肿瘤细胞经过血液循环进入骨内膜处毛细血管，肿瘤细胞穿越出毛细血管在局部定位生长形成微转移灶。微转移灶中的肿瘤细胞会刺激成骨细胞分泌IL-6和RANKL(receptor activator ofnuclear factor kappa B ligand,RANKL)，进而诱导破骨细胞分化成熟，产生溶骨作用，引起骨骼破坏进而从矿化的骨基质中释放出诸如PDGF、TGF-β、FGF等细胞因子，进一步刺激肿瘤生长和增殖，因而进入一个恶性循环。由此可见，癌细胞骨转移基本上是一个溶骨为主的病理改变过程，而骨微环境中Shh-IL6-RANKL信号网络的活化是溶骨改变产生的一个重要因素。因此，肿瘤细胞与骨基质细胞之间通过Shh-IL6-RANKL信号网络交互作用而产生了一个恶性循环，最终促进癌细胞转移的转移；前期的研究表明，采用shRNA干扰技术降低前列腺癌细胞系中shh基因的表达能够明显地抑制肿瘤的转移能力，反之，过表达细胞中shh基因能够促进癌细胞转移能力。
多西他赛(docetaxel,DTXL)是FDA批准的用于癌症治疗一线化疗药物，但是其临床应用受到耐药、水溶性差、毒副作用大等问题阻碍，常选择与其他药物联合应用来增强DTXL疗效并减轻毒副作用。多西他赛在前列腺癌治疗中的耐受与多种机制关系密切，而Shh信号通路的活化能够赋予前列腺癌细胞凋亡抵抗和多西他赛等紫杉烷类药物耐受。(Statkiewicz M,Maryan N,Lipiec A,Grecka E,Grygorowicz MA,Omiotek M,Gorska A,Mikula M,Malecki M.The role of the SHH gene in prostate cancer cellresistance to paclitaxel.Prostate.2014,74(11):1142-52.)过表达shh基因能够诱导癌细胞产生ABC类耐药蛋白，产生药物耐受；反之，沉默shh基因的表达能够增敏化疗药物紫杉醇杀伤肿瘤细胞。此外，Shh-IL-6-RANKL信号网络下游的RANKL分子能够诱导前列腺癌细胞表达多种耐药蛋白如MRP1、BCRP和LRP，诱导耐药的产生。而采用siRNA干扰shh基因或采用药物抑制Shh信号通路能够明显地抑制肿瘤细胞转移、增殖。(Rimkus TK,Carpenter RL,Qasem S,Chan M,Lo HW.Targeting the Sonic Hedgehog Signaling Pathway:Review ofSmoothened and GLI Inhibitors.Cancers(Basel).2016,8(2).pii:E22.)此外，共用多西他赛和Shh信号通路阻断剂能够明显地增加G2/M期细胞比例，且能够明显地降低肿瘤细胞的侵袭能力。鉴于游离化疗药物(或游离siRNA)渗透进入骨转移瘤的量不足，不足以有效地杀伤骨转移瘤这一临床难题；结合骨微环境中Shh-IL6-RANKL信号网络在促进前列腺癌骨转移中的重要作用。应用钙磷复合脂质靶向纳米药物递送系统进行多西他赛和shh siRNA的共递送，靶向治疗癌症骨转移灶，发挥化疗-基因治疗的协同作用，减毒增效，抑制转移，克服耐药，最大程度的杀伤肿瘤细胞。
为此，设计一种治疗前列腺癌药物的制备方法，解决以上问题。
发明内容
本发明为克服以上不足，提供一种治疗前列腺癌药物的制备方法，所述的用于治疗癌症骨转移纳米药物载体由磷酸盐和氯化钙复合形成的磷酸钙、白蛋白或多糖、磷脂、胆固醇复合而成，负载的药物为siRNA和多西他赛。
本发明所述的一种治疗前列腺癌药物的制备方法，包括以下步骤：
步骤一：将白蛋白或多糖溶于含有磷酸盐的DMEM培养基或者HEPES缓冲液中，加入含有siRNA的氯化钙溶液反应，然后离心，用去离子水清洗，分散在去离子水中；
步骤二：将磷脂、胆固醇和多西他赛溶于氯仿中，旋转蒸发形成一层膜，之后加入制备好的磷酸钙分散液，形成磷脂包裹磷酸钙的纳米药物载体；在纳米药物载体的分散液中加入阿仑膦酸钠，反应10分钟时间后，离心去除未结合在纳米药物载体表面的阿仑膦酸钠，将纳米药物载体分散在PBS缓，冲液或Tris缓冲液中。
进一步，优选的，磷酸钙、白蛋白或多糖、磷脂、胆固醇、siRNA和多西他赛的比重分别为10～20％、20～30％、40～60％、2～6％、0.3～5％和0.3～3％。
优选的，多糖为海藻酸盐、改性纤维素、黄原胶、改性淀粉、瓜儿豆胶、果胶中的一种或者两种。
优选的，磷脂为1,2-二硬脂酰基磷脂酰乙醇胺、1,2-二棕榈酰-sn-甘油-3-磷酰乙醇胺、1,2-二油酰-sn-甘油-3-磷酸乙醇胺、1,2-十四酰基磷脂酰乙醇胺、二硬脂酰基磷脂酰基丝氨酸、二棕榈酸磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、(2,3-二油酰基-丙基)三甲基氯化铵中的一种或两种以上。
优选的，siRNA的序列为GAAACTCCGAGCGATTTAA。
本发明的有益效果是：
通过所述的一种治疗前列腺癌药物的制备方法制成的纳米药物载体可以负载siRNA和多西他赛用于前列腺癌，乳腺癌和肺癌骨转移的治疗，能够靶向富集至转移灶，在转移灶缓慢序贯释放药物，发挥多西他赛和siRNA双重协同治疗的优势，克服单一治疗的局限性，达到减毒增效作用，发挥协同杀伤肿瘤细胞的作用。
说明书附图
图1为载药纳米药物载体分别对前列腺癌细胞系LNCaP和PC-3的凋亡诱导作用；
图2为采用钙黄绿素染色方法评价载药纳米药物载体分别对前列腺癌LNCaP细胞系和PC-3细胞系的杀伤作用；
图3为采用激光共聚焦技术观察载FAM-siRNA纳米药物载体分别被LNCaP细胞和PC-3细胞摄取的过程。
具体实施方式
实施例1
步骤一：将1g的白蛋白溶于100ml的DMEM培养基中，其中磷酸根的浓度为1mM，搅拌30min，加入1ml氯化钙(lM)溶液，其中含有1mg的siRNA,继续搅拌30min,然后离心，转速15000rpm，时间15min，再加去离子水清洗两次，分散在10mL的去离子水中，为CaP分散液；
步骤二：将0.1g的1,2-二硬脂酰基磷脂酰乙醇胺、0.01g的胆固醇和0.01g多西他赛溶于氯仿中，旋转蒸发除去氯仿，加入5mL的步骤1中CaP分散液，放在摇床上摇动1h。然后向其中加入0.2g阿仑膦酸钠，反应1h，然后加入1mL的Tris缓冲液终止反应，离心去除未结合阿仑膦酸钠，得到结合阿仑膦酸钠的纳米药物载体分散液。
实施例2
步骤一：将1g的透明质酸钠溶于100ml的HEPES缓冲液(pH7.4)中，搅拌30min，加入1ml氯化钙(lM)溶液，其中含有1mg的siRNA,继续搅拌30min,然后离心，转速15000rpm，时间15min，再加去离子水清洗两次，分散在10mL的去离子水中，为CaP分散液；
步骤二：将0.1g的1,2-二硬脂酰基磷脂酰乙醇胺、0.01g的胆固醇和0.01g多西他赛溶于氯仿中，旋转蒸发除去氯仿，加入5mL的步骤1中CaP分散液，放在摇床上摇动1h。然后向其中加入0.2g阿仑膦酸钠，反应1h，然后加入1mL的Tris缓冲液终止反应，离心去除未结合阿仑膦酸钠，得到结合阿仑膦酸钠的纳米药物载体分散液。
实施例3
将PC-3细胞和LNCaP细胞进行分组，且分为不加药物，加入多西他赛，载有药物的纳米药物载体和结合阿仑膦酸钠的纳米药物载体处理，孵育24h后取出培养板。将6孔板内的培养液吸出至一合适离心管内，PBS洗涤细胞一次，加入0.5mL的胰酶消化细胞，消化2min，吸除胰酶，避免胰酶的过度消化，加入无血清的DMEM培养液收集细胞，同时与上述收集的培养液混合在一起，进行离心(1000rpm×5min)，弃上清，加入PBS重悬细胞，再次离心(1000rpm×5min)去上清，加入195μL的Annexin V-FITC结合液重悬细胞，之后加入5μL的Annexin V-FITC染液，轻轻混匀，再加入10μL的碘化丙啶染色液，轻轻混匀，室温避光孵育10-20min，随后置于冰浴。调整好各参数，之后进行流式细胞仪检测。以Annexin-V FITC为横坐标，PI为纵坐标进行作图，Annexin V-FITC单阳性的为早期凋亡细胞，Annexin V-FITC和PI双阳性的为晚期凋亡细胞。
实施例4
将PC-3细胞和LNCaP细胞进行分组，且分为不加药物，加入多西他赛，载有药物的纳米药物载体和结合阿仑膦酸钠的纳米药物载体处理，处理24h后取出培养板，将其中的培养液吸出，使用PBS充分洗涤细胞2次，同时使用PBS将Calcein-AM贮存液稀释成2μM将工作液加入到培养板内，放入培养箱内37℃条件孵育30min，之后使用PBS充分洗涤细胞两次以去除多余的染料，在荧光显微镜下进行拍照观察。
实施例5
将LNCaP细胞、PC-3细胞接种于激光共聚焦小皿，细胞密度为1×104个/皿，将其放入至培养箱内，在37℃、5％CO2条件下进行培养，待细胞贴壁之后，分别加入游离的FAM(500μL、1μg/mL)、包载FITC的纳米药物载体分散液(FAM浓度为1μg/mL)500μL，在37℃、5％CO2条件下继续进行培养2h或8h。取出激光共聚焦皿，将其中的培养液吸出，使用PBS洗涤细胞两次。加入溶酶体探针Lyso-Tracker Red标记细胞器溶酶体。标记过程：取5μL的Lyso-Tracker Red(1mM)贮存液加入到50mL不含血清的DMEM细胞培养液内，混匀配制成Lyso-Tracker Red工作液，向每个共聚焦皿内加入1mL的工作液，37℃条件下孵育30min，之后吸出工作液，并使用PBS洗涤细胞两次，加入浓度为5μg/mL的4',6-二脒基-2-苯基吲哚(4',6-diamidino-2-phenylindole)(DAPI)染色液1mL，孵育10min。DAPI能够与细胞核内的双链DNA发生强有力地结合，DAPI染色结束之后，使用4％的多聚甲醛对细胞进行有效地固定，之后使用激光共聚焦显微镜进行观察。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (4)
1.一种治疗前列腺癌药物的制备方法，其特征在于，包括如下步骤：
步骤一：将1g的白蛋白溶于100mL的DMEM培养基中，其中磷酸根的浓度为1mol/L，搅拌30min，加入1mL的1mol/L氯化钙溶液，其中含有1mg的siRNA,继续搅拌30min，然后离心，转速15000rpm，时间15min，再加去离子水清洗两次，分散在10mL的去离子水中，为CaP分散液；
步骤二：将0.1g的1,2-二硬脂酰基磷脂酰乙醇胺、0.01g的胆固醇和0.01g多西他赛溶于氯仿中，旋转蒸发除去氯仿，加入5mL的步骤一中CaP分散液，放在摇床上摇动1h；然后向其中加入0.2g阿仑膦酸钠，反应1h，然后加入1mL的Tris缓冲液终止反应，离心去除未结合阿仑膦酸钠，得到结合阿仑膦酸钠的纳米药物载体分散液；
siRNA的序列为GAAACTCCGAGCGATTTAA。
2.一种治疗前列腺癌药物的制备方法，其特征在于，包括如下步骤：
步骤一：将1g的透明质酸钠溶于pH为7.4的100mL的HEPES缓冲液中，搅拌30min，加入1mL的1mol/L氯化钙溶液，其中含有1mg的siRNA,继续搅拌30min,然后离心，转速15000rpm，时间15min，再加去离子水清洗两次，分散在10mL的去离子水中，为CaP分散液；
步骤二：将0.1g的1,2-二硬脂酰基磷脂酰乙醇胺、0.01g的胆固醇和0.01g多西他赛溶于氯仿中，旋转蒸发除去氯仿，加入5mL的步骤一中CaP分散液，放在摇床上摇动1h；然后向其中加入0.2g阿仑膦酸钠，反应1h，然后加入1mL的Tris缓冲液终止反应，离心去除未结合阿仑膦酸钠，得到结合阿仑膦酸钠的纳米药物载体分散液；
siRNA的序列为GAAACTCCGAGCGATTTAA。
3.根据权利要求1或2所述的一种治疗前列腺癌药物的制备方法制得的结合阿仑膦酸钠的纳米药物载体分散液。
4.根据权利要求3所述的结合阿仑膦酸钠的纳米药物载体分散液用以制备治疗前列腺癌的药物。
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