CN115227833B - 一种氟化二氧化硅载药纳米粒及其制备方法、用途 - Google Patents
一种氟化二氧化硅载药纳米粒及其制备方法、用途 Download PDFInfo
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Abstract
本发明属于医药技术领域，涉及一种氟化二氧化硅载药纳米粒及其制备方法、用途。该氟化二氧化硅载药纳米粒是将亲水性小分子***物载入介孔二氧化硅纳米粒之中，形成二氧化硅载药纳米粒，再对二氧化硅载药纳米粒进行表面全氟化学修饰得到。本发明提供的氟化二氧化硅载药纳米粒可以提高载药量，且该氟化二氧化硅载药纳米粒可以分散在全氟碳溶液里，进一步提高氟化二氧化硅载药纳米粒的载药量；同时利用超声波辐射，全氟碳液可微泡化显影并释放***，使得亲水小分子***物高效通过血脑屏障发挥作用。
Description
技术领域
本发明属于医药技术领域，涉及一种氟化二氧化硅载药纳米粒及其制备方法、用途，具体涉及一种氟化二氧化硅载药纳米粒、利用氟化二氧化硅载药纳米粒制备的氟化二氧化硅载药相变纳米液滴及进一步包覆得到的全氟碳复合微液滴及其制备方法、用途。
背景技术
中枢神经***(central nervous system,CNS)疾病是造成健康生命损失最高的疾病，且发病人数呈上升趋势，其治疗的主要困难是药物很难通过血脑屏障(blood brainbarrier,BBB)，无法快速高效作用于病变的脑实质。疏水中枢神经***药物若直接静脉注射，将无法均匀分散于亲水的血液***，当药滴直径大于5μm易引起血管栓塞，因此需要制成亲水制剂，但是亲水性修饰后又会引起BBB通过率低、包材代谢不良等问题。
亲水小分子药物结构类似于大脑神经递质、含氮类激素、局部介质等功能物质，但由于其亲水性强，多数难以通过BBB，部分药物可以通过提高剂量达到药效，然而不良反应增强。其中，镇静***物广泛用于手术麻醉及重症监护，***临床效果高度依赖于BBB通透效率，亲水小分子***物静注后无法快速起效、停药后无法快速清除，是临床镇静效果的重大缺陷。以亲水镇静药γ-羟丁酸钠为例，γ-羟丁酸钠是第一个也是唯一的天然全身***物，可模拟伽马氨基丁酸(gamma-aminobutyric acid,GABA)，产生似生理性睡眠，不影响脑血流量，不增加颅内压，可保护缺血器官，具有呼吸、循环抑制小，增加心肌缺氧耐受力，对肝肾无毒性作用、安全范围大等优点，但由于疏水性差，BBB通透率低，γ-羟丁酸钠麻醉诱导量为50-80mg/kg，为疏水镇静药丙泊酚的30-40倍，依托咪酯的200-300倍，需要20-30min才充分起效，停药后60-90min后苏醒，个别4-5h才苏醒，难以满足快速、高效的临床镇静需求。
酯化药物前体和纳米靶向载体是提高亲水小分子药物BBB通透的常用策略。酯化药物前体策略主要通过小分子药物的亲水基团与疏水基团酯化交联，降低小分子药物的亲水性，提高BBB通过率，前药多无药效，在体内通过酯酶水解释放活性药物，但普通酯酶水解效率低，且分布广泛，导致前药起效缓慢(约2h)、用药量大、不良反应高、无脑靶向功能。纳米载体可以通过调整包材种类、载药形式、释放形式、连接靶头等，使亲水小分子药物延长体内循环时间、缓慢释放、靶向给药，从而减少给药量、降低不良反应。为实现脑靶向给药，纳米载体通常需要连接靶头，依靠内吞方式，缓慢通过BBB，导致制备费用高、BBB通过率低、起效时间长，难以避免免疫***吞噬，仍无法根本解决亲水小分子药物的问题。
因此，提高亲水小分子***物BBB通透效率，是麻醉学科亟待解决的重要课题，也是亲水小分子CNS药物的发展方向。
除了传统给药方式，***给药还可以采用电、磁、光和超声波等方式。电 场响应性药物载体以具有电场响应性的高分子材料作为载体包裹药物，在外界电 场或载体本身产生的电流刺激下，高分子载体的结构发生变化，导致药物快速释 放，其优点是通过控制电场的方向、强度和持续时间来调控药物定时、定点和定 量释放，但由于人体是电场导体，电流的刺激不仅对人体有影响，人体的存在也会干扰电场响应性药物释放，难以控释药物通过BBB。磁场响应性药物载体采用具有磁性的纳米材料，通过表面修饰后形成稳定的纳米颗粒，在外界磁场的诱导下，富集于病灶部位，可有效实现药物的定点输送。由于目前磁性纳米粒子热效不高，磁性加热设备需要高磁场强度，导致设备价格昂贵。磁场刺激需要将磁性颗粒加入载体，导致载体无法通过BBB，更无法降解清除磁性纳米成分。光药物控释体系具有灵敏度高的优点，主要用于溶液和体表的药物治疗，但其生物组织内穿透深度浅，无法到达人体深部组织(如腹部和脑部)，尚未用于药物脑部控释。
与上述策略不同，加拿大Sunnybrook健康科学中心的科学家们发现超声联合微泡(ultrasound combining microbubbles，USCM)技术具有可逆、无创地开放特定部位脑组织BBB的特性，BBB开放效果与超声、微泡造影剂参数相关，静注USCM可显著增强FUS无创性开放BBB的效果，BBB在24h之内就完全恢复正常，并且没有引起神经元损伤。USCM是由壳膜包裹核心气体或全氟碳液(体内超声后产生微泡)构成的微泡，其粒径在微米级甚至纳米级，具有超声微泡成像、超声微泡打开BBB和超声微泡药物控释的特点。超声对正常的组织细胞没有破坏性，具有强穿透性，可准确定位，应用于脑部具有明显的优势。超声控制释药体系以超声敏感材料作为药物载体，当超声辐照于靶组织或靶器官时，靶体内载体可定向释放出包裹或附着的药物，实现对负载药物的定时、定量、定点释放，达到提高药物输送效率或基因转染率的目的。因此，利用超声联合微泡打开BBB，成为解决亲水小分子***物高效通过BBB的重要策略。
目前商业超声造影剂多为磷脂、蛋白等包裹惰性气体微泡，而相对于气体，全氟碳化合物具有较大的分子量、极低的水溶解度和缓慢的扩散速率，但由于全氟碳脂溶性和水溶性均较差，药物只能包裹在外层，使得现有的全氟碳纳米粒载药量较低。
发明内容
鉴于以上技术问题，本发明提供以下技术方案：
本发明提供一种氟化二氧化硅载药纳米粒的制备方法，是将亲水性小分子***物载入介孔二氧化硅纳米粒之中，形成二氧化硅载药纳米粒，再对所述二氧化硅载药纳米粒进行表面全氟化学修饰得到。
优选地，所述表面全氟化学修饰是将所述二氧化硅载药纳米粒与1H,1H,2H,2H-全氟癸基三乙氧基硅烷反应使二氧化硅纳米颗粒表面被全氟碳链修饰，得到氟化二氧化硅载药纳米粒。
优选地，所述介孔二氧化硅纳米粒与所述亲水性小分子***物的质量比为10∶1～2；
所述介孔二氧化硅载药纳米粒与所述1H,1H,2H,2H-全氟癸基三乙氧基硅烷的质量比为1∶1～5。
本发明还提供一种根据上述方法制备得到的氟化二氧化硅载药纳米粒。
本发明还提供一种氟化二氧化硅载药相变纳米液滴的制备方法，其是将所述氟化二氧化硅载药纳米粒分散于全氟碳中，再经超声乳化得到。
优选地，所述氟化二氧化硅载药纳米粒与所述全氟碳的质量比为1∶1～5。
本发明还提供一种根据上述方法制备得到的氟化二氧化硅载药相变纳米液 滴。
本发明还提供一种全氟碳复合微液滴的制备方法，其是将所述氟化二氧化硅载药相变纳米液滴与盐酸多巴胺按照质量比2∶1混合进行聚合反应后得到。
本发明还提供一种根据上述方法制备得到的全氟碳复合微液滴。
本发明还提供了所述全氟碳复合微液滴在制备***物中的用途。
对比现有技术，本发明的有益效果为：
1、本发明先利用介孔二氧化硅纳米粒负载亲水性小分子***物，使载药量提高；再对二氧化硅载药纳米粒表面进行氟化修饰，得到的氟化二氧化硅载药纳米粒就可以分散到全氟碳溶液里，从而将药物分子装载于全氟碳液之内，使全氟碳的内部空间被利用起来，进一步提高氟化二氧化硅载药纳米粒的载药量。
2、本发明用全氟碳溶液包裹氟化二氧化硅载药纳米粒，外面加聚多巴胺包裹以后得到全氟碳复合微液滴。这种复合微液滴不仅载药量比现有的全氟碳纳米液滴大5-10倍(载体大部分是全氟碳溶液)，而且超声波辐射以后，全氟碳液可微泡化显影并释放***物。
3、本发明制备得到的全氟碳复合微液滴，在相控阵聚焦超声作用下产生微泡，微泡形成时可以超声显影，破裂时可以释放药物，不仅可以监测药物释放过程，还可以控制药物释放过程，同时可根据超声微泡成像信号推测药物释放量，调整脑部药物释放量。
4、本发明提供的全氟碳复合微液滴，可以提高亲水小分子***物BBB通透效率，实时监测并调控***物脑内释放量，从而实现亲水小分子***物高效镇静、苏醒快、个体化精准给药、用药量少、毒副作用小、可控性强等镇静效果，有望进一步拓展广阔的CNS亲水小分子药物市场。
5、本发明提供的氟化二氧化硅载药纳米粒粒径20-50nm，孔隙率>20％，载药量>20％，在全氟碳溶液里可以分散。
附图说明
图1是氟化二氧化硅载药纳米粒的透射电镜照片；
图2是全氟碳复合微液滴的透射电镜照片；
图3是本发明自行搭建的超声药物控制释放装置；
图4是全氟碳复合微液滴在超声触发释放前的显微镜照片；
图5是全氟碳复合微液滴在超声触发释放后的显微镜照片；
图6是超声触发的药物累计释放曲线；
图7是全氟碳复合微液滴药物释放前后B超图像。
具体实施方式
下面通过结合具体实施案例进一步对本发明进行进一步详细说明。各实施例及试验例中所用的设备和试剂如无特殊说明，均可从商业途径得到。这些实施案例所描述的具体实施例仅用以解释本发明而用于限定本发明。
为了更好地理解本发明而不是限制本发明的范围，在本发明中所用的表示用量、时间、百分比的所有数字、以及其他数值，在所有情况下都应理解为以词语“大约”所修饰。因此，除非特别说明，否则在说明书和所附权利要求书中所列出的数字参数都是近似值，其可能会根据试图获得的理想效果的不同而加以改变。
本发明提供一种氟化二氧化硅载药纳米粒，是将亲水性小分子***物载入介孔二氧化硅纳米粒之中，形成二氧化硅载药纳米粒，再对该二氧化硅载药纳米粒进行表面全氟化学修饰得到。该氟化二氧化硅载药纳米粒的粒径为20-50nm，孔隙率>20％，载药量>20％，在全氟碳溶液里可以分散。其中，介孔二氧化硅纳米粒可以采用现有技术中的介孔二氧化硅纳米粒，在此不做限制。
利用上述氟化二氧化硅载药纳米粒可以进一步制备氟化二氧化硅载药相变纳米液滴，具体是将氟化二氧化硅载药纳米粒分散于全氟碳中，再经超声乳化得到。该氟化二氧化硅载药相变纳米液滴的载药量相较于现有的全氟碳纳米液明显提高，且超声波辐射以后，全氟碳液可微泡化显影并释放***。
为了进一步提高上述氟化二氧化硅载药相变纳米液滴的稳定性和生物相容性，本发明对氟化二氧化硅载药相变纳米液滴的表面进行了聚多巴胺包覆，最终制得全氟碳复合微液滴，粒径为80-220nm，载药量>7％，表面聚多巴胺层5-50nm。
下面结合具体实施例进行说明。
实施例1
一种氟化二氧化硅载药纳米粒，是按照以下方法制备得到的：
1、介孔二氧化硅纳米球颗粒的制备：
采用软模板法，将10mg亲水性小分子***物(γ-羟丁酸钠)与50mL质量分数10％的阳离子表面活性剂十六烷基三甲基氯化铵(CTAC)溶液混合，加入质量分数10％的三乙醇胺溶液，将其混合加热至95℃。在磁力搅拌的条件下，缓慢滴加100mg正硅酸乙酯，水解合成二氧化硅纳米球颗粒；待该反应进行充分之后，再滴加50mg双-(γ-三乙氧基硅基丙基)四硫化物与100mg正硅酸乙酯的混合溶液，在二氧化硅纳米颗粒外形成具有更大孔径的介孔有机硅结构；最后利用0.2ml氨水刻蚀掉内部的无机二氧化硅，进一步提高二氧化硅纳米粒的载药能力。
2、γ-羟丁酸钠-二氧化硅纳米粒制备
将制备好的100mg介孔二氧化硅纳米粒加入至含有10mgγ-羟丁酸钠的溶液中，进行药物吸附，吸附完成后离心分离制备γ-羟丁酸钠-二氧化硅纳米粒。
3、氟化二氧化硅载药纳米粒的制备：
将100mgγ-羟丁酸钠-二氧化硅纳米粒与500mg1H,1H,2H,2H-全氟癸基三乙氧基硅烷反应，使二氧化硅纳米颗粒表面被全氟碳链修饰，制备得到γ-羟丁酸钠-氟化二氧化硅纳米粒。
实施例2
一种氟化二氧化硅载药纳米粒，其制备方法与实施例1的不同之处在于：将制备好的50mg介孔二氧化硅纳米粒加入至含有10mgγ-羟丁酸钠的溶液中，进行药物吸附，吸附完成后离心分离制备γ-羟丁酸钠-二氧化硅纳米粒。
实施例3
一种氟化二氧化硅载药纳米粒，其制备方法与实施例1的不同之处在于：将500mgγ-羟丁酸钠-二氧化硅纳米粒与500mg1H,1H,2H,2H-全氟癸基三乙氧基硅烷反应，使二氧化硅纳米颗粒表面被全氟碳链修饰，制备得到γ-羟丁酸钠-氟化二氧化硅纳米粒。
对实施例1制备的γ-羟丁酸钠-氟化二氧化硅纳米球(实施例1～3制备得到的纳米球的性能基本相同，故此处仅以实施例1为例进行说明)的孔隙率、粒径、载药量进行分析。结果显示(图1)，氟化二氧化硅载药纳米粒粒径20-50nm，孔隙率>20％，载药量>20％，在全氟碳溶液里可以分散。
实施例4
一种γ-羟丁酸钠-氟化二氧化硅相变纳米液滴，是按照以下方法制备得到：
将实施例1中经全氟表面修饰后得到的10mgγ-羟丁酸钠-氟化二氧化硅纳米粒分散于50ml全氟碳中，接着加入0.5ml的10mmol/L三羟甲基氨基甲烷(Tris)溶液，在超声波和表面活性剂的作用下，进行乳化制备得到γ-羟丁酸钠-氟化二氧化硅相变纳米液滴。γ-羟丁酸钠-氟化二氧化硅相变纳米液滴将药物分子装载于全氟碳液之内，全氟碳的内部空间被充分利用起来，不仅大幅度提高了γ-羟丁酸钠-氟化二氧化硅纳米球全氟碳乳化液滴的载药量，还可以利用全氟碳相变产生微泡来超声控制***-氟化二氧化硅纳米粒释放。
实施例5
一种全氟碳复合微液滴，是按照以下方法进行制备：
为了进一步提高γ-羟丁酸钠-氟化二氧化硅相变纳米液滴的稳定性和生物相容性，对其进行聚多巴胺表面包覆。向分散在Tris溶液中的10mgγ-羟丁酸钠-氟化二氧化硅相变纳米液滴中加入500uL浓度为10mg/mL的盐酸多巴胺溶液，进行聚合反应24小时，反应结束后进行透析纯化，得到全氟碳复合微液滴，于4℃冰箱冷藏保存。
采用透射电镜、马尔文粒度仪、紫外分光度仪测量全氟碳复合微液滴的外观形态、粒径、载药量。结果显示(图2)，全氟碳复合微液滴的粒径为80-220nm，载药量>7％，表面聚多巴胺层5-50nm。
实施例6
对于制备的全氟碳复合微液滴，我们利用自行搭建的超声药物控制释放装置(图3)进行了超声释放实验。
对相变纳米液滴施加超声刺激(超声功率6.5W/cm2，中心频率1.2MHz)，纳米液滴发生相变，如图4-5所示。
从图6所示结果看出，在进行三次超声处理之后，药物的释放已超过20％，而对照组几乎没有释放。除此之外，该控释***的药物释放过程还可以通过超声成像对其进行监控，释放前后超声图像中的信号强弱有明显差异，如7所示。超声作用4分钟内，***物释放超过20％，二次超声再释放20％，三次超声作用释放超过80％，如增强触发超声参数可一次触发释放。此外，超声仪器可以连续3次以上作用释放***物，作用时间超过30分钟，每次作用时间超过10分钟。
以上公开的仅为本发明的具体实施例，但是，本发明实施例并非局限于此，任何本领域的技术人员能思之的变化都应落入本发明的保护范围。
Claims (3)
1.一种全氟碳复合微液滴的制备方法，其特征在于，包括以下步骤：
将亲水性小分子***物γ-羟丁酸钠载入介孔二氧化硅纳米粒之中，形成二氧化硅载药纳米粒，再对所述二氧化硅载药纳米粒进行表面全氟化学修饰得到氟化二氧化硅载药纳米粒；
将所述氟化二氧化硅载药纳米粒分散于全氟碳中，再经超声乳化得到氟化二氧化硅载药相变纳米液滴；
将所述氟化二氧化硅载药相变纳米液滴与盐酸多巴胺按照质量比2∶1混合进行聚合反应，得到全氟碳复合微液滴；
其中，所述表面全氟化学修饰是将所述二氧化硅载药纳米粒与1H,1H,2H,2H-全氟癸基三乙氧基硅烷反应使二氧化硅纳米颗粒表面被全氟碳链修饰；
所述介孔二氧化硅纳米粒与所述亲水性小分子***物γ-羟丁酸钠的质量比为10∶1～2；
所述二氧化硅载药纳米粒与所述1H,1H,2H,2H-全氟癸基三乙氧基硅烷的质量比为1：1～5;
所述氟化二氧化硅载药纳米粒与所述全氟碳的质量比为1∶1～5。
2.一种根据权利要求1所述的方法制备得到的全氟碳复合微液滴。
3.权利要求2所述全氟碳复合微液滴在制备***物中的用途。
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| CN102441179B (zh) * | 2011-12-07 | 2013-07-17 | 中国科学院上海硅酸盐研究所 | 二氧化硅基超声造影剂/hifu增效剂及其制备方法 |
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