CN105999310A - 一种同时能rna干扰和mr成像的纳米囊泡及其制备方法和应用 - Google Patents
一种同时能rna干扰和mr成像的纳米囊泡及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于纳米医学与生物医学工程领域，具体公开了一种同时能RNA干扰和MR成像的纳米囊泡及其制备方法和应用。所述纳米囊泡基于一种两亲性嵌段聚合物载体线性聚乙烯亚胺‑聚乳酸。利用囊泡的疏水空腔对亲水性磁纳米粒子SPIO进行负载，表面PEI复合siRNA，体外高效标记神经干细胞、沉默抑制神经元分化基因，体内移植后，在实现干细胞实时定位的同时，促进其向神经元方向分化，提高脑梗死治疗效果，应用前景广阔。
Description
技术领域
本发明涉及纳米医学与生物医学工程领域，更具体地，涉及一种同时能RNA干扰和MR成像的纳米囊泡及其制备方法和应用。
背景技术
脑梗死，即急性缺血性脑卒中(Acute Ischemic Stroke,AIS)，是由于脑动脉的闭塞导致的脑组织的梗死，伴随着神经元、星形胶质细胞、少突胶质细胞的损伤，导致神经元回路破坏、肢体功能障碍，甚至残疾或死亡，是现代社会中导致致死和致残的最重要的中枢神经系统血管事件。目前，临床上最常用的治疗方式是通过经美国FDA批准的临床用药重组组织型纤溶酶原激活剂(rt-PA)进行血栓溶解再通脑梗塞区域的血管，如今世界各地虽仍在用rt-PA治疗AIS，但其存在十分窄的时间窗限制(美国为发病3小时内，欧洲至多为发病4.5小时)和并发症可能(如出血)，临床上溶栓治疗获益病人非常少，这就要求一种不受时间窗、更安全有效的治疗方式。近年来，神经干细胞(NSCs)疗法，作为一种治疗中枢神经系统疾病的潜在方式，具有非常大的应用前景。NSCs是一种具有活跃的自我更新能力及多向分化能力的祖细胞，NSCs在体外培养后进行体内移植，可分化成神经元、胶质细胞，替代修复神经元回路，促进脑梗死后神经功能的恢复。值得一提的是，移植的NSCs具有很强的受损组织归巢能力，即使在受损区的较远处，也可表现出直接或间接的修复性能。然而其临床应用却仍面临着重大挑战，主要归因于体内长期治疗下，难以实现对干细胞脑组织内迁移及存活分布进行有效的定位。
分子成像技术能对干细胞进行活体示踪，用于连续、纵向监测干细胞在宿主组织内的分布及迁移。理想的分子成像技术应具备以下优点：高空间分辨率、高灵敏度和特异性、可量化并安全可靠，此外，具有非侵袭性，可实现临床转化。目前活体成像技术主要包括放射性核素成像，荧光和生物发光，MR成像(MRI)。相对于核素成像的短半衰期与荧光成像穿透深度有限及它们共同存在的问题—低空间分辨率，MRI因其具有极佳的分辨率(可对深部组织进行精确定位和定量分析)、无创伤、可重复性强等优点，广泛用于肿瘤、心血管和神经损伤等疾病的检测。然而，干细胞本身在MRI上并不具有特异性信号，给临床检测带来了相当程度的困难。为了提高MRI分辨对比度，临床上常采用MRI造影剂来进行干细胞磁性标记，使得干细胞出现特异性信号改变而被识别，而在众多的磁共振成像造影剂中，SPIO以其无毒、高生物相容性、高成像敏感性及表面易修饰等优点受到了广大研究者的重视。
NSCs具有分化为神经神经元、星形胶质细胞和小胶质细胞的多向分化能力，但在脑梗死中只有分化成神经元才能替代损伤、丢失的神经元，重建神经元回路，修复组织损伤。而多数研究报道表明，移植到体内的NSCs大多数会分化成胶质细胞，而非神经元，这大大限制了其修复能力。因此，定向诱导更多的NSCs向神经元分化有望提高干细胞治疗效果。大量研究表明，Nogo-66受体(NgR)存在于神经元细胞及其轴突上，脑梗死组织释放的髓鞘相关抑制因子与过表达的NgR相互作用，可抑制NSCs向神经元分化、神经再生。因此，抑制NgR的表达可促进NSCs向神经元的分化。RNA干扰为特异性靶向基因沉默技术，可利用NgR-siRNA(siNgR)下调NgR的表达，促进NSCs分化为神经元细胞，提高干细胞移植脑梗死后分化的神经元有效数量，促进干细胞重建神经元回路，让干细胞治疗应用前景更加瞩目。
发明内容
本发明为了克服现有技术的上述不足，提供一种能自组装共同负载SPIO和siRNA的两亲性嵌段聚合物。
本发明的另一个目的是提供上述两亲性嵌段聚合物的制备方法。
本发明的另一个目的是提供上述两亲性嵌段聚合物在制备能同时RNA干扰和MR成像的纳米囊泡中的应用。
本发明的另一个目的是提供一种能同时RNA干扰和MR成像的纳米囊泡。所述纳米囊泡能促进神经干细胞向神经元的分化，达到提高治疗脑梗死疗效的目的；同时引入高灵敏磁造影剂，就干细胞治疗中对其迁移及分布进行有效的、实时的定位监测。
本发明的另一个目的是提供上述纳米囊泡在制备促进神经性干细胞定向分化治疗脑梗死药物中的应用。
为了实现上述目的，本发明是通过以下技术方案予以实现的：
一种能共同负载SPIO和siRNA的两亲性嵌段聚合物，所述聚合物由聚乙烯亚胺亲水段和聚乳酸疏水段两嵌段共聚物构成；所述聚乙烯亚胺亲水段分子量为900Da，聚乳酸疏水段分子量为8000～10000Da。
本发明为了实现NSCs体外培养时siRNA药物能被细胞高效摄取，选取经典的基因载体聚乙烯亚胺(PEI)作为亲水段，负载siRNA；另一方面，为降低载体毒性，选取生物相容的可降解材料聚乳酸作疏水段，同时也有利于SPIO在细胞内的再聚集，可满足高灵敏度MRI造影剂的要求。
优选地，所述聚乙烯亚胺亲水段分子量为900Da，聚乳酸疏水段分子量为9000Da。更优选地，所述聚乙烯亚胺亲水段与聚乳酸疏水段的质量比为1:10。
如上所述能共同负载SPIO和siRNA的两亲性嵌段聚合物的制备方法，由以下方法制备得到：
S1.2-乙基-唑啉的开环聚合合成聚(2-乙基-唑啉)(PEOX)；再用盐酸脱去保护基可得到线性聚乙烯亚胺(PEI)；
S2.以十二醇作引发剂，辛酸亚锡作催化剂，引发丙交酯开环聚合得到聚丙交酯/聚乳酸(PDLLA)；再用羰基二咪唑(CDI)将其末端羟基活化得PDLLA-CDI；
S3.活化后的聚乳酸(PDLLA-CDI)直接与PEI对接得到目标嵌段聚合物PEI-PDLLA。
如上所述两亲性嵌段聚合物在制备能同时RNA干扰和MR成像的纳米囊泡中的应用。一种能同时RNA干扰和MR成像的纳米囊泡，所述纳米囊泡由如上所述的两亲性嵌段聚合物自组装后，将亲水磁性纳米粒子SPIO负载于其亲水空腔内，并利用其表面PEI实现对siRNA的负载，得到能同时RNA干扰和MR成像的纳米囊泡。
本发明所述的两亲性嵌段聚合物自组装后能形成一种纳米尺寸的正电荷囊泡，将亲水性的磁性纳米颗粒(SPIO)负载在囊泡的水腔内，而负电siRNA则通过聚电子作用被负载在囊泡表面，得到同时负载MRI造影剂SPIO和siRNA的纳米囊泡，将这种纳米囊泡与神经干细胞在体外共同培养，可控标记NSC，下调NSCs的Nogo受体表达，促进其向神经元分化的同时呈现干细胞体内移植的有效实时监测。
优选地，所述的siRNA能下调神经干细胞疗法的Nogo受体表达，促进神经干细胞向神经元分化，提高干细胞移植脑梗死后分化的神经元有效数量，促进干细胞重建神经元回路，让干细胞治疗应用前景更加瞩目。本发明所述的siRNA是指本技术领域已知的能下调神经干细胞疗法的Nogo受体表达的所有种类的siRNA。
优选地，所述能同时RNA干扰和MR成像的纳米囊泡的具体制备方法为：将两亲性嵌段聚合物PEI-PDLLA溶解在2mL的氯仿中，超声乳化作用下加入溶有2mg SPIO的水溶液，得到第一次乳化液；第一次乳化液在超声作用下滴加到20mL水中，乳化均匀后旋蒸除去氯仿，并通过磁铁吸附作用分离出负载SPIO的纳米囊泡(V-SPIO)；得到V-SPIO后，将其与siRNA按特定的N/P比复合30min，即得最终的多功能复合物(V-SPIO/siRNA)。
如上所述的纳米囊泡在制备促进神经性干细胞定向分化治疗脑梗死药物中的应用。
与现有技术相比，本发明具有以下有益效果：
本发明提供了一种多功能纳米复合物的制备及应用方法，针对现有神经干细胞疗法中治疗修复效果差的缺陷，利用RNA干扰技术，促进神经干细胞(NSCs)向神经元的分化，达到提高疗效的目的；同时引入高灵敏磁造影剂，就干细胞治疗中对其迁移及分布进行有效的、实时的定位监测。有望在干细胞疗法的应用方面提供一个新的思路。
附图说明
图1为复合物的制备示意图。
图2为凝胶阻滞电泳验证囊泡对siRNA的复合能力图。
图3为负载siRNA前(A,C)后(B,D)纳米粒子的粒径和TEM图。
图4为水溶SPIO及囊泡负载siRNA前后的T2曲线。
图5为复合物的细胞毒性测试：(A)流式细胞计数法；(B)CCK8法。
图6为mRNA水平(A)和蛋白水平(B,C)评价siRNA复合物的干扰效果。
具体实施方式
下面结合说明书附图和具体实施例，进一步阐述本发明。这些实施例仅用于说明本发明而不用于限制本发明的范围。下例实施例中未注明具体条件的实验方法，通常按照本领域常规条件或按照制造厂商建议的条件。本领域的技术人员在本发明的基础上所做的任何非实质性的变化及替换均属于本发明所要求保护的范围。实施例中所述siRNA的序列为：正义链5′AGC ACG CUU UCC GUG GCUUTT3′，反义链5′AAG CCA CGG AAA GCG UGC CTT3′。实施例中siRNA的种类并不能限定本发明的保护范围，本技术领域已知的能下调神经干细胞疗法的Nogo受体表达的所有种类的siRNA都在本发明的保护范围之内。
实施例1 两亲性嵌段聚合物的合成
(1)线性聚乙烯亚胺(PEI)的合成，反应机理及过程如下：
先利用2-乙基-唑啉的开环聚合合成聚(2-乙基-唑啉)(PEOX)。称取0.372g对甲苯磺酸甲酯(2mmol)加入50mL三口瓶中，常温真空干燥2h，加入20mL新蒸的乙腈溶解，再称取4.5g 2-乙基-唑啉(45mmol)加入反应瓶中，80℃回流72h；冷却后将反应瓶浸入冰水浴中，通入干燥的氨气(经过氧化钙和氢氧化钠干燥塔)1h终止聚合反应，旋蒸除去乙腈，用三氯甲烷溶解，再沉淀在大量乙醚中，离心、干燥得淡黄色聚(2-乙基-唑啉)(PEOX)。
PEOX经盐酸脱去保护基可得到线性聚乙烯亚胺。简单地，在25mL反应瓶中加入4.2g PEOX(2mmol)，加入15mL 10％的盐酸，100℃回流反应12h，冷却后反应体系变为乳白色，用氢氧化钠溶液调节pH值至12，当pH值为5-9时溶液澄清，当pH﹥9时又恢复成乳白色浑浊。离心取下层沉淀，用去离子水洗涤三次后冻干，得淡黄色粉末端氨基线性聚乙烯亚胺
(2)聚乳酸的合成及其端羟基的活化，反应机理及过程如下：
聚乳酸(PDLLA)由十二醇引发丙交酯开环聚合而成。将135μL正十二烷醇(0.60mmol)加入干燥的100mL反应瓶中，65℃下真空除水2h，冷至室温后，加入5.76g新重结晶的D,L-丙交酯(40mmol)和少量辛酸亚锡(丙交酯质量的0.5％)，室温真空干燥4h，加入新蒸的无水甲苯20mL溶解后，120℃下进行回流12h，可观察到溶液由清液变成白色浊液。冷却后用大量无水乙醇沉淀，冷冻、离心、干燥后，用二氯甲烷溶解，再次用无水乙醇沉淀，抽滤，干燥后得白色产物PDLLA-OH。
PDLLA末端羟基可经羰基二咪唑(CDI)活化后与PEI的伯胺基反应。于100mL反应瓶中加入3.0g PDLLA-OH(0.32mmol)，65℃下真空干燥8h除水后，加入20mL新蒸四氢呋喃溶解，氩气保护下，将聚合物溶液慢慢滴加到CDI的四氢呋喃溶液(0.52g，10eq.)中，室温反应24h后沉淀在大量无水乙醇中，冷冻、分离、真空干燥后用二氯甲烷溶解，再次用无水乙醇沉淀，冷冻、分离、干燥得PDLLA-CDI。
(3)两亲性嵌段聚合物PEI-PDLLA的合成，反应机理及过程如下：
在50mL反应瓶中加入0.45g PEI(5mmol,2.5eq.)，用10mL新蒸三氯甲烷溶解。1.9g PDLLA-CDI(0.2mmol,1eq.)溶于20mL新蒸三氯甲烷后，在氩气保护下，逐滴加入到PEI溶液中，在室温下搅拌反应24h。反应液用透析袋(MW＝3.5kDa)在三氯甲烷中透析除去过量的lPEI，然后沉淀在无水乙醇中，冷冻、分离、干燥后得到淡黄色产物PEI-PDLLA。
实施例2 纳米复合物的制备及表征
取实施例1制备得到的两亲性嵌段聚合物按纳米复合物制备方法准备V-SPIO，如图1所示。然后通过凝胶阻滞电泳实验验证其负载siRNA的能力，具体地，先配置1g/L的琼脂糖溶液，倒入平板后加1.5μL溴化乙锭(EB)，并搅匀。按N/P比为0.5、1、2、4、6、8、10准备好复合物样品，待凝胶完全凝固，拔出梳子，将凝胶放入电泳槽中，加入电泳液没过凝胶，每个样品中加入2μL50％甘油，混合均匀后将加到上样孔中，恒压100V电泳40min后停止电泳仪，取出凝胶，置于凝胶成像系统中，紫外灯下观察电泳条带并拍照。结果如图2所示，当N/P比(聚合物的氮和siRNA中磷的摩尔比)较低时，聚合物不足以将siRNA完全封装复合，游离的siRNA向阳极移动，形成亮的条带，随着N/P比的增大，条带逐渐减弱，至N/P比足够大能将siRNA完全复合，条带消失。图中结果显示，当N/P比大于4时，siRNA能被完全复合。
选取N/P比为8时的复合物作为细胞实验时复合点，测定其水力学直径及形貌结构，结果如图3所示。复合siRNA前后，粒径没有明显的变化，均在150nm左右。电镜结果表明，纳米粒子呈均匀的球形结构，复合siRNA后，SPIO聚集结构外圈出现明显的复合物层，证明其对siRNA的有效负载。
实施例3 纳米粒子弛豫率的MRI检测
将水溶性SPIO、V-SPIO及V-SPIO/siNgR纳米粒子于96孔板内按浓度梯度逐级稀释，进行MRI(Philips Inter,1.5T)体外测试。MRI扫描参数如下：快速自旋回波T1加权图像：TR/TE,500/20ms，层厚，1.5mm，FOV，90×60mm，矩阵，256×256；T2加权图像：TR/TE,2600/100ms，层厚，1.5mm，FOV，100×100mm，矩阵，384×256。获取T2的弛豫时间。以铁浓度(mM)为横坐标，T的倒数(r2)为纵坐标，采用线性最小二乘回归分析，直线斜率即为T2的弛豫度。图4结果显示，囊泡负载后，因SPIO的团簇效应，T2弛豫率大大增强，而负载siRNA前后，其弛豫率并无明显变化。
实施例4 嵌段聚合物及复合物的细胞毒性检测
我们采用CCK8法检测了聚合物纳米囊泡与NSCs孵育后细胞的存活率，用流式细胞计数仪定量检测了孵育后NSCs的凋亡情况，综合评价纳米粒子对细胞的毒性，结果如图5所示，纳米复合物显示了极小的细胞毒性。这对于其应用于标记后NSCs的长期体内治疗有明显的帮助。
实施例5 体外干扰效果研究
我们通过实时PCR和Western blot实验分别在mRNA水平和蛋白水平评估纳米囊泡负载NgR siRNA在NSCs内沉默NgR基因的效果，如图6所示。在实时PCR实验中，经纳米复合物治疗后，NgR的mRNA表达水平与对照组相比有明显的降低。Western blot实验也得到了类似的结果，即相对于空白组和使用scrambled RNA孵育的细胞，携带NgR-siRNA复合物孵育细胞的NgR蛋白有明显下调表达，定量结果有统计学意义。
Claims (6)
1.一种可自组装成纳米囊泡且共同负载SPIO和siRNA的两亲性嵌段聚合物，其特征在于，所述聚合物由聚乙烯亚胺亲水段和聚乳酸疏水段两嵌段共聚物构成。
2.根据权利要求1所述的两亲性嵌段聚合物，其特征在于，所述聚乙烯亚胺亲水段分子量为900
Da，聚乳酸疏水段分子量为8000～10000 Da。
3.权利要求1或2所述的两亲性嵌段聚合物的制备方法，其特征在于，由以下方法制备得到：
S1. 2-乙基-唑啉的开环聚合合成聚(2-乙基-唑啉)；再用盐酸脱去保护基得到线性聚乙烯亚胺；
S2. 以十二醇作引发剂，辛酸亚锡作催化剂，引发丙交酯开环聚合得到聚丙交酯/聚乳酸；再用羰基二咪唑将其末端羟基活化得PDLLA-CDI；
S3. PDLLA-CDI直接与线性聚乙烯亚胺对接得到目标两亲性嵌段聚合物PEI-PDLLA。
4.权利要求1或2所述两亲性嵌段聚合物在制备能同时RNA干扰和MR成像的纳米囊泡中的应用。
5.一种能同时RNA干扰和MR成像的纳米囊泡，其特征在于，由权利要求1或2所述的两亲性嵌段聚合物自组装后，将亲水磁性纳米粒子SPIO负载于其亲水空腔内，并利用其表面PEI实现对siRNA的负载，得到能同时RNA干扰和MR成像的纳米囊泡。
6.权利要求5所述的纳米囊泡在制备促进神经性干细胞定向分化治疗脑梗死药物中的应用。
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