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CN108187151A - 一种药物涂层的支架 - Google Patents

一种药物涂层的支架 Download PDF

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CN108187151A
CN108187151A CN201810064908.7A CN201810064908A CN108187151A CN 108187151 A CN108187151 A CN 108187151A CN 201810064908 A CN201810064908 A CN 201810064908A CN 108187151 A CN108187151 A CN 108187151A
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stent
drug
coating
gefitinib
vascular
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冉峰
赵琪
卓华威
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Nanjing Drum Tower Hospital
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Abstract

一种含药物涂层的血管支架，血管支架基体为裸金属或合金，在血管支架涂覆有吉非替尼药物涂层。吉非替尼药物与聚乳酸载体一道构成涂层，吉非替尼药物与聚乳酸载体的质量比例是5mg/g。将吉非替尼及其载体聚乳酸溶解于100WT％的乙醇溶液中并加热到40—80℃保持1个小时以上；将金属支架基体固定并保持在60±10℃，将药物涂层液体滴在支架基体上烘干，反复3‑10次滴至涂层厚度达到10‑100微米；或者将金属支架浸泡在药物涂层液体中，后烘干形成涂层，反复3‑10多次至需要的涂层厚度。

Description

一种药物涂层的支架
技术领域
本发明涉及医用器械，一种将功能药物涂层负载在常见CoPt、不锈钢等合金网格组成的常见支架基材上形成的一种药物负载支架。
背景技术
美国专利5697967就公布了这样的一种药物负载支架。美国专利9204982公布了对这类支架进行药物注入的方法。将雷帕素负载在裸支架上应用在血管中，可以有效抑制再狭窄的发生。目前临床使用的外周支架多为金属裸支架，但支架植入术长期受限于支架内再狭窄(in-stent restenosis，ISR)，金属裸支架(bare metal stent，BMS)置入术后20％～30％的患者会发生支架内再狭窄(in-stent restenosis，ISR)，成为介入治疗面临的重要问题[1]。研究表明药物涂层支架(drug-eluting stents，DES)能进一步降低ISR的发生率[2],但DES仍面临着晚期支架内血栓(late stents thrombosis，LST)、极晚期支架内血栓(very late stent thrombosis，VLST)[3]等问题，影响介入治疗疗效。国外还有在研究紫杉醇等药物的药物涂层支架。紫杉醇DES和西罗莫司(Siromlius)及其衍生物DES是目前临床上较为常用的血管支架，其作用原理为抑制血管平滑肌增殖和迁移。与传统金属裸支架相比，它们能抑制内膜增生，降低ISR的发生。然而，对植入这些药物涂层支架的患者的随访发现，晚期内皮细胞不能完全覆盖成为该药物涂层支架最大的缺点。内皮化(re-endothelialization，RE)不全是由于洗脱药物非特异性的抗增殖的作用，这些药物在抑制血管平滑肌增殖的同时，抑制血管内皮细胞的生长。
参考文献
[1]F.Alfonso,M.J.Perez-Vizcayno,A.Cruz,J.Garcia,P.Jimenez-Quevedo,J.Escaned,R.Hernandez,Treatment of patients with in-stent restenosis,EuroIntervention 5(Suppl.D)(2009)D70–D78.
[2]S.McGinty,S.McKee,R.M.Wadsworth,C.McCormick,Modelling drug-elutingStents,Math.Med.Biol.28(1)(2011)1–29.
[3]Takano M,Yamamoto M,Inami S,et al.Long-Term Follow-Up EvaluationAfter Sirolimus-Eluting Stent Implantation by Optical Coherence Tomography[J].Jacc,2008(9):968-969.
发明内容
本发明目的是，提出一种药物涂层支架，本发明的药物涂层支架包括支架与涂覆在支架上的药物涂层，所说的药物涂层为含有吉非替尼的聚合物，在基本不影响内皮细胞生长的同时，有效抑制血管平滑肌细胞的增殖，从而达到抑制支架内再狭窄的作用。
本发明技术方案是：一种含药物涂层的支架，即采用新型复合药物涂层功能化的血管支架，血管支架基体为常用的裸金属或合金(或其其他支架材料)，在血管支架金属网处涂覆有吉非替尼药物涂层。
吉非替尼药物与聚乳酸载体一道构成涂层，吉非替尼药物与聚乳酸载体的质量比例是5mg/g。
所述的含药物涂层的血管支架的制备方法，其典型的复合药物涂层液体制造工艺是，将吉非替尼及其载体聚乳酸溶解于100WT％的乙醇溶液中并加热到40—80℃保持1个小时以上；将金属支架基体固定并保持在60±10℃，将药物涂层液体滴在支架基体上烘干，反复3-10次滴至涂层厚度达到10-100微米；或者将金属支架浸泡在药物涂层液体中，后烘干形成涂层，反复3-10多次至需要的涂层厚度。
将金属支架浸泡在复合药物涂层液体中，后烘干形成涂层，反复3-10多次至需要的涂层厚度。制备成本发明吉非替尼涂层支架GES。
吉非替尼(Gefitinib)是一种口服表皮生长因子受体酪氨酸激酶(EGFR-TK)抑制剂,目前临床用于局部晚期或转移性非小细胞肺癌的化疗，有体外实验表明，吉非替尼与紫杉醇相比可更特异性地抑制血管平滑肌细胞(SMC)的增殖，而对血管内皮细胞(VEC)的细胞毒性作用低于紫杉醇。本研究观察了gefitinib药物涂层支架对小型猪股动脉模型支架内再狭窄的预防效果，有关这方面的研究国内外尚未见报道。
本发明是一种采用新型药物涂层功能化的血管支架，体外试验及动物试验表明，本发明能在基本不影响内皮细胞生长的同时，有效抑制血管平滑肌细胞的增殖，从而达到抑制支架内再狭窄的作用。
DES的问世被誉为血管介入领域的又一个“里程碑”，DES为表面结合有携带药物的载体的支架，在置入病变部位后成为一个药物池，不断向病变局部释放药物，具有靶向性好，有效治疗时间长，全身副作用小等优点。支架内再狭窄的机制尚未完全被阐明，有研究表明，内膜的增生和ISR的发生有密切关系。有多种因素影响了内膜的增生，而平滑肌细胞的增殖和迁徙发挥着极其重要的作用[5]。紫杉醇DES和西罗莫司(Siromlius)及其衍生物DES是目前临床上较为常用的血管支架，其作用原理为抑制血管平滑肌增殖和迁移。与传统金属裸支架相比，它们能抑制内膜增生，降低ISR的发生。然而，对植入这些药物涂层支架的患者的随访发现，晚期内皮细胞不能完全覆盖成为该药物涂层支架最大的缺点。内皮化(re-endothelialization，RE)不全是由于洗脱药物非特异性的抗增殖的作用，这些药物在抑制血管平滑肌增殖的同时，抑制血管内皮细胞的生长。本实验采用吉非替尼制成DES，并从血管彩超、CTA、组织病理学角度证实了GES能有效抑制支架内再狭窄的发生，而不影响内皮化。
本研究通过体外实验，确定了最佳的药物浓度，以达到抑制血管平滑肌细胞增殖的同时，基本不影响血管内皮细胞的正常生长。将GES植入小型猪股动脉后，术后一月彩超提示GES内血流通畅，流速正常。术后3月CTA提示支架在位，无明显移位变形，支架直径正常，其内血流通畅。同时取出带支架血管标本，组织病理分析提示GES组(n＝10)相较于BMS组(n＝10)，在血管直径、损伤评分无明显差异(P>0.05),但GES组管腔面积较BES组明显增加，支架上内膜厚度、新生内膜面积均较BES组减少。可见在支架植入后的3个月内，GES能有效抑制内膜增生，避免支架内再狭窄的发生。为DES的药物选择提供了一种新的思路。
附图说明
图1为本发明GES扫描电镜放大观察图。
具体实施方式
1.1实验材料
1.1.1细胞株和主要试剂：猪骨髓干细胞、胎牛血清、DMEM培养液、EBM-2培养液、PDGF-BB生长因子、PBS、胰酶、FITC、DAPI核燃料、MTT、DMSO。
1.1.2药物、载体及支架：吉非替尼、聚乳酸、100％乙醇、3cm*2.5mm冠脉球扩支架(Buma)
1.1.3实验动物：本实验采用巴马小型猪，雌雄不限，体重20-25kg,购自南京鼓楼医院动物实验中心
1.2实验方法
1.2.1血管平滑肌细胞、血管内皮细胞的诱导及免疫荧光鉴定：将正常生长的猪骨髓干细胞，分别用含PDGF-BB生长因子的DMEM培养液、EBM-2培养液培养，细胞培养箱的参数调整为5％CO2，环境温度调整为37℃。将其诱导分化为血管平滑肌细胞及血管内皮细胞。并行免疫荧光分析。其中血管平滑肌细胞特异性一抗为α-actin,血管内皮细胞特异性一抗为vWF及CD34。
1.2.2药物涂层支架的制备及扫描电镜观察：本实验采用浸涂法制备支架。将冠脉裸支架消毒备用。将Gefitinib及其载体聚乳酸以0、1mg/g、2mg/g、5mg/g、10mg/g的质量比溶解于100ml 100％乙醇中，将支架分别浸入含浓度梯度药物的乙醇中，37℃浸涂24h。取出各药物浓度梯度支架，充分风干，行扫描电镜观察药物与支架的结合情况。并将所有支架再次消毒备用。
1.2.3MTT法确定合适的吉非替尼药物浓度：将0、1mg/g、2mg/g、5mg/g、10mg/g的浓度梯度的支架，分别置入50ml PBS中，37℃恒温搅拌72h，制成浸提液。并以各浓度梯度GES浸提液为培养基底物，分别培养SMC及VEC，并连续四日行MTT试验，取对数生长期细胞制成1×104细胞悬液，接种于96孔板，每孔100μl至细胞贴壁后，吸弃旧培养液，加入不同浓度梯度浸提液培养基(、1mg/g、2mg/g、5mg/g、10mg/g)，继续培养24，48，72，96h后，每孔加MTT液20μl，继续孵育4h，吸弃每孔培养液，加入150μl的DMSO,至摇床上震荡20min，测得各组OD490下的吸光度。计算各浓度梯度浸提液对MSC及EPC的抑制率，根据MTT结果选取最合适的吉非替尼药物浓度。
1.2.4GES植入猪股动脉内：按上述最适宜浓度制备GES并消毒。选取10头巴马小型猪，肌肉内注射氯胺酮(100mg)和氟哌利多卡因(5mg)麻醉后，将猪仰卧位固定于手术板上。备皮和消毒双侧腹股沟后，取腹股沟垂直切口，钝性分离肌肉间隙，暴露双侧颈动脉，绕带备用，全身肝素化后(100U/kg),哈巴狗夹阻断颈动脉近心段和远心端，在阻断的股动脉前壁取横行切口，长度约为5mm，向近心端置入0.014mm导丝，将需要释放的GES通过导丝送至预释放的血管出，在10大气压的压力下打开球囊，将支架释放至血管腔内，撤出释放球囊。术毕取8-0prolene线连续缝合颈动脉横行切口，开放血流观察血管是否通畅，有无局部狭窄，仔细止血后，逐层关闭股动脉切口。手术完成前静脉给予青霉素80万U，术后给予阿司匹林抗血小板(300mg/d)。
1.2.5术后一月复查彩超：术后一月，肌肉内注射氯胺酮(100mg)和氟哌利多卡因(5mg)麻醉并备皮后。所有动物行双侧股动脉彩超检查。
1.2.6术后三月行CTA检查：术后三月，基础麻醉后，于小型猪耳缘静脉注入碘伏醇50ml,CT扫描双前肢动脉并行三维重建。
1.2.7组织学检查：术后三月，暴露植入支架的股动脉段，肉眼观察动脉通畅与否及其外观情况。切取含支架段股动脉标本，平均分为3段。第一段固定于10％福尔马林溶液中，后包埋至甲基丙烯酸甲酯中，硬组织切片机切片至50μm后，行苏木素-伊红染色。第二段支架标本纵行切开，平铺支架，浸泡至1.6％的戊二醛中，准备行扫描电镜观察内皮细胞生长情况。第三段支架标本行免疫组化分析
2、结果
2.1免疫荧光鉴定结果
猪血管平滑肌细胞和内皮细胞生长状态良好，免疫荧光结果提示平滑肌细胞α-actin阳性，内皮细胞CD34、vWF阳性,以上结果证实两种细胞均符合表型。
2.2GES的制备及扫描电镜结果
根据上述方法成功制得药物涂层支架，经扫描电镜检查，可见药物颗粒均匀分布于BMS表面，且BMS表面仍较为光滑，未受制备过程影响(图1)。
2.3MTT结果
本实验采用MTT法探究不同药物浓度GES对VSMC及VEC杀伤作用，以确定合适的药物浓度。各浓度梯度GES的对两种细胞的抑制率，可见Gefitinib可明显抑制VSMC的生长，而对VEC的生长抑制作用较弱。Gefitinib对VSMC抑制作用与药物浓度、作用时间成正相关，然而，当药物浓度过高(10mg/g)时，对VEC也已有了较明显的抑制作用，96h抑制率为15％。综合考虑药物对VSMC及VEC影响，选择5mg/g作为后续动物实验的药物浓度。
2.4术后B超情况
术后1月复查B超，可见GES支架内血流通畅，流速正常。

Claims (3)

1.一种含药物涂层的血管支架，其特征是血管支架基体为裸金属或合金，在血管支架涂覆有吉非替尼药物涂层。
2.根据权利要求1所述的含药物涂层的血管支架，其特征是吉非替尼药物与聚乳酸载体一道构成涂层，吉非替尼药物与聚乳酸载体的质量比例是5mg/g。
3.根据权利要求1所述的含药物涂层的血管支架的制备方法，其特征是其典型的复合药物涂层液体制造工艺是，将吉非替尼及其载体聚乳酸溶解于100WT%的乙醇溶液中并加热到40—80℃保持1个小时以上；将金属支架基体固定并保持在60±10℃，将药物涂层液体滴在支架基体上烘干，反复3-10次滴至涂层厚度达到10-100微米；或者将金属支架浸泡在药物涂层液体中，后烘干形成涂层，反复3-10多次至需要的涂层厚度。
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