CN113583224A - Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜 - Google Patents
Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜 Download PDFInfo
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- CN113583224A CN113583224A CN202110817316.XA CN202110817316A CN113583224A CN 113583224 A CN113583224 A CN 113583224A CN 202110817316 A CN202110817316 A CN 202110817316A CN 113583224 A CN113583224 A CN 113583224A
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- gentamicin
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Abstract
本发明涉及一种结构式(I)表示的Ala‑Gln‑PPDO聚合物和一种Ala‑Gln‑PPDO/PLGA/PLCA/庆大霉素膜的制备及其在制备治疗肠胃的药物中的用途。
Description
技术领域
本发明涉及一种静电纺丝膜，尤其涉及一种Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜的制备及其应用。
背景技术
因肠道疾病需要进行肠吻合手术的患者年逾百万，尽管近年来外科手术技术得到了长足的进步，但吻合口瘘仍是临床一大困扰。吻合口瘘是由于伤口愈合不良导致的，主要是由于肠上皮细胞增殖缓慢，在导致愈合不良的同时也会导致伤口处成纤维细胞的过度增殖，从而导致粘连及吻合口狭窄的几率大大增加。目前预防粘连最通用的方法是在粘连部位放置屏障材料，如聚乳酸类屏障材料。但该类材料降解周期较长，其作为异物长期存在于腹腔，会带来极高的感染风险；而且由于感染的存在也会加剧粘连，有些现有的防粘连材料不仅抗感染效果不好，而且加剧粘连的可能性更高。因此，迫切需要一种具有抗感染作用的屏障材料，该材料既具有抗感染作用也具有较好的抗粘连作用，从而使得伤口吻合。
谷氨酰胺(Gln)是肠上皮细胞重要的营养物质，可通过调控EGFR信号传导来调控促进肠上皮细胞的增殖。丙氨酰基-谷氨酰胺二肽(Ala-Gln)也有同样的作用，但目前尚未有关于将Ala-Gln在肠吻合吻合口局部应用方面的报道。
因此，本领域的技术人员致力于开发一种具有抗感染作用的屏障材料，在吻合术后预防粘连发生的同时，尽快促进上皮细胞的增殖形成连续上皮层，不仅可以促进吻合口的愈合也可以在一定程度上抑制粘连的产生。
发明内容
有鉴于现有技术的上述缺陷，本发明所要解决的技术问题是提供一种具有抗感染作用的屏障材料，在促进吻合口愈合同时也可以抑制粘连的产生。
本发明人意外发现，如果将具有促进肠上皮细胞增殖作用的丙氨酰基-谷氨酰胺二肽(Ala-Gln)以共价键的形式结合在聚合物PPDO之上形成Ala-Gln-PPDO聚合物，再由该Ala-Gln-PPDO聚合物制备得到的静电纺丝膜既具备抗感染效果又可有效地抑制粘结。
具体地，本申请发明了一种可缓慢释放Ala-Gln促进肠上皮细胞增殖的抗感染屏障材料Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜。在该静电纺丝膜中， Ala-Gln可被持续、稳定释放至局部发挥其生物学功能。因此，将本发明的抗感染屏障材料Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜包覆于肠吻合口上，在预防肠吻合术后粘连的同时也促进了肠吻合口的愈合，从而防止肠瘘的形成，提高了肠吻合术的成功率。
尽管聚合物PPDO本身不具备抗粘结或抗过度繁殖的相关功能，但由于其在脂肪族聚酯材料中亲水性较好，可以增加其制备成膜后膜的贴附性；且由于PPDO 聚合温度低，聚合活性高，所以本发明选择PPDO作为载体来制备Ala-Gln-PPDO 类膜。发明人发现由PPDO作为载体来制备的Ala-Gln-PPDO/PLGA/PLCA膜具有促进上皮细胞增殖，预防吻合口瘘的作用。进一步地，制备的 Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜即可促进上皮细胞增殖，预防吻合口瘘，还可起到抗感染的作用，因此本发明的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜既可抗感染，而且该膜的抗粘连性较好。因此，在促进吻合口愈合的同时也可进一步预防粘连。
为实现上述目的，一方面，本发明提供了一种Ala-Gln-PPDO聚合物，其结构如分子式(I)所示。
本发明的Ala-Gln-PPDO聚合物可通过以下合成路线进行制备。以Ala-Gln二肽与PDO(对二氧环己酮)化合物为原料，进行合成制备得到Ala-Gln-PPDO聚合物。
1.Ala-Gln-PPDO的制备
Ala-Gln-PPDO的制备。
如上所示，Ala-Gln二肽游离的氨基作为引发剂，引发PDO开环聚合得到 Ala-Gln-PPDO聚合物，通过其核磁谱图中峰积分面积的比值可以得到 Ala-Gln-PPDO聚合物的数均分子量；也可以通过控制Ala-Gln与PDO的投料比(物质的量比)，从而控制Ala-Gln-PPDO聚合物的分子量。
本发明的一较佳实施方式中，所述聚合物的分子量为0.5-1.5kDa，聚合物中 Ala-Gln的摩尔含量为7.7％-25％。在本发明的另一优选实施方式中，Ala-Gln与PDO 的投料比(质量比)在1∶3至1∶20之间，得到Ala-Gln摩尔含量7.7％-15％之间的Ala-Gln-PPDO聚合物，该聚合物相应分子量范围为0.52-1.5kDa。更优选地， Ala-Gln与PDO的投料比(质量比)在1∶5-1∶20。更优选地，Ala-Gln与PDO的投料比(质量比)在1∶5-1∶7，得到Ala-Gln摩尔含量为7.7％-11.12％的Ala-Gln-PPDO 聚合物。该聚合物相应分子量范围为0.6-1kDa。
2.Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜的制备
Ala-Gln-PPDO聚合物虽然能缓慢释放Ala-Gln，因此也具备促进内皮细胞增殖的作用，但该聚合物没法单独成膜，主要是无法具有成膜的物理形状与物理功能。通过将制备得到的Ala-Gln-PPDO聚合物链接支撑聚合物PLGA/PLCA 后可制备得到促进内皮细胞增殖的膜。进一步地，由于庆大霉素的抑菌作用，因此，通过再链接庆大霉素而制备得到的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜即可抗感染也可以进一步预防粘连的发生。
本发明的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜可通过多种业内已知方法制备得到，如流涎法、相分离法、静电纺丝法等。但发明人发现通过流涎法制备的 Ala-Gln-PPDO/PLGA/PLCA/庆大霉素致密流涎膜的降解速率非常慢。优选地，本发明的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜通过乳液静电纺丝方法制备得到 Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜。具体地，将支撑聚合物 PLGA/PLCA与Ala-Gln-PPDO聚合物溶入溶剂中，加入乳化剂后，在高速匀浆机中超高速混匀下逐滴加入硫酸庆大霉素生理盐水溶液，形成乳液后进行静电纺丝，从而得到Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜。
优选地，乳化剂为Span 80。
本发明的分子式(I)聚合物Ala-Gln-PPDO制备得到的 Ala-Gln-PPDO/PLGA/PLCA膜对吻合口瘘及术后粘连具有较好治疗作用。且本发明的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜兼备抑制细胞增殖和感染的功能。尤其是Ala-Gln-PPDO/PLGA/PLCA静电纺丝膜和Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜。具体地，通过将由Ala-Gln-PPDO聚合物制备得到的膜植入体内后，聚合物主链可被逐渐降解，即聚合物中Ala-Gln与PPDO结合的酰胺键在体内可被降解，亲水的Ala-Gln端富集于分散在有机相的水相中，被疏水PPDO、PLGA(聚乳酸-羟基乙酸共聚物)、PLCA(L-乳酸/柠檬酸共聚物)链段包裹，从而释放缓慢，且释放出后较难通过氢键被吸附。因此，Ala-Gln可被持续、稳定释放至局部从而发挥其生物学功能，从而达到促进肠上皮细胞的增殖，预防吻合口瘘的作用。同时聚合物释放的庆大霉素又可预防腹腔内的感染对愈合造成的不良影响，上皮的迅速愈合又可以阻止纤维过度增生导致的粘连。因此，本发明的 Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜兼备抑制细胞增殖和抗感染的功能。尤其是Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜，其抑制细胞增殖和抗感染的效果更佳。
另一方面，本发明还涉及Ala-Gln-PPDO/PLGA/PLCA膜、 Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜在制备治疗肠胃的药物中的用途，尤其涉及Ala-Gln-PPDO/PLGA/PLCA静电纺丝膜、Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜在制备治疗肠胃的药物中的用途。进一步地，涉及上述包含 Ala-Gln-PPDO聚合物的各种膜在制备治疗肠胃手术吻合药物中的用途。
技术效果
以下将结合附图对本发明的构思、具体结构及产生的技术效果作进一步说明，以充分地了解本发明的目的、特征和效果。
附图说明
图1是本发明的一个较佳实施例的Ala-Gln-PPDO聚合物的1H NMR图谱。
图2是本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜的形态。
图3是本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜的Ala-Gln的累积释放曲线。
图4是本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜的庆大霉素的累积释放曲线。
图5是本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜对大鼠空肠上皮细胞(IEC-6)增殖的影响。
图6本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜抑菌作用。
图7是本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜对大鼠肠吻合术后粘连预防作用。(*代表p＜0.05，效果应用粘连评分评价，0分表示无粘连，1分表示轻微粘连，2分表示轻度粘连，3分表示中度粘连，4分表示重度粘连)
图8是本发明的一个较佳实施例的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜对大鼠肠吻合术后愈合强度的影响。(*代表p＜0.05)
具体实施方式
下面通过实施例的方式进一步说明本发明，本发明的范围并不因此局限于下述实施例，而是由本发明的说明书和权利要求书限定。
实施例1
1)Ala-Gln-PPDO聚合物的制备
表1.不同组别静电纺丝膜的构成。
实施例2
Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜的释放
将Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜置于PBS缓冲溶液中(50 mg置于15mL缓冲溶液中)，37℃进行培养，指定时间(即观察Ala-Gln释放规律的时间点)取出0.5mL培养介质进行检测，加入0.5mL新鲜PBS继续培养。 Ala-Gln释放测定：培养介质进行HPLC检测(等度洗脱，C18柱，流动相体积比水∶乙腈为95∶05，0.8mL/min，紫外检测210nm)庆大霉素释放测定：采用庆大霉素与邻苯二醛(OPA)反应的分光光度法，首先将2.5g该试剂溶解在63mL甲醇、3mL2-巯基乙醇和560mL钠硼酸(pH≈10)的混合物中，制得OPA溶液，避光保存，配制后48h内使用。将等量样品(0.3mL)与0.3mL的OPA溶液和0.3 mL的异丙醇混合，在室温下反应。30分钟后，用紫外/可见分光光度计在332nm 处测定混合物的吸光度。以浓度在1～100μg/mL的标准GS溶液为标准溶液建立校正曲线。对照得到庆大霉素的累积释放曲线，结果如图3、4所示。
由图3可知，与不含庆大霉素的Ala-Gln-PPDO/PLGA/PLCA静电纺丝膜M1 相比，Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜M3中Ala-Gln可被持续平缓地释放至降解介质，而不含庆大霉素的Ala-Gln-PPDO/PLGA/PLCA静电纺丝膜 M1的释放随着时间有谷值出现，这是由于M1释放出的Ala-Gln又被未降解的肽键以氢键的形式吸附至M1膜上所致。M3未出现这一现象且Ala-Gln的释放量小于M1，这是由于通过乳液静电纺丝方法制备得到的M3是中亲水的Ala-Gln端富集于分散在有机相的水相中，被疏水PPDO、PLGA、PLCA链段包裹，因此Ala-Gln 释放缓慢，且释放出后较难通过氢键被吸附。如图4所示， Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜M3中庆大霉素也可被持续释放至降解介质，累积释放量出现峰值也是由于释放至降解介质的庆大霉素被膜再次吸附所致。
实施例3
Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜对大鼠空肠上皮细胞 (IEC-6)增殖的影响
将M1、M3、M6分别置于96孔板中，加入100微升DMEM培养基，将IEC-6
Ala-Gln(1g)二肽游离的氨基作为引发剂引发PDO开环聚合(5g)得到 Ala-Gln-PPDO聚合物，其核磁表征图谱如图1所示。通过核磁谱图中a+b峰积分面积与峰积分面积的比值可以得到Ala-Gln-PPDO的数均分子量。通过控制Ala-Gln 与PDO的投料比(质量比)在1∶5，得到Ala-Gln摩尔含量11.12％的Ala-Gln-PPDO 聚合物，其数均分子量为1.033KDa。具体地，如图1所示，化学位移1.25ppm为Ala-Gln甲基峰，积分面积为3，3.7ppm为PDO亚甲基峰，积分面积12.57， Ala-Gln-PPDO的分子量为Mw(Ala-Gln)+Mw(PDO)*[(14.82/2)/(2.78/3)]＝1033.02 g/mol。
1H NMR(400MHz，DMSO-d6，ppm：4.66(Gln，CH，1H)，4.22(PDO， -CO-CH2-O-CH2-CH2-O-，2H)，4.17(PDO，-CO-CH2-O-CH2-CH2-O-)，4.04(Ala，CH，1H)，3.70(PDO，-CO-CH2-O-CH2-CH2-O-，2H)，1.77-2.13(Gln，-CH2-CH2-，4H)，1.25 (Ala，CH3，3H)，收率60％。
2)Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜的制备将支撑聚合物 PLGA/PLCA(质量比2/1，PLGA 100kDa，PLCA 250kDa)与Ala-Gln-PPDO按照设定比例(质量比4/6-2/8)溶于六氟异丙醇中，加入乳化剂1％Span 80，加入庆大霉素生理盐水溶液4wt％(庆大霉素占聚合物总量的2wt％)，高速匀浆机30000 rpm超高速混匀形成乳液后进行静电纺丝。参数：正极7.7kV，负极-2kV，流量3 mL/hour，正负极距离10cm；得到的Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜形态如图2所示。为了进行比对研究Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜(M3)的各项性能，发明人还设计了不含庆大霉素的 Ala-Gln-PPDO/PLGA/PLCA静电纺丝膜(M1)及不含Ala-Gln的PPDO/PLGA/PLCA 静电纺丝膜(M6)(表1)，这些聚合物Ml、M3及M6均是通过静电纺丝法制备，所有物质均可溶于有机溶剂，无需制备乳液。
具体其制备方法：将支撑聚合物PLGA/PLCA(质量比2/1，PLGA 100kDa， PLCA250kDa)与Ala-Gln-PPDO(M1)、PPDO(M6)按照设定比例(质量比4/6-2/8) 溶于六氟异丙醇中。电纺参数：正极7.7kV，负极-2kV，流量3mL/hour，正负极距离10cm。
细胞以104/孔的密度种植于孔板材料上，37℃常规培养1、2、3、4天后加入CCK-8培养4小时后测定495nm处OD值。如图5所示，与不含Ala-Gln的M6相比， M1和M3显著促进了IEC-6细胞的增殖，这说明M1、M3释放的Ala-Gln促进了细胞的增殖。且种植于M1的细胞增殖更快，这与实施例2中M1的Ala-Gln释放量大于M3的结果是一致的。
实施例4
Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜抑菌作用
将不含庆大霉素的M1、M3以及M1和庆大霉素进行对照研究，具体地，将材料灭菌后置于细菌培养基上，种植金黄色葡萄球菌与大肠杆菌于培养基上(菌液浓度为0.5McFarland，体积100微升)，不含庆大霉素的M1上滴加与M3负载总量相同量的游离的庆大霉素注射液作为对照。如图6所示，与M1和M1+庆大霉素对照组相比，M3具有更优异的抑菌效果，其抑菌效果不仅优于M1还要优于滴加庆大霉素的M1膜，这说明M3缓慢持续释放庆大霉素可以增加药物的稳定性，使其具有更好的抑菌效力。
实施例5
Ala-Gln-PPDO/PLGA/PLCA/庆大霉素静电纺丝膜对大鼠肠吻合术后粘连预防及其对愈合强度的影响
相同条件下，大鼠肠吻合术后将M1、M3、M6膜分别包覆于吻合口处，对照组吻合术后不做任何处理，每组六只大鼠，术后一周处死大鼠，对各组大鼠的粘连情况进行评分并求出每组的平均粘连分数。如图7所示，大鼠肠吻合术后应用M1 及M3膜可以显著抑制术后粘连的发生。其中，M6异物反应较强反而加剧了粘连，主要是由于Ala-Gln的引入提高了材料的相容性，减弱了材料的异物反应。M3的效果优于M1的原因是M3可以持续释放庆大霉素，在肠道有菌环境下可以有效抗感染，从而进一步增强材料的抗粘连作用。
同等条件下，大鼠肠吻合术后将M1、M3、M6膜分别包覆于吻合口处，对照组吻合术后不做任何处理，每组六只大鼠，术后一周将大鼠进行麻醉，测定吻合***破压力。如图8所示，对照组与M6组大鼠吻合口粘连十分严重，肠系膜填塞及纤维化较严重；尤其是M6组。这也导致了这二组大鼠吻合口的***压较高，同时这两组均有部分大鼠出现了梗阻。而M1与M3组大鼠未出现纤维化、系膜填塞及梗阻现象，同时吻合***破压与对照组无显著差别，这说明M1与M3的应用促进了吻合口的正常愈合(非过度纤维化)。
以上详细描述了本发明的较佳具体实施例。应当理解，本领域的普通技术无需创造性劳动就可以根据本发明的构思作出诸多修改和变化。因此，凡本技术领域中技术人员依本发明的构思在现有技术的基础上通过逻辑分析、推理或者有限的实验可以得到的技术方案，皆应在由权利要求书所确定的保护范围内。
Claims (6)
1.一种用下列结构式(I)表示的Ala-Gln-PPDO聚合物：
其中，所述聚合物的分子量为0.5-1.5kDa，聚合物中Ala-Gln的摩尔含量为7.7％-25％。
2.一种Ala-Gln-PPDO/PLGA/PLCA膜，其特征是包括权利要求1所述的式(I)Ala-Gln-PPDO聚合物。
3.一种Ala-Gln-PPDO/PLGA/PLCA/庆大霉素膜，其特征是包括权利要求1所述的式(I)Ala-Gln-PPDO聚合物。
4.如权利要求2或3所述的膜为静电纺丝方法制备的静电纺丝膜。
5.如权利要求2或3所述的膜在制备治疗肠胃的药物中的用途。
6.如权利要求2或3所述的膜在制备治疗肠胃手术吻合药物中的用途。
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