CN116637173A - 一种多胍抗菌肽口腔微针 - Google Patents
一种多胍抗菌肽口腔微针 Download PDFInfo
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- CN116637173A CN116637173A CN202310529252.2A CN202310529252A CN116637173A CN 116637173 A CN116637173 A CN 116637173A CN 202310529252 A CN202310529252 A CN 202310529252A CN 116637173 A CN116637173 A CN 116637173A
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Abstract
本发明公开了一种多胍抗菌肽口腔微针。本发明所述的多胍抗菌肽口腔微针，是由多胍聚合物材料、抗菌肽、口腔微针基质三种成分构成，其中多胍聚合物与抗菌肽先通过静电作用形成纳米颗粒，然后该纳米颗粒负载于微针基质中形成多胍抗菌肽口腔微针。本发明口腔微针贴片抗菌谱广，不易产生耐药，释药周期长，兼具提升多胍抗菌肽的生物利用度和简化给药过程提升用药依从性的作用，具有一定的临床转化潜力。
Description
技术领域
本发明属于生物医药技术领域，涉及一种多胍抗菌肽口腔微针。
背景技术
种植牙被认为是缺失牙患者最理想的修复方案，而种植体周围炎是种植体失败的主要原因。据报道，种植体周围炎的发生率约为15.3％，随着种植体技术的广泛应用，种植体周围炎病例的数量不断增加。种植体周围炎的主要病因在于，口腔是一个有菌的环境，种植体表面也存在微生物粘附。细菌及其代谢无的持续产生可能会导致持续的种植体周围感染诱发种植体周围炎。除对种植体材料进行表面改性外，解决种植体周围炎问题主要策略在于局部药物治疗。
传统的抗生素治疗采用静脉注射抗生素和局部应用抗生素，两者的疗效都有限，而微生物的抗生素耐药性由于过度使用抗生素而持续增长。金黄色葡萄球菌和白色念珠菌等强毒细菌和真菌分别会附着在植入物表面并发育生物膜，尤其是在免疫系统受损的情况下。因此，在这种情况下，预防感染是很重要的。几世纪来，针对抗菌问题，科学家们进行了大量的研究，常见的一些抗菌材料，如：金属离子、抗生素和季铵盐化合物，都能有效阻止细菌的黏附和增殖。但是，这些材料对环境有一定的污染、存在耐药性、高成本和相对复杂的加工工艺等不利因素。
发明内容
本发明的目的在于设计和优化具有良好生物安全性和抗菌活性的高分子材料、利用这些抗菌材料与高抗菌活性的抗菌肽、以及口腔微针贴片技术，构建具有长效抗菌抗炎活性口腔微针贴片。
本发明的目的可通过以下技术方案实现：
首先，基于多胍类材料的抗菌活性，利用PEI材料为主体，进行化学修饰，提升PEI的生物安全性，增加其抗菌活性；其次，基于多胍材料与抗菌肽间的静电作用构建负载抗菌肽纳米颗粒，作为抗菌肽的药物储库，持续长效的释放药物。此外，利用PVP基质的微针贴片负载该纳米结构，用药时只需将贴片贴于粘膜，实现极简化局部给药。本发明将为种植体周围炎治疗提供一种新的药物传递策略。
一种多胍抗菌肽纳米颗粒，主要由多胍聚合物材料、抗菌肽、口腔微针基质组成，其中多胍聚合物材料由PEI修饰不同数量的胍基构成，胍基对PEI氨基的取代度为5％-90％；胍聚合物材料、口腔微针基质的质量比为：1:1～1:4，胍聚合物材料和口腔微针基质总质量与蜂毒肽的质量比为10：1～10：2。
作为本发明的一种优选，所述的PEI为直链或支链结构，分子量为600-80000；所述的胍基为单胍基、双胍基苯单胍基、或苯双胍基。
作为本发明的进一步优选，PEI的分子量为5000-25000Da，胍基对PEI氨基的取代度为15％-75％。当PEI的分子量大于5000Da时，负载的抗菌肽可实现长效缓释(达到半数释放的时间超过2天)；胍基对PEI氨基的取代度大于15％时，可明显降低PEI的毒性(细胞生存抑制率小于20％)。
作为本发明的一种优选，所述的多胍聚合物材料通过以下方法制备得到：将单胍/双胍苯甲酸的羧基与支链PEI上的氨基在催化剂作用下在溶剂中，进行成酰胺反应，得到不同取代度多胍衍生PEI。所述的催化剂体系可为：二环己基碳二亚胺，二异丙基碳二亚胺，1-(3-二甲胺基丙基)-3-乙基碳二亚胺，4-二甲氨基吡啶，1-羟基苯并三唑，N-羟基琥珀酰亚胺等及其组合，优选为二环己基碳二亚胺和N-羟基琥珀酰亚胺组合。所述溶剂可为：N,N-二甲基甲酰胺,二甲基亚砜,pH为7的磷酸盐缓冲液等及其组合，优选为N,N-二甲基甲酰胺。
作为本发明的一种优选，所述的抗菌肽为序列如H-Gly-Ile-Gly-Ala-Val-Leu-Lys-Val-Leu-Thr-Thr-Gly-Leu-Pro-Ala-Leu-Ile-Ser-Trp-Ile-Lys-Arg-Lys-Arg-Gln-Gln-OH-NH2(SEQ ID NO.1)所示的蜂毒肽。
作为本发明的一种优选，所述的口腔微针基质为透明质酸。
作为本发明的进一步优选，所述多胍抗菌肽纳米颗粒通过如下方法制备：将一定量的多胍聚合物、口腔微针基质、抗菌肽分别溶解到适量的超纯水中，搅拌下，将含有口腔微针基质和抗菌肽的溶液缓慢滴加到含多胍聚合物的水中，继续搅拌6-12h，可得到粒径200～300nm的颗粒即为所述的多胍抗菌肽纳米颗粒。
本发明所述的多胍抗菌肽纳米颗粒在制备口腔抑菌制剂或医疗器械中的应用。
一种多胍抗菌肽口腔微针，由本发明所述的多胍抗菌肽纳米颗粒制备。
作为本发明的一种优选，所述的多胍抗菌肽口腔微针通过以下方法制备得到：将所述的多胍抗菌肽纳米颗粒(5-15μg/mL)均匀分散于去离子水中，滴加在微针模具表面，然后放置模具于真空下处理20-40min，随后加入15-20wt％PVP溶液在模具上并在室温下干燥6-12h，完全干燥后，将微针贴片与微针模具分离，所述微针膜具优选为15×15阵列，600μm高度，700μm中心间距。
本发明所述的多胍抗菌肽口腔微针，是由多胍聚合物材料、抗菌肽、口腔微针基质三种成分构成，其中多胍聚合物与抗菌肽先通过静电作用形成纳米颗粒，然后该纳米颗粒负载于微针基质中形成多胍抗菌肽口腔微针。
本发明具有以下有益效果：(1)多胍材料与抗菌肽均为高效的广谱抗菌成分，不易产生耐药；(2)多胍抗菌肽纳米颗粒具有超长的缓释效果，常见抗菌肽或微针制剂多在2-12小时内即释放完全，本发明制备的多胍抗菌肽纳米颗粒释放时长可达36小时，可发挥长效的抗菌作用；(3)口腔微针贴片兼具提升多胍抗菌肽的生物利用度和简化给药过程提升用药依从性的作用，具有一定的临床转化潜力。
附图说明
图1为本发明实施例1中苯双胍修饰的PEI核磁表征。
图2为本发明实施例2中多胍透明质酸蜂毒肽纳米颗粒的DLS表征。
图3为本发明实施例2的多胍透明质酸蜂毒肽纳米颗粒的TEM表征。其中，左图为200nm比例尺下的表征结果，右图为1μm比例尺下的表征结果。
图4为本发明实施例3中微针贴片实物照片与4X显微镜照片。
图5为本发明实施例3中微针贴片SEM表征。
图6为本发明实施例4的多胍蜂毒肽口腔微针贴片的体外释放。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将发明限制在所述的实施例范围之中。
实施例1：不同取代度的多胍聚合物合成
以多聚苯双胍为例，将4-氨基苯甲酸(4mmol)和盐酸(4mmol)溶解在12mL蒸馏水中，加入双氰胺(8mmol)。将溶液在80℃搅拌6小时。之后，将产物浓缩并用丙酮处理。通过从丙酮和水(1:1)的混合溶液中重结晶进一步纯化沉淀物得苯双胍。之后将得到的苯双胍、二环己基碳二亚胺和N-羟基琥珀酰亚胺以等量摩尔比溶解在N,N-二甲基甲酰胺中。将溶液在室温搅拌6小时。然后加入溶解在2mL二甲亚砜中的支链PEI(分子量为20kDa)，加入三乙胺，室温下搅拌3天，然后透析纯化。所得聚合物核磁谱图如图1所示。其中支链PEI与苯双胍的质量比为1:1.5-1:15根据投料不同，可得不用取代度的多胍聚合物，不同取代度的多胍聚合物细胞毒性和抑菌活性具有明显差异，当支链PEI与苯双胍的质量比分别为1:1.5，1:3,1:5,1:15所得PEI的取代度分别为15％，27％,46％和75％，如表1所示。当苯双胍的取代度超过10％后，PEI的细胞毒性显著下降，
同时随取代度的提升抗菌活性明显提升。因此，选择合成中的最大取代度为75％。
表1苯双胍修饰的PEI取代度对应3T3细胞毒性(IC50)及E.coliMDR 1060抑菌活性(MIC)
实施例2：负载蜂毒肽的多胍纳米粒的制备条件优化
选择实施例1中取代度为75％的多胍PEI,制备负载蜂毒肽的多胍纳米粒。多胍聚合物与透明质酸比例的筛选：将浓度分别为(0.1，0.5，1.0，2.0，5.0，10.0μg/mL)的多胍聚合物溶液与等体积的浓度为1.0μg/mL的透明质酸溶液充分混合，并在室温下静置10分钟。然后使用Malvern ZetaSizer Nano系列通过动态光散射测定粒径和zeta电位，结果如表2所示。其中，透明质酸比例过低无法形成纳米结构，因此最终优选的多胍聚合物与透明质酸的质量比为1：1。
多胍聚合物-透明质酸总质量与蜂毒肽摩尔比筛选：固定多胍与透明质酸的质量比为1：1，先将不同质量的蜂毒肽与透明质酸溶液(1μg/mL)混合得到不同浓度的蜂毒肽混合液(0.1，0.5，1，2，4，8μg/mL)，然后再与等体积的多胍聚合物溶液混合，孵育30min后，用超滤管(10kDa)超滤浓缩，并用HPLC测定游离的蜂毒肽浓度，计算蜂毒肽包封率，结果如表3所示，优选的多胍/透明质酸：蜂毒肽质量比为1：0.1。
表2多胍与透明质酸质量比的筛选
表3多胍/透明质酸与蜂毒肽质量比例的筛选
(1)以多胍聚合物的质量计算
实施例3负载蜂毒肽的多胍纳米粒的形貌表征
用超纯水配制1mL透明质酸和蜂毒肽的混合溶液，透明质酸和蜂毒肽的浓度分别为1.0μg/mL和0.1μg/mL。选择实施例1中取代度为75％的多胍PEI,用超纯水配制成浓度为1.0μg/mL的多胍聚合物溶液。将等体积的多胍聚合物溶液(1mL)与透明质酸/蜂毒肽溶液充分混合1小时。所得纳米颗粒DLS表征和TEM表征如图2和3所示。
实施例4：负载多胍蜂毒肽纳米粒的口腔微针贴片的制备。
将实施例3中的多胍抗菌肽纳米颗粒超滤浓缩并用去离子水稀释至含多胍聚合物10μg/mL，取100μL滴加在微针模具表面。然后放置模具于真空下处理30分钟。随后加入1mLPVP溶液(20wt％)在模具上并在室温下干燥过夜约8h。完全干燥后，将微针贴片与模具分离。所得微针贴片如图4，5所示。
实施例5：多胍蜂毒肽口腔微针贴片的体外释放
分别将含有10μg蜂毒肽的溶液剂、纳米颗粒(实施例3所述)和微针贴片(实施例4所述)置于截留分子量为30kDa的透析袋，然后放置于PBS中进行透析。在不同的时间点取出100μL溶液，利用HPLC定量释放的蜂毒肽，并进行记录得到不同时间蜂毒肽释放量。结果如图6所示。可观察到该微针贴片系统可显著延迟蜂毒肽的释放，使得其能够长期维持药效同时避免潜在的毒性。
Claims (10)
1.一种多胍抗菌肽纳米颗粒，其特征在于主要由多胍聚合物材料、抗菌肽、口腔微针基质组成，其中多胍聚合物材料由PEI修饰不同数量的胍基构成，胍基对PEI氨基的取代度为5％-90％；胍聚合物材料、口腔微针基质的质量比为：1:1～1:4，胍聚合物材料和口腔微针基质总质量与蜂毒肽的质量比为10：1～10：2。
2.根据权利要求1所述的多胍抗菌肽纳米颗粒，其特征在于所述的PEI为直链或支链结构，分子量为600-80000；所述的胍基为单胍基、双胍基苯单胍基、或苯双胍基。
3.根据权利要求2所述的多胍抗菌肽纳米颗粒，其特征在于PEI的分子量为5000-25000Da，胍基对PEI氨基的取代度为15％-75％。
4.根据权利要求2所述的多胍抗菌肽纳米颗粒，其特征在于所述的多胍聚合物材料通过以下方法制备得到：将单胍/双胍苯甲酸的羧基与支链PEI上的氨基在催化剂作用下在溶剂中，进行成酰胺反应，得到不同取代度多胍衍生PEI；所述的催化剂选自：二环己基碳二亚胺，二异丙基碳二亚胺，1-(3-二甲胺基丙基)-3-乙基碳二亚胺，4-二甲氨基吡啶，1-羟基苯并三唑，N-羟基琥珀酰亚胺或其组合，优选为二环己基碳二亚胺和N-羟基琥珀酰亚胺组合；所述溶剂选自：N,N-二甲基甲酰胺,二甲基亚砜,pH为7的磷酸盐缓冲液或其组合，优选为N,N-二甲基甲酰胺。
5.根据权利要求2所述的多胍抗菌肽纳米颗粒，其特征在于所述的抗菌肽为序列如SEQID NO.1所示的蜂毒肽。
6.根据权利要求2所述的多胍抗菌肽纳米颗粒，其特征在于所述的口腔微针基质为透明质酸。
7.根据权利要求1-6中任一项所述的多胍抗菌肽纳米颗粒，其特征在于所述多胍抗菌肽纳米颗粒通过如下方法制备：将一定量的多胍聚合物材料、口腔微针基质、抗菌肽分别溶解到适量的超纯水中，搅拌下，将含有口腔微针基质和抗菌肽的溶液缓慢滴加到含多胍聚合物的水溶液中，继续搅拌6-12h，得到粒径200～300nm的颗粒即为所述的多胍抗菌肽纳米颗粒。
8.权利要求7所述的多胍抗菌肽纳米颗粒在制备口腔抑菌制剂或医疗器械中的应用。
9.一种多胍抗菌肽口腔微针，其特征在于由权利要求7所述的多胍抗菌肽纳米颗粒制备。
10.根据权利要求9所述的多胍抗菌肽口腔微针，其特征在于所述的多胍抗菌肽口腔微针通过以下方法制备得到：将权利要求7所述的多胍抗菌肽纳米颗粒均匀分散于去离子水中，将其滴加在微针模具表面，然后放置模具于真空下处理20-40min，随后加入15-20wt％PVP溶液在模具上并在室温下干燥6-12小时，完全干燥后，将微针贴片与微针模具分离，所述微针膜具优选为15×15阵列，600μm高度，700μm中心间距。
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