CN114191567B - 一种多功能纳米复合材料及其制备方法和应用 - Google Patents
一种多功能纳米复合材料及其制备方法和应用 Download PDFInfo
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- CN114191567B CN114191567B CN202111515381.3A CN202111515381A CN114191567B CN 114191567 B CN114191567 B CN 114191567B CN 202111515381 A CN202111515381 A CN 202111515381A CN 114191567 B CN114191567 B CN 114191567B
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Abstract
本发明涉及牙周炎治疗技术领域,为了解决目前使用牙周炎传统治疗方法难以清除深部感染细菌生物膜以及深部炎症治疗的问题,公开了一种多功能纳米复合材料及其制备方法和应用,所述一种多功能纳米复合材料,包括以下成分:金纳米棒、介孔二氧化硅、NO供体以及光敏剂。本发明制备的复合材料可以进入组织深部,产生高效的杀伤细菌,消散顽固的细菌生物膜,不引起细菌的耐药性,充分发挥抗菌抗感染的作用;复合材料能够缩小感染范围的同时,还能起到调节炎症的作用,调控炎症因子的表达,影响炎症小体的组装,从而有效控制炎症进展,该复合材料适用于深部的感染治疗,不限于牙周炎的治疗,具有良好的应用前景。
Description
技术领域
本发明涉及牙周炎治疗技术领域,尤其涉及一种多功能纳米复合材料及其制备方法和应用。
背景技术
牙周病作为第六大流行的慢性炎症性疾病,与脑血管病、冠心病、心血管病、癌症等慢性非传染性疾病密切相关。目前,牙周炎的治疗主要使用机械清创和辅助抗生素治疗相结合的治疗方法。然而,即使在专业的龈上清创后,一些牙菌斑仍然存在。龈下清创是利用器械尽可能多的去除生物膜和龈下结石,由于器械进入区域和可见度有限,很少能完全去除龈下菌斑和牙石,尽管细菌数量可通过机械清创大幅减少,但是由于细菌可能存在于软组织,不规则根面以及牙本质小管等器械难以到达的部位,使细菌生物膜难以彻底清除,存在难以清除深部感染细菌生物膜以及深部炎症治疗的问题。
发明内容
本发明的目的是为了解决现有技术中存在的缺点,而提出的一种多功能纳米复合材料及其制备方法和应用。
为了实现上述目的,本发明采用了如下技术方案:
一种多功能纳米复合材料,包括以下成分:金纳米棒、介孔二氧化硅、NO供体以及光敏剂。
优选的,所述含NO供体的物质为有机硝酸盐、金属亚硝基盐、N-重氮二元酸盐以及亚硝基硫醇中的一种。
优选的,所述光敏剂为吲哚花菁素IR类碘化物和吲哚菁绿中的一种。
上述多功能纳米复合材料的制备方法,包括以下步骤:
步骤1:称取氯金酸、十六烷基三甲基溴化铵和硼氢化钠配制得到金种子液;
步骤2:称取氯金酸、硝酸银、抗坏血酸及金种子液依次添加到十六烷基三甲基溴化铵溶液中,剧烈搅拌后,静置过夜,离心分离得到产物,并清洗数次,得到所述的金纳米棒;
步骤3:将金纳米棒配制成pH为10的碱性溶液后,滴加适量的正硅酸乙酯和乙醇的混合液,再静置过夜,次日离心分离得到产物,并清洗数次,得到金纳米棒介孔二氧化硅;
步骤4:向金纳米棒介孔二氧化硅中依次添加3-巯丙基三乙氧基硅烷和氨水,搅拌过夜,再离心分离得到产物,并清洗数次,得到所述的表面巯基化的金纳米棒介孔二氧化硅;
步骤5:将表面巯基化的金纳米棒介孔二氧化硅溶于甲醇和甲苯中,再加入亚硝酸叔丁酯,避光搅拌,再离心分离得到产物,并清洗数次,得到表面带有NO供体的金纳米棒介孔二氧化硅;
步骤6:将表面带有NO供体的金纳米棒介孔二氧化硅溶于一定量的甲醇,滴入ICG甲醇溶液,避光搅拌,离心分离得到产物,并清洗数次,通过冷冻干燥得到多功能纳米复合材料。
优选的,所述步骤3中金纳米棒和介孔二氧化硅的摩尔之比为1:(3.3938-13.575)。
优选的,步骤5中甲醇、甲苯和亚硝酸叔丁酯的体积比为1:0.25:(0.042-0.1038)。
优选的,步骤2-6中离心分离的转速为8000-10000rpm/min。
一种纳米药物,部分或全部包含上述的多功能纳米复合材料。
上述纳米药物在制备消散菌斑生物膜及炎症免疫调节药物中的应用。
上述纳米药物在制备用于治疗牙周炎药物中的应用。
本发明的有益效果为:
本发明实施例制备的纳米复合材料具备优异的消散菌斑生物膜以及炎症调节的性能,通过采用金纳米棒、介孔二氧化硅、NO供体以及光敏剂等作为原料,制备方法较为简单,制备原料较为廉价。制备得到的复合材料可以进入组织深部,有效发挥其抗菌消散生物膜的作用。复合材料的使用不会造成细菌耐药性。既可以在细菌定植前通过破坏细菌膜结构杀伤大部分细菌,又能够快速消散已经形成细菌生物膜;在控制感染的同时,还能够有效调节炎症。释放的NO能够下调控炎症因子,并且对NLRP3炎症小体的组装具有抑制作用。因此,在牙周炎的炎症过程起到重要的调控作用。本实施例制备的纳米复合材料生物安全性高,在牙周炎的治疗方面甚至是相似的感染性疾病的治疗方面具有广阔的市场应用前景。
附图说明
图1为本发明实施例提供的复合材料的制备方法的流程示意图。
图2为本发明实施例提供的各级产物包括金纳米棒介孔二氧化硅、表面带有NO供体的金纳米棒介孔二氧化硅、多功能纳米复合材料样品的TEM图。
图3为本发明实施例提供的复合材料的元素的扫描分析谱图。
图4为本发明实施例提供的各级产物的FTIR谱图。
图5为本发明实施例提供的各级产物的UV-Vis谱图。
图6为本发明实施例提供的各级产物的Zeta电位图。
图7为本发明实施例提供的复合材料的光热效果图。
图8为本发明实施例提供的复合材料的时间与释放NO的关系图。
图9为本发明实施例提供的复合材料的时间与释放的单线态氧与探针的关系图。
图10为本发明实施例提供的复合材料培养的细胞存活率实时动态监测曲线图
图11为本发明实施例提供的复合材料在人牙龈成纤维细胞培养的细胞存活率结果图。
图12为本发明实施例提供的复合材料的血液相容性结果图。
图13为本发明实施例提供的复合材料的对P.gingivalis以及F.nucleatum膜通透性影响图。
图14为本发明实施例提供的复合材料对P.gingivalis以及F.nucleatum形成的生物膜和成熟生物膜活/死细菌比率统计结果图。
图15为本发明实施例提供的复合材料P.gingivalis以及F.nucleatum形成的生物膜和成熟生物膜的CFU值统计结果图。
图16为本发明实施例提供的复合材料对不同细菌的影响TEM图。
图17为本发明实施例提供的复合材料对细菌相关黏附因子和毒力因子的相对mRNA表达结果图。
图18为本发明实施例提供的复合材料在炎症调节中的相对mRNA表达结果图。
图19为本发明实施例提供的不同样品在免疫组化染色中的HE染色结果图。
图20为本发明实施例提供的不同样品在免疫组化染色中的Masson染色结果图。
图21为本发明实施例提供的复合材料在免疫组化染色中的IHC结果图。
图22为本发明实施例提供的复合材料在体内炎症调节中的阳性细胞计数结果图。
图23为本发明实施例中小鼠用药42天后主要器官的组织学切片图像。
具体实施方式
下面将结合本发明实施例中的附图,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。
实施例1
步骤a,金纳米棒的制备:首先配制金种子液。将市售1g 99%氯金酸三水合物(HAuCl4·3H2O)在100mL避光容量瓶配制成25mM氯金酸水溶液作为储存液。取出2mL 25mM氯金酸水溶液加入3mL去离子水配制10mM氯金酸水溶液工作液。使用电子天平称取3.6445g十六烷基三甲基溴化铵(CTAB)溶解于100mL去离子水中配制0.1M CTAB水溶液,在30℃水浴锅中搅拌30min至完全溶解。取出7.5mL 0.1MCTAB水溶液于20mL玻璃瓶中,取出0.25mL 10mM氯金酸水溶液并混合均匀。称取硼氢化钠0.0227g于60mL冰去离子水中,迅速取出0.6mL加入上述混合溶液中。以1200r的转速剧烈搅拌2min后,溶液静置10min。
取0.068g AgNO3溶于40mL去离子水中配置0.1M AgNO3水溶液。取0.176g抗坏血酸溶于10mL去离子水中配置0.1M抗坏血酸水溶液。在搅拌条件下,取4.75mL 0.1M CTAB溶液于另一玻璃瓶中,依次向玻璃瓶中添加0.2mL 10mM氯金酸水溶液、30μL 0.10M AgNO3水溶液、30μL 0.10M抗坏血酸水溶液和20μL金种子溶液,之后转为剧烈搅拌,搅拌速度为1200r并保持10s。所述溶液保持在27℃静置过夜,9000rpm/min的转速进行离心15min分离得到产物,并用去离子水清洗2次后使用去离子水定容至10mL备用。
步骤b,金纳米棒介孔二氧化硅复合纳米粒子(GNR@mSiO2)的制备:将上述定容的10mL金纳米棒溶液置于30℃水浴锅中以650r的转速搅拌。添加0.1M NaOH溶液直至溶液pH值达到10并保持20min。同时配制正硅酸乙酯/乙醇溶液(v/v=4:1)并置于超声震荡。使用微量注射器将20μL的正硅酸乙酯/乙醇溶液(v/v=4:1)逐滴滴入上述溶液中,间隔30min再次滴加等量的20%(v/v)正硅酸乙酯乙醇溶液,一共滴加三次。并在30℃条件下静置过夜。次日9000rpm/min的转速进行离心15min分离得到产物,并用无水乙醇清洗2次后使用无水乙醇定容至10mL备用。
步骤c,修饰NO供体的金纳米棒介孔二氧化硅复合纳米粒子(GNRs@mSiO2-SNO)的制备:将上述定容的10mL GNRs@mSiO2/乙醇溶液置于磁力搅拌器上以650r的转速搅拌。并添加40μL MPTES和60μL NH3·H2O(25-28wt%),在室温下搅拌过夜,次日9000rpm/min的转速进行离心15min分离得到产物,并用无水乙醇清洗2次、甲醇清洗1次后,得到产物。将上述产物分散在15ml甲醇/甲苯(v/v=4:1)溶液中,并置于磁力搅拌器上以650r的转速避光搅拌。加入1ml亚硝酸叔丁酯(TBN)于该溶液中,并保持反应24小时。9000rpm/min的转速进行离心15min分离得到产物,并用甲醇清洗2次后,使用甲醇定容至10mL备用。
步骤d,上载光敏剂的多功能纳米复合材料(GNRs@mSiO2-SNO/ICG)的制备:将上述定容的10mL GNRs@mSiO2-SNO/甲醇溶液置于磁力搅拌器上以650r的转速避光搅拌。取0.1mg吲哚菁绿(ICG)溶于4mL甲醇中。将ICG甲醇溶液逐滴加入上述的GNRs@mSiO2-SNO/甲醇溶液中,在室温下搅拌24h,9000rpm/min的转速进行离心15min分离得到产物,并用无水乙醇清洗2次,去离子水清洗一次。最后通过冷冻干燥得到产物。
步骤e,上载光敏剂的无一氧化氮供体的复合材料(GNRs@mSiO2/ICG)的制备:将步骤b中得到的GNR@mSiO2溶于10mL甲醇中,GNRs@mSiO2/甲醇溶液置于磁力搅拌器上以650r的转速避光搅拌。取0.1mg吲哚菁绿(ICG)溶于4mL甲醇中。将ICG甲醇溶液逐滴加入上述的GNRs@mSiO2-SNO/甲醇溶液中,在室温下搅拌24h,9000rpm/min的转速进行离心15min分离得到产物,并用无水乙醇清洗2次,去离子水清洗一次。最后通过冷冻干燥得到产物。
实施例2
与实施例1相比,除了将步骤a中所述的氯金酸水溶液的加入量替换为0.5mL外,其他与实施例1相同。
实施例3
与实施例1相比,除了将步骤a中所述的氯金酸水溶液的加入量替换为0.75mL外,其他与实施例1相同。
实施例4
与实施例1相比,除了将步骤b中所述的0.1M NaOH替换为0.1MNH3·H2O外,其他与实施例1相同。
实施例5
与实施例1相比,除了将步骤b中所述的20μL的正硅酸乙酯/乙醇溶液的加入量替换为10μL外,其他与实施例1相同。
实施例6
与实施例1相比,除了将步骤b中所述的20μL的正硅酸乙酯/乙醇溶液的加入量替换为30μL外,其他与实施例1相同。
实施例7
与实施例1相比,除了将步骤b中所述的20μL的正硅酸乙酯/乙醇溶液的加入量替换为40μL外,其他与实施例1相同。
实施例8
与实施例1相比,除了将步骤b中的“30℃条件下静置过夜”替换为“室温静置过夜”外,其他与实施例1相同。
实施例9
与实施例1相比,除了将步骤c中所述的40μL MPTES的加入量替换为20μL外,其他与实施例1相同。
实施例10
与实施例1相比,除了将步骤c中所述的40μL MPTES的加入量替换为60μL外,其他与实施例1相同。
实施例12
与实施例1相比,除了将步骤c中所述的1ml TBN的加入量替换为0.5ml外,其他与实施例1相同。
实施例13
与实施例1相比,除了将步骤c中所述的1ml TBN的加入量替换为0.75ml外,其他与实施例1相同。
实施例14
与实施例1相比,除了将步骤c中所述的1ml TBN的加入量替换为1.25ml外,其他与实施例1相同。
实施例15
与实施例1相比,除了将步骤d中所述的0.1mg ICG的加入量替换为0.05mg外,其他与实施例1相同。
实施例16
与实施例1相比,除了将步骤c中所述的0.1mg ICG的加入量替换为0.2mg外,其他与实施例1相同。
实施例17
与实施例1相比,除了将步骤d中所述的“冷冻干燥”替换为“自然晾干”外,其他与实施例1相同。
实施例18
将实施例1中制备得到的GNRs样品、GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品分别进行透射电镜表征(Transmission Electron Microscope,简称TEM),具体的TEM图见图2所示。其中金纳米棒大小较为均一,分散性良好。GNRs@mSiO2中二氧化硅层包覆均匀,可见平行和放散状孔道结构。GNRs@mSiO2-SNO以及GNRs@mSiO2-SNO/ICG可见二氧化硅层最外有一薄层有机物。
实施例19
为了验证实施例1中制备得到的最终产物GNRs@mSiO2-SNO/ICG样品的成分,本实施例对GNRs@mSiO2-SNO/ICG样品进行能谱(EDX,Energy Dispersive X-RaySpectroscopy,能量色散X射线光谱仪)分析,具体的EDX图如图3所示,从图3中可以确定,最终产物GNRs@mSiO2-SNO/ICG样品中含有Au、Si、O、S、N、Na元素,能谱结果定性说明了在最终产物GNRs@mSiO2-SNO/ICG样品中,含有NO供体SNO成分以及光敏剂ICG。
实施例20
将实施例1中制备得到的GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品进行FTIR(Fourier Transform Infrared Spectrometer,傅里叶变换红外光谱仪)表征,具体的FTIR谱图见图4所示。同时,将实施例1中制备得到的GNRs样品、GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品进行UV-Vis(Ultravioletand visible spectrophotometry,紫外-可见光分光光度法)表征,具体的UV-Vis谱图见图5所示,是利用紫外-可见光分光光度计测试的待检测样品的紫外-可见吸收光谱。
从图4中可以看出,GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品的傅里叶红外图谱范围是400-4000cm-1,三个样品中均可以看到位于1080cm-1处的Si-O吸收峰。2925cm-1和2854cm-1处的吸收峰与CTAB中的-CH3和-CH2基团有关。1506cm-1处的特征峰对应于N=O基团,证明了成功的-SNO共轭。
从图5中可以看出,GNRs样品、GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品的紫外-可见吸收光谱测量范围为300-950nm。纯GNRs的吸收峰在800nm左右,经介孔SiO2和SNO分子修饰后,红外特征吸收峰发生蓝移。当上载ICG后,吸收峰再次红移,最终吸收峰固定在780nm处。其中,SNO基团的特定峰出现在350-410nm处,这也证明SNO基团成功地与GNRs@mSiO2共轭。
实施例21
将实施例1中制备得到的GNRs样品、GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品分别进行Zeta电位(Zeta potential)分析,具体的Zeta电位图见图6所示,是利用Zetasizer系列电位仪测量的待检测样品的ζ电势,从图6中可以看出,GNRs样品、GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品的表面ζ电位分别为51.1±1.9mV,-17.6±1.2mV,-18.1±0.3mV,-18.7±0.3mV。
实施例22
将实施例1中制备得到的GNRs样品、GNRs@mSiO2样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品分别进行光热性质的测试。如图7所示,所有样品首先在1W cm-2的条件下以50μg mL-1的浓度进行光热性质检测。所有样品在最初的4分钟内都表现出非常明显的光热效应,并且随着辐照时间的增加,温度升高。图7b显示GNRs@mSiO2-SNO/ICG样品光热性质与浓度变化的关系。如图7b所示,其光热性质呈现浓度依赖性。在1W cm-2的条件下,当浓度增加到100μg mL-1时,温度从27℃迅速升高到49.6℃。图7c显示GNRs@mSiO2-SNO/ICG样品光热性质与辐照强度的关系。如图7c所示,其光热性质呈现辐照强度依赖性。当辐照强度增加到2W cm-2时,温度从27℃迅速升高到51.2℃。如图7d所示,经过四个周期的辐照开关实验,在每个周期中进行600秒的辐照和1100秒的冷却时间,加热-冷却曲线可以重复,没有显著变化,证明了显著的光热稳定性。上述结果表明GNRs@mSiO2-SNO/ICG样品能快速将近红外光转化为热能。
实施例23
将实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品采用Griess法测定NO的体外释放能力。如图8所示,在辐照条件下,NO快速释放。当关闭辐照光时,在接下来的10min内仍有少量NO持续产生。再过10min,几乎没有气体被检测到。当再次进行辐照时,NO气体继续产生。表明这种依赖于近红外辐射的NO释放过程可以重复多次,并且是可控的。然而,当连续给予辐照时,当药物浓度为100μg mL-1时,30min内NO产量可达5μm。
实施例24
为了验证复合材料产生ROS的能力,使用1,3-二苯基异苯并呋喃(1,3-Diphenylisobenzofuran,DPBF)对实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品进行检测。使用近红外光辐照,每次辐照5min后对复合材料的紫外-可见吸收光谱进行检测。复合材料随时间变化的紫外-可见吸收光谱的结果如图9所示。DPBF的特征吸收峰在410nm。从图9中可以看出,由于产生的单线态氧与DPBF发生了反应,随辐照延长,其特征峰迅速下降。当辐照时间达到10min,探针的特征峰下降约60%。当辐照时间达到20min,探针的特征峰基本下降至与基线水平的程度。同时位于780nm ICG的特征峰也略有下降,证明了ICG在这一过程中被消耗。
实施例25
将实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品无菌处理后,通过超声分散悬浮在完全培养基中以形成浓度为100μg mL-1的胶体悬浮液。
实施例26
将实施例25中得到的胶体悬浮液通过梯度稀释的方法配制成浓度为100μg mL-1,50μg mL-1,25μg mL-1,10μg mL-1的样品,分别记作100μg mL-1组、50μg mL-1组、25μg mL-1组、10μg mL-1组,同时,将完全培养基作为对照,记作Control组。将上述各组进行体外生物安全性分析,具体是使用实时细胞分析系统(Real Time Cell Analysis,RTCA)动态分析72小时内L929在不同浓度药物下(10μg mL-1组-100μg mL-1组)的细胞活性,如图10所示,为本发明实例提供的不同样品在鼠成纤维细胞培养的细胞存活率实时动态监测曲线图。当药物浓度为50μg mL-1以内,细胞在72h内呈显著增长,表明复合材料具有良好的生物安全性。进一步使用CCK-8检测人牙龈成纤维细胞(Human gingival fibroblasts,HGFs)的细胞活性来验证结果。如图11所示,细胞活性在药物浓度为100μg mL-1呈现显著变化,因此药物浓度为50μg mL-1以内为安全药物浓度。实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品具有良好的体外生物安全性。
在本实施例中,用红细胞裂解测定法评估实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品的血液相容性(10μg mL-1组-100μg mL-1组),具体是将10μg mL-1组、25μg mL-1组、50μg mL-1组以及100μg mL-1组分别与人红细胞(redbloodcell,RBC)相容,同时以聚乙二醇辛基苯基醚(Triton-X 100)和磷酸缓冲盐溶液(phosphate buffer saline,PBS)分别用作阳性对照与阴性对照,分别记作Positive与Negative,观察对应的兔RBC的照片和溶血分析结果,具体的血液相容性结果见图12所示。从图12可以看出,随药物浓度的增加,溶血率呈现下降状态,所有测试药物浓度对应的溶血率不超过6%,表现出优异的血液相容性。
实施例27
将实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品无菌处理后,通过超声分散悬浮在细菌培养基(Tryptic soy broth,TSB)中以形成浓度为100μg mL-1的胶体悬浮液。
实施例28
将实施例27中得到胶体悬浮液配制终浓度为50μg mL-1的样品用于抗菌性能分析。在本实施例中,通过评估细菌膜的完整性、细菌活/死染色法、菌落形成计数法以及RT-qPCR等评估复合材料的抗菌性能及其消散细菌生物膜的性能。
在本实施例中,首先评估了样品对细菌膜的完整性影响,即在260nm处通过紫外-可见吸收光谱测量从细胞质释放的核酸量。简言之,将处于对数期的牙龈卟啉单胞菌(P.gingivalis)和具核梭杆菌(F.nucleatum),的微生物浓度分别调整为2×108CFU/mL。以P.gingivalis为例,取出1ml菌液分别置于五个试管中,随后将等体积的实施例1中制备得到的GNRs@mSiO2样品、GNRs@mSiO2/ICG样品、GNRs@mSiO2-SNO样品、GNRs@mSiO2-SNO/ICG样品以及空白细菌培养基组分别添加到五个试管中分别给予808nm,1W cm-2,5min的辐照处理。随后,在每10分钟内立即收集0.5mL细菌悬浮液,并通过0.22μm过滤器去除细菌。然后稀释上清液,并测量260nm处的OD值。如图13所示,GNRs@mSiO2-SNO/ICG样品组的OD260值在60min内显著高于其他分组的OD260值,表明细菌体内DNA和RNA泄漏较其他样品组更多,细菌膜结构被破坏的更为严重。
在本实施例中,其次评估了样品对细菌生物膜的消散作用。实施例1中制备得到的GNRs@mSiO2样品、GNRs@mSiO2/ICG样品、GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品处理形成或建立细菌生物膜,应用条件为808nm,1W cm-2,5min,连续应用3天
对照组使用任何处理。使用活/死细菌染料对所有组的细菌生物膜处理,并且通过激光共聚焦采集各组样品的图片。使用Image J分析活/死细菌比例。如图14所示,GNRs@mSiO2样品组对细菌具有一定的杀伤作用。GNRs@mSiO2/ICG样品组能够显著增加整个细菌生物膜中的死菌率。GNRs@mSiO2-SNO/ICG样品组由于引入了NO气体,显示出更高的杀灭效率和显著的抗生物膜能力。
在本实施例中,将上述的实验组分别进行计算菌落形成单位(Colony-FormingUnit,CFU)值。具体的,将上述各个样品组处理后的细菌生物膜重悬于1mL培养基中,通过梯度稀释法将重悬菌液稀释,并分区滴定在血琼脂板上。经过4天培养后,分别计算CFU值。如图15所示,在形成生物膜的模型中,GNRs@mSiO2/ICG样品组由于PDT与PTT的结合作用,与对照组CFU相比减少了3-4log,具有PDT/PTT/NO协同功能的GNRs@mSiO2-SNO/ICG样品组可使CFU进一步减少至少1log。在成熟生物膜的模型中,由于细菌生物膜的致密性,GNRs@mSiO2/ICG样品组和GNRs@mSiO2-SNO样品组的杀菌效果与形成生物膜的模型中的杀菌效果相对持平或略差。GNRs@mSiO2-SNO/ICG样品组的杀菌效果基本持平,展现出其良好的杀菌性能和消散细菌生物膜的能力。
在本实施例中,培养多菌种生物膜,使用上述相同的治疗方法治疗。其中,多菌种包括P.gingivalis、F.nucleatum以及戈登链球菌(S.gordonii)。将上述的实验组分别进行TEM测试。具体的,将上述各个样品组处理后的多菌种细菌生物膜重悬于电镜固定液中,并经过处理后制备细菌样品用于TEM图像采集。如图16所示,对照组细菌形态正常,几乎没有死亡细菌,不同种类的细菌之间有菌毛连接。在GNRs@mSiO2-SNO样品组中,视野中的死亡细菌数量显著增加。几乎观察不到不同细菌之间的菌毛连接,视野下细胞壁破裂,内容物泄漏。GNRs@mSiO2-SNO/ICG样品组中,除了上述现象外,还表现为镜下细菌形态异常。
在本实施例中,培养P.gingivalis细菌生物膜,使用上述相同的治疗方法治疗。对相关粘附素分子基因(fimA,HagA和HagB)和毒力因子基因(PPAD、Kgp、RgpA和RgpB)使用RT-qPCR进行评价。如图17所示,在GNRs@mSiO2样品组中,相关粘附素分子基因fimA,HagA和HagB的表达与对照组相比分别下降到72.2%、45.2%和50.3%,表明温度压力会使相关粘附素分子基因的表达下调。GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品组中相关粘附素分子基因的表达进一步下调,表明氧压力或亚硝化压力对mRNA的表达产生影响。然而,在GNRs@mSiO2样品组中,相关毒力因子如PPAD、Kgp、RgpA与对照组均无差异,表明温度对这些相关毒力因子影响较小。在GNRs@mSiO2-SNO样品以及GNRs@mSiO2-SNO/ICG样品组中,PPAD、Kgp、RgpA和RgpB的mRNA表达均显著降低,表明ROS和NO对细菌毒力蛋白的抑制作用。
实施例29
将处于对数期的P.gingivalis细菌菌液稀释并调整至OD600=0.2。然后在4℃下以12000g 15min直接离心细菌悬浮液,然后使用0.22μm过滤器过滤上清液以去除细菌。最后,在无菌管中收集提取物。
实施例30
将实施例25中得到胶体悬浮液配制终浓度为50μg mL-1的GNRs@mSiO2-SNO/ICG样品用于炎症调节性能的分析。使用含有体积分数10%的实施例29收集的提取物作为炎性刺激物刺激小鼠巨噬细胞RAW 264.7 6h,用于模拟牙周炎微环境。6h后换用含有GNRs@mSiO2-SNO/ICG样品用于治疗。其治疗条件是808nm,1W cm-2,5min,每天3次。对照组换成完全培养基。继续培养24h。RT-qPCR检测促炎细胞因子白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、肿瘤坏死因子(TNF-α)、诱导型一氧化氮合酶(iNOS)和NLRP3炎症相关成分NLRP3和半胱天冬酶1(Caspase 1)的mRNA表达水平。如图18所示,IL-1β、IL-6、iNOS和TNF-α等促炎细胞因子的基因表达在炎性刺激物刺激后显著升高。另一方面,通过GNRs@mSiO2-SNO/ICG样品的治疗后,这些促炎因子的表达水平能够得到有效调节。此外,与炎症对照组相比,NLRP3炎症小体成分NLRP3和Caspase-1的mRNA表达显著降低。
实施例31
将实施例1中制备得到的GNRs@mSiO2-SNO/ICG样品无菌处理后,通过超声分散悬浮在PBS中以形成浓度为100μg mL-1的胶体悬浮液。
实施例32
将实施例31中得到胶体悬浮液配制终浓度为50μg mL-1的GNRs@mSiO2-SNO/ICG样品用于动物实验。具体是在Wistar雄性大鼠用细菌和结扎棉线刺激建立的牙周炎模型进行。处理7天后模型建立。使用终浓度为50μg mL-1的GNRs@mSiO2-SNO/ICG样品对大鼠进行治疗,其治疗条件为808nm,1W cm-2,5min,每天1次持续3天。治疗后切取组织进行HE染色,马松染色以及免疫组化(IHC)染色,并对表达阳性细胞做统计。其中,PBS注射组作为空白对照,建立炎症模型而未进行治疗组为阴性对照。如图19所示,对照组显示大量的炎性细胞浸润,而其他样品组炎症细胞向炎症部位募集较少,说明所有治疗组产生不同的治疗效果。如图20所示,空白对照组可见致密有序的胶原纤维(蓝色染色)。而在炎症对照组,大多数胶原纤维呈降解状态,呈红色染色。视野下GNRs@mSiO2-SNO样品和GNRs@mSiO2-SNO/ICG样品组大多数胶原纤维成蓝染且致密,说明胶原纤维在受到损伤后能够很好的修复。如图21所示,视野下对照组显示大量的棕色阳性细胞,而不同治疗组阳性细胞数不同程度的减少。为进一步说明问题,对HE染色以及IHC染色中的阳性细胞进行统计。如图22所示,GNRs@mSiO2样品组的阳性免疫细胞数量与炎症对照组的阳性免疫细胞数量无统计学差异。GNRs@mSiO2-SNO样品和GNRs@mSiO2-SNO/ICG样品组的阳性免疫细胞数量呈现显著下降;促炎因子阳性细胞的表达与阳性免疫细胞的表达趋势类似。由于GNRs@mSiO2-SNO/ICG样品组释放的NO量大于GNRs@mSiO2-SNO样品组,GNRs@mSiO2-SNO/ICG样品组比GNRs@mSiO2-SNO样品组阳性细胞的表达进一步减少。综合以上,NO在炎症调节方面具有重要作用,促进胶原纤维再生,调节促炎因子的表达,保护牙周组织,促进牙周愈合。
实施例33
将实施例31中得到胶体悬浮液配制终浓度为用于动物长期体内生物安全性评价。具体是在BALB/c裸鼠中局部注射50μg mL-1的GNRs@mSiO2-SNO/ICG样品,42天后进行主要器官的HE组织学切片染色。具体的小鼠用药42天后主要器官的组织学切片图像见图23所示。图23表明,龈下注射GNRs@mSiO2-SNO/ICG样品后未发生形态学变化或发炎迹象,表明GNRs@mSiO2-SNO/ICG样品不会引起小鼠全身重大的毒性反应。
以上所述,仅为本发明较佳的具体实施方式,但本发明的保护范围并不局限于此,任何熟悉本技术领域的技术人员在本发明揭露的技术范围内,根据本发明的技术方案及其发明构思加以等同替换或改变,都应涵盖在本发明的保护范围之内。
Claims (5)
1.一种多功能纳米复合材料,其特征在于,包括以下成分:金纳米棒、介孔二氧化硅、NO供体以及光敏剂;
所述的一种多功能纳米复合材料的制备方法,包括以下步骤:
步骤1:称取氯金酸、十六烷基三甲基溴化铵和硼氢化钠配制得到金种子液;
步骤2:称取氯金酸、硝酸银、抗坏血酸及金种子液依次添加到十六烷基三甲基溴化铵溶液中,剧烈搅拌后,静置过夜,离心分离得到产物,并清洗数次,得到所述的金纳米棒;
步骤3:将金纳米棒配制成pH为10的碱性溶液后,滴加适量的正硅酸乙酯和乙醇的混合液,再静置过夜,次日离心分离得到产物,并清洗数次,得到金纳米棒介孔二氧化硅;
步骤4:向金纳米棒介孔二氧化硅中依次添加3-巯丙基三乙氧基硅烷和氨水,搅拌过夜,再离心分离得到产物,并清洗数次,得到所述的表面巯基化的金纳米棒介孔二氧化硅;
步骤5:将表面巯基化的金纳米棒介孔二氧化硅溶于甲醇和甲苯中,再加入亚硝酸叔丁酯,避光搅拌,再离心分离得到产物,并清洗数次,得到表面带有NO供体的金纳米棒介孔二氧化硅;
步骤6:将表面带有NO供体的金纳米棒介孔二氧化硅溶于一定量的甲醇,滴入ICG甲醇溶液,避光搅拌,离心分离得到产物,并清洗数次,通过冷冻干燥得到多功能纳米复合材料;
所述步骤3中金纳米棒和介孔二氧化硅的摩尔之比为1:(3.3938-13.575);
步骤5中甲醇、甲苯和亚硝酸叔丁酯的体积比为1:0.25:(0.042-0.1038)。
2.根据权利要求1所述的一种多功能纳米复合材料,其特征在于,步骤2-6中离心分离的转速为8000-10000rpm/min。
3.一种纳米药物,其特征在于,包含权利要求1-2任一所述的多功能纳米复合材料。
4.如权利要求3所述的纳米药物在制备消散菌斑生物膜及炎症免疫调节药物中的应用。
5.如权利要求3所述的纳米药物在制备用于治疗牙周炎药物中的应用。
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