CN108892743A - 用于光动力抗菌的纳米光敏剂,其制备方法及应用 - Google Patents
用于光动力抗菌的纳米光敏剂,其制备方法及应用 Download PDFInfo
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0024—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid beta-D-Glucans; (beta-1,3)-D-Glucans, e.g. paramylon, coriolan, sclerotan, pachyman, callose, scleroglucan, schizophyllan, laminaran, lentinan or curdlan; (beta-1,6)-D-Glucans, e.g. pustulan; (beta-1,4)-D-Glucans; (beta-1,3)(beta-1,4)-D-Glucans, e.g. lichenan; Derivatives thereof
- C08B37/0027—2-Acetamido-2-deoxy-beta-glucans; Derivatives thereof
- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P31/04—Antibacterial agents
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Abstract
本发明涉及一种用于光动力抗菌的纳米光敏剂,其制备方法及应用。本发明将光敏剂与壳聚糖或壳聚糖衍生物通过化学耦合反应,得到光敏剂接枝的壳聚糖或其衍生物,这种两亲性聚合物可自组装形成纳米光敏剂。这种纳米光敏剂改善了原型光敏剂的疏水性,提高了其稳定性和生物相容性。此外,光敏剂接枝的壳聚糖或其衍生物在生理溶液中形成带正电荷的纳米光敏剂,通过静电作用可以更好地被病原微生物所摄取,在可见光/近红外光的作用下,将环境中的氧分子转化为单线态氧,可用于光动力抗菌。
Description
技术领域
本发明涉及光学应用、纳米系统、病原微生物防治等技术领域,具体涉及一种光动力抗菌的纳米光敏剂,其制备方法和应用。
背景技术
自二十世纪以来,伴随着抗生素滥用导致多重耐药菌的出现,已经严重威胁到公众健康,研发新的药物和新的治疗手段替代抗生素治疗,已经成为各个国家科研工作的研究热点。其中光动力治疗抗菌作为一种新的治疗手段已经受到广泛的关注。
光动力抗菌主要由光敏剂和适合的光源组成。在合适光源的照射下,光敏剂吸收短波长的光,由基态(S0)经跃迁到单线态(S1)再转变为激发三线态(T1),然后由激发三线态(T1)与周围介质中的氧分子发生反应,生成氢氧自由基(·OH)或者单线态氧(1O2)等活性物质,进一步作用于菌体,可与菌体的生物大分子(脂质、蛋白质、核酸)发生氧化反应,使菌体损伤、凋亡。光敏剂(photosensitizer,以下简称PS)作为光动力抗菌过程中的关键介质,现在研究较多的光敏剂包括噻吩嗪类,卟啉类和二氢卟吩e6类等,大多数光敏剂(PS)在水中的溶解度极低,且在水溶液中具有不稳定、易聚集的缺点,严重阻碍了其在光动力抗菌中的广泛应用。
发明内容
本发明的目的在于提供一种用于光动力抗菌的纳米光敏剂的制备方法。
为实现上述技术目的,本发明采用如下技术方案:
将光敏剂、耦合试剂共同溶解于有机溶剂中,避光条件下活化,之后加入壳聚糖的醋酸水溶液或壳聚糖衍生物的醋酸水溶液中避光条件下反应制取光敏剂接枝的壳聚糖或其衍生物的粗产物,最后对粗产物提纯获得纯化产物,纯化产物在生理溶液中自组装形成所述纳米光敏剂。
壳聚糖及其衍生物(CS)是一类由2-乙酰氨基-2-脱氧-D-吡喃葡聚糖和2-氨基-2-脱氧-D-吡喃葡聚糖为主体,以β-1,4-糖苷键连接而成的多糖聚合物,具有良好的生物相容性和安全低毒等特性,在医药、化工、食品与营养、农业与环境保护等领域已经有广泛的应用。作为天然的阳离子聚合物,壳聚糖或壳聚糖衍生物可与微生物细胞表面带有负电荷的生物大分子相结合,提高病原微生物对纳米光敏剂的摄取率,提高光动力治疗的效果。
本发明中将活化的光敏剂(PS)与壳聚糖或壳聚糖衍生物通过化学耦合反应,得到光敏剂接枝的壳聚糖或壳聚糖衍生物,这种两亲性聚合物可自组装形成纳米光敏剂。这种纳米光敏剂改善了光敏剂(PS)的疏水性,提高了光敏剂(PS)的稳定性和生物相容性。此外,光敏剂接枝的壳聚糖或其衍生物在生理溶液中形成带正电荷的纳米光敏剂,通过静电作用可以更好的被致病微生物所摄取,进一步在可见光/近红外光的作用下,将环境中的氧分子转化为具有强细胞毒性的单线态氧(1O2),可作为光动力抗菌的优良光敏剂,应用于多种病原微生物的杀灭与抑制。
进一步的,所述耦合试剂选自以下任一种:
N-羟基琥珀酰亚胺(NHS)与N,N’-二环己基碳二亚胺(DCC)的混合试剂;优选以摩尔比1∶1混合;
或三乙胺(Et3N)与O-苯并三唑-四甲基脲六氟磷酸盐(HBTU)的混合试剂;优选以摩尔比1∶1混合;
或N,N-二异丙基乙胺(DIPEA)与O-苯并三唑-N,N,N',N'-四甲基脲四氟硼酸盐(TBTU)的混合试剂;优选以摩尔比2∶1混合;
或N,N-二异丙基乙胺(DIPEA)、1-羟基苯并三唑(HOBt)与1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)的混合试剂;优选以摩尔比2∶1∶1混合;
进一步的,所述有机溶剂选用二甲基亚砜或二甲基甲酰胺。
进一步的,所述光敏剂与耦合试剂的摩尔比为1∶4-1∶16。
进一步的,加入质量分数为0.5%-4%的壳聚糖的醋酸水溶液或壳聚糖衍生物的醋酸水溶液中避光条件下反应制取粗产物。
进一步的,所述壳聚糖或壳聚糖衍生物的分子量范围为5×103-3×105Da,脱乙酰度范围为55%-95%。
进一步的,所述光敏剂为二氢卟吩e6(Ce6);
进一步的,将粗产物通过葡聚糖凝胶柱用质量分数为0.5%-3%的醋酸水溶液洗脱,获取纯化产物,之后将纯化产物转移至透析袋中以生理溶液为介质进行透析,即得到纳米光敏剂。
进一步的,所述纳米光敏剂中,光敏剂接枝到壳聚糖或者壳聚糖衍生物的接枝率范围是1%-10%。
本发明的另一目的在于提供上述方法制备的纳米光敏剂。
本发明的又一目的在于提供所述纳米光敏剂在抑制病原微生物中的应用。本发明的产物壳聚糖接枝光敏剂或壳聚糖衍生物接枝光敏剂(PS-CS)复合物为带正电荷的纳米光敏剂,通过静电作用可以更好的被致病微生物所摄取,进一步在可见光/近红外光的作用下,将环境中的氧分子转化为强细胞毒性的单线态氧(1O2),可作为光动力抗菌的优良光敏剂,应用于多种病原微生物的杀灭与抑制。
本发明所述的壳聚糖衍生物为一类羟基官能团发生取代反应而改性的化合物,应当具有下述结构式:
例如,可以是苯甲酸壳聚糖酯、对羟基苯甲酰壳聚糖酯、富马酰壳聚糖、山梨酰壳聚糖、N-(2-羟丙基三甲基)壳聚糖、N,O-羧甲基化壳聚糖、O-羧甲基化壳聚糖、O-羧乙基化壳聚糖、二乙基甲基壳聚糖、壳聚糖乙酰基硫脲、壳聚糖氯乙酰基硫脲、3-甲基-1,2,4-三唑壳聚糖、3-氯甲基-1,2,4-三唑壳聚糖、壳聚糖苯甲酸炔丙酯1,2,3-三唑、壳聚糖烟酸炔丙酯1,2,3-三唑、壳聚糖烷基二硫代氨基甲酸酯、壳聚糖二硫代氨基甲酸三乙烯二胺盐、壳聚糖氨基硫脲、壳聚糖取代苯基缩氨基硫脲、壳聚糖二硫代氨基甲酸盐、壳聚糖α-氨基正丁基膦酸乙酯、壳聚糖α-氨基正丙基膦酸乙酯、壳聚糖α-氨基苯氧基嘧啶膦酸甲酯、壳聚糖α-氨基苯氧基嘧啶膦酸乙酯、壳聚糖α-氨基呋喃基膦酸甲酯、壳聚糖α-氨基呋喃基膦酸乙酯、壳聚糖锌配合物、壳聚糖镍配合物、壳聚糖铜盐、壳聚糖锌盐等。
本发明通过将活化的光敏剂(PS)与壳聚糖或壳聚糖衍生物化学耦合制得纳米光敏剂PS-CS,光敏剂(PS)的疏水性得到了明显的改善,提高了光敏剂(PS)在水溶液中的稳定性和生物相容性;此外,纳米光敏剂PS-CS是一种阳离子聚合物,有利于被多种病原微生物所摄取。在波长为660nm的激光照射下,纳米光敏剂PS-CS可以将周围环境中的氧分子转化为单线态氧,可应用于大肠杆菌(以下简称为E.coli)、金黄色葡萄球菌(以下简称为SA)、耐甲氧西林金黄色葡萄球菌(以下简称为MRSA)、枯草芽孢杆菌(以下简称为BS)、鲍曼不动杆菌(以下简称为AB)等多种病原微生物的杀灭与抑制过程。
附图说明
图1为本发明制备方法的流程图;
图2为本发明实施例1中制得的PS-CS纳米光敏剂的紫外-可见吸收光谱图(其中PS-CS为Ce6-Chitosan);
图3为本发明实施例1中制得的PS-CS纳米光敏剂的动态光散射粒径分布图(其中PS-CS为Ce6-Chitosan);
图4为本发明实施例1中制得的PS-CS纳米光敏剂的红外光谱图(其中PS-CS为Ce6-Chitosan);
图5为本发明实施例1中制得的PS-CS纳米光敏剂的单线态氧测定图(其中PS-CS为Ce6-Chitosan);
图6为本发明实施例1中制得的PS-CS纳米光敏剂对大肠杆菌的抑菌效果图(其中PS-CS为Ce6-Chitosan);
图7为本发明实施例1中制得的PS-CS纳米光敏剂对金黄色葡萄球菌的抑菌效果图(其中PS-CS为Ce6-Chitosan);
图8为本发明实施例1中制得的PS-CS纳米光敏剂对耐甲氧西林金黄色葡萄球菌的抑菌效果图(其中PS-CS为Ce6-Chitosan);
图9为本发明实施例1中制得的PS-CS纳米光敏剂对枯草芽孢杆菌的抑菌效果图(其中PS-CS为Ce6-Chitosan);
图10为本发明实施例1中制得的PS-CS纳米光敏剂对鲍曼不动杆菌的抑菌效果图(其中PS-CS为Ce6-Chitosan)。
具体实施方式
下面结合附图与实施例对本发明进行进一步的说明。
附图1为本发明制备方法的流程图。本发明通过将光敏剂(PS)、耦合试剂共同溶解于有机溶剂中,避光控温搅拌制得活化的光敏剂(PS)溶液;活化的光敏剂(PS)溶液加入到壳聚糖的醋酸水溶液或壳聚糖衍生物的醋酸水溶液中进行控温搅拌,得到PS-CS粗产物;PS-CS粗产物通过葡聚糖凝胶柱,并采用醋酸水溶液洗脱得到PS-CS纯化产物;将PS-CS纯化产物以生理溶液为介质进行透析,同时纯化产物在生理溶液中自组装形成PS-CS纳米光敏剂。
实施例中光敏剂选用二氢卟吩e6(Ce6)。壳聚糖或壳聚糖衍生物的分子量范围为5×103-3×105Da,脱乙酰度范围为55%-95%。
实施例1
S1:分别称取N,N’-二环己基碳二亚胺(DCC)6.9mg,N-羟基琥珀酰亚胺(NHS)4.0mg和二氢卟吩e6(Ce6)10mg混合后溶于10mL二甲基亚砜(DMSO),在25℃避光下搅拌0.5h后得到活化后的二氢卟吩e6溶液;
S2:将活化后的二氢卟吩e6溶液用滤膜过滤除去不溶型副产物后,缓慢滴加至质量分数为0.5%的壳聚糖醋酸水溶液(100mL)中,在25℃条件下避光搅拌反应12h,得到二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)粗产物;
S3:取二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)粗产物溶液滴加至葡聚糖凝胶柱上方,待进入凝胶内部后,用质量分数为0.5%的醋酸水溶液洗脱,得到二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)纯化产物。
S4:二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)纯化产物转移至透析袋内,以生理溶液为介质过夜透析,同时纯化产物在生理溶液中自组装形成二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)纳米光敏剂;其中透析袋的分子截留量为12000,产物二氢卟吩e6接枝壳聚糖中二氢卟吩e6接枝到壳聚糖的接枝率范围是1%-10%。
实施例2
S1:分别称取三乙胺(Et3N)8.4mg,O-苯并三氮唑-四甲基脲六氟磷酸酯(HBTU)31.6mg和二氢卟吩e6(Ce6)10mg混合后溶于10mL二甲基甲酰胺(DMF),在20℃避光下搅拌12h后得到活化后的二氢卟吩e6溶液;
S2:将活化后的二氢卟吩e6溶液用滤膜过滤除去不溶型副产物后,缓慢滴加至质量分数为3.2%的N-(2-羟丙基三甲基)壳聚糖醋酸水溶液(100mL)中,在20℃条件下避光搅拌反应24h,得到二氢卟吩e6接枝N-(2-羟丙基三甲基)壳聚糖粗产物;
S3:取二氢卟吩e6接枝N-(2-羟丙基三甲基)壳聚糖粗产物溶液滴加至葡聚糖凝胶柱上方,待进入凝胶内部后,用质量分数为1%的醋酸水溶液洗脱纯化,得到二氢卟吩e6接枝N-(2-羟丙基三甲基)壳聚糖纯化产物;
S4:将二氢卟吩e6接枝N-(2-羟丙基三甲基)壳聚糖纯化产物转移至透析袋内,以生理溶液为介质过夜透析,同时纯化产物在生理溶液中自组装形成二氢卟吩e6接枝N-(2-羟丙基三甲基)壳聚糖纳米光敏剂;其中透析袋的分子截留量为12000,产物二氢卟吩e6接枝N-(2-羟丙基三甲基)壳聚糖纳米光敏剂中二氢卟吩e6接枝到N-(2-羟丙基三甲基)壳聚糖的接枝率范围是1%-10%。
实施例3
S1:分别称取N,N-二异丙基乙胺(DIPEA)17.3mg,O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)21.4mg和二氢卟吩e6(Ce6)5mg混合后溶于10mL二甲基甲酰胺(DMF),在30℃避光下搅拌6h后得到活化后的二氢卟吩e6溶液;
S2:将活化后的二氢卟吩e6溶液用滤膜过滤除去不溶型副产物后,缓慢滴加至质量分数为3.2%的壳聚糖α-氨基苯氧基嘧啶膦酸乙酯醋酸水溶液(50mL)中,在30℃条件下避光反应48h,得到二氢卟吩e6接枝壳聚糖α-氨基苯氧基嘧啶膦酸乙酯粗产物;
S3:取二氢卟吩e6接枝壳聚糖α-氨基苯氧基嘧啶膦酸乙酯粗产物溶液滴加至葡聚糖凝胶柱上方,待进入凝胶内部后,用质量分数为2%的醋酸水溶液洗脱纯化,得到二氢卟吩e6接枝壳聚糖α-氨基苯氧基嘧啶膦酸乙酯纯化产物;
S4:将二氢卟吩e6接枝壳聚糖α-氨基苯氧基嘧啶膦酸乙酯纯化产物转移至透析袋内,以生理溶液为介质过夜透析,同时纯化产物在生理溶液中自组装形成二氢卟吩e6接枝壳聚糖α-氨基苯氧基嘧啶膦酸乙酯纳米光敏剂;其中透析袋的分子截留量为12000,产物二氢卟吩e6接枝壳聚糖α-氨基苯氧基嘧啶膦酸乙酯纳米光敏剂中二氢卟吩e6接枝到壳聚糖α-氨基苯氧基嘧啶膦酸乙酯的接枝率范围是1%-10%。
实施例4
S1:分别称取N,N-二异丙基乙胺(DIPEA)17.2mg,1-羟基苯并三唑(HOBt)9.1mg、1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDC·HCl)12.8mg和二氢卟吩e6(Ce6)10mg混混合后溶于10mL二甲基甲酰胺(DMF),在40℃避光下搅拌6h后得到活化后的二氢卟吩e6溶液;
S2:将活化后的二氢卟吩e6溶液用滤膜过滤除去不溶型副产物后,缓慢滴加至质量分数为4%的二乙基甲基壳聚糖醋酸水溶液(80mL),在40℃条件下避光反应48h,得到二氢卟吩e6接枝二乙基甲基壳聚糖粗产物;
S3:取二氢卟吩e6接枝二乙基甲基壳聚糖粗产物溶液滴加至葡聚糖凝胶柱上方,待进入凝胶内部后,用质量分数为3%的醋酸水溶液洗脱纯化,得到二氢卟吩e6接枝二乙基甲基壳聚糖纯化产物;
S4:将二氢卟吩e6接枝二乙基甲基壳聚糖纯化产物转移至透析袋内,以生理溶液为介质过夜透析,同时纯化产物在生理溶液中自组装形成二氢卟吩e6接枝二乙基甲基壳聚糖光敏剂,其中透析袋的分子截留量为12000,产物二氢卟吩e6接枝二乙基甲基壳聚糖光敏剂中二氢卟吩e6接枝到二乙基甲基壳聚糖的接枝率范围是1%-10%。
实施例5
实施例5说明实施例1的产物二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)性质。
图2是二氢卟吩e6(Ce6)、二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)和壳聚糖(Chitosan)的水溶液在300-800nm的紫外-可见吸收光谱图;从图中可以看出壳聚糖基本没有吸收,二氢卟吩e6和二氢卟吩e6接枝壳聚糖在400nm和650nm有一个明显的吸收峰,表明成功二氢卟吩e6接枝壳聚糖;
图3是二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)水溶液的动态光散射粒径分布图;从图中可以看出二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)的平均水化粒径为346±15.9nm,表明二氢卟吩e6接枝壳聚糖是纳米聚合物;
图4是二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)水溶液在4000-500cm-1的红外光谱图;图中可知1078cm-1是壳聚糖C-O-C的伸缩振动吸收峰;1707cm-1、3419cm-1分别是二氢卟吩e6的C=O和OH的伸缩振动吸收峰,表明二氢卟吩e6成功接枝壳聚糖;
图5是二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)溶液的单线态氧测定图;采用9,10-二甲基蒽(DMA)检测单线态氧,将9,10-二甲基蒽溶于N,N-二甲基甲酰胺溶液(DMF)中,加入0.5-1mL的二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)溶液,在波长为660nm的激光持续照射10-30min后,在374nm激发光下检测溶液荧光强度,图中DMA在475nm发射出强烈的荧光;DMA和二氢卟吩e6接枝壳聚糖混合溶液在660nm激光照射后,二氢卟吩e6接枝壳聚糖产生单线态氧与DMA(单线态氧捕获剂)结合后,使得DMA的结构发生变化,荧光淬灭;未经660nm的激光照射的DMA和二氢卟吩e6接枝壳聚糖混合溶液在475nm发射出强烈的荧光,说明在660nm的激光照射下二氢卟吩e6接枝壳聚糖(Ce6-Chitosan)能够产生单线态氧。
实施例6
本实施例说明本发明的纳米光敏剂在抑制病原微生物中的应用。
以实施例1的产物二氢卟吩e6接枝壳聚糖纳米光敏剂(Ce6-Chitosan)为例,具体实验步骤如下:
S1:将大肠杆菌(以下简称为E.coli)、金黄色葡萄球菌(以下简称为SA)、耐甲氧西林金黄色葡萄球菌(以下简称为MRSA)、枯草芽孢杆菌(以下简称为BS)、鲍曼不动杆菌(以下简称为AB)分别接种于液体培养基中,置于摇床中37℃,200rpm培养12h;
S2:取培养过夜的菌液分别用磷酸盐缓冲液(pH 7.4)洗涤并稀释至合适的浓度(吸光度为0.5),再向菌液中加入磷酸盐缓冲液(pH 7.4)或者二氢卟吩e6接枝壳聚糖的水溶液(体积比为9:1),其中磷酸盐缓冲液为对照组,二氢卟吩e6接枝壳聚糖为实验组;
S3:将菌体混合液在660nm激光照射15min后,光照结束后取一定体积菌体混合液接种于液体培养基中,置于摇床中37℃,200rpm培养,在不同时间点取样并测试样品的吸光度,考查二氢卟吩e6接枝壳聚糖纳米光敏剂的抑菌效果;
图6-10分别是磷酸盐缓冲液(对照组)和二氢卟吩e6接枝壳聚糖纳米光敏剂(实验组)对大肠杆菌(以下简称为E.coli)、金黄色葡萄球菌(以下简称为SA)、耐甲氧西林金黄色葡萄球菌(以下简称为MRSA)、枯草芽孢杆菌(以下简称为BS)、鲍曼不动杆菌(以下简称为AB)的抑菌效果图;从图中可以看出大肠杆菌(以下简称为E.coli)、金黄色葡萄球菌(以下简称为SA)、耐甲氧西林金黄色葡萄球菌(以下简称为MRSA)、枯草芽孢杆菌(以下简称为BS)、鲍曼不动杆菌(以下简称为AB)在处理后培养2h,对照组和实验组没有明显区别,随着培养时间的延长,对照组的菌体量均呈现指数增长而实验组的菌体量没有变化,表明实验组菌群完全被抑制,二氢卟吩e6接枝壳聚糖对大肠杆菌(以下简称为E.coli)、金黄色葡萄球菌(以下简称为SA)、耐甲氧西林金黄色葡萄球菌(以下简称为MRSA)、枯草芽孢杆菌(以下简称为BS)、鲍曼不动杆菌(以下简称为AB)均具有良好的抑菌效果。
对实施例2-4的二氢卟吩e6接枝壳聚糖衍生物纳米光敏剂进行抑菌测试,效果如下表所示:
表1二氢卟吩e6接枝壳聚糖衍生物纳米光敏剂的抑菌效果表
备注:“-”表示目标菌群完全被抑制
本发明是通过实施例进行描述的,本领域技术人员知悉,在不脱离本发明的精神和范围的情况下,可以对这些特征和实施例进行各种改变或等效替换。另外,在本发明的指导下,可以对这些特征和实施例进行修改以适应具体的情况及材料而不脱离本发明的精神和范围。因此,本发明不受此处所公开的具体实施例的限制,所有落入本申请的权利要求内的实施例都属于本发明保护的范围。
Claims (10)
1.一种用于光动力抗菌的纳米光敏剂的制备方法,其特征在于,将光敏剂、耦合试剂共同溶解于有机溶剂中,避光条件下活化,之后加入壳聚糖的醋酸水溶液或壳聚糖衍生物的醋酸水溶液中,避光条件下反应制取光敏剂接枝的壳聚糖或其衍生物的粗产物,最后对粗产物提纯获得纯化产物,纯化产物在生理溶液中自组装形成所述纳米光敏剂。
2.根据权利要求1所述的方法,其特征在于,所述耦合试剂选自以下任一种或几种组合:
N-羟基琥珀酰亚胺与N, N’-二环己基碳二亚胺的混合试剂;
或三乙胺与O-苯并三唑-四甲基脲六氟磷酸盐的混合试剂;
或N,N-二异丙基乙胺与O-苯并三唑-N,N,N',N'-四甲基脲四氟硼酸盐的混合试剂;
或N,N-二异丙基乙胺、1-羟基苯并三唑与1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐的混合试剂。
3.根据权利要求1所述的方法,其特征在于,所述有机溶剂选用二甲基亚砜或二甲基甲酰胺。
4.根据权利要求1所述的方法,其特征在于,所述光敏剂与耦合试剂的摩尔比为1∶4-1∶16。
5. 根据权利要求1所述的方法,其特征在于,加入质量分数为0.5% - 4%的壳聚糖的醋酸水溶液或壳聚糖衍生物的醋酸水溶液中避光条件下反应制取粗产物。
6. 根据权利要求1所述的方法,其特征在于,所述壳聚糖或壳聚糖衍生物的分子量范围为5×103 - 3×105 Da,脱乙酰度范围为55% - 95%。
7. 根据权利要求1或6所述的方法,其特征在于,所述光敏剂为二氢卟吩e6 (Ce6)。
8. 根据权利要求1所述的方法,其特征在于,将粗产物通过葡聚糖凝胶柱用质量分数为0.5% - 3%的醋酸水溶液洗脱,获取纯化产物,之后将纯化产物转移至透析袋中以生理溶液为介质进行透析,即得到纳米光敏剂。
9.权利要求1~8任一项所述方法制备的纳米光敏剂。
10.权利要求9所述纳米光敏剂在抑制病原微生物中的应用。
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