CN115246799A - 化合物及其制备方法和包含该化合物的纳米光热试剂 - Google Patents
化合物及其制备方法和包含该化合物的纳米光热试剂 Download PDFInfo
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- CN115246799A CN115246799A CN202111537339.1A CN202111537339A CN115246799A CN 115246799 A CN115246799 A CN 115246799A CN 202111537339 A CN202111537339 A CN 202111537339A CN 115246799 A CN115246799 A CN 115246799A
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Abstract
Description
技术领域
本发明涉及对疾病微环境智能响应光热试剂的合成及应用领域,具体涉及一种化合物及其制备方法和包含该化合物的纳米光热试剂。
背景技术
光热试剂是能够将光能转换为热能,使组织的温度提高进而杀死病原菌,由于光具有非侵入性、能量调控方便以及时空分辨率高的优势,光热治疗备受人们关注。在光热治疗中,光热试剂的性能是影响疗效的关键因素。现有的金纳米材料或者诸如碳纳米管的碳材料是具有代表性的两类光热试剂,然而这类光热试剂在体内难于分解,治疗后的代谢不明,引发了对于其毒性的担忧。与之相对应的有机小分子光热试剂,其进入体内后更容易代谢分解,已经临床使用的吲哚菁绿光治疗试剂是其中的典型代表。
需要注意的是,细菌会通过调控热休克蛋白等的表达来抵抗高热的伤害,因此要得到理想的治疗效果,需要产生足够的热量才能有效杀灭致病菌,在治疗过程中就需要高功率的光进行辐照,但是这类高功率的光辐照所产生的的高热(通常大于50摄氏度)对正常组织的伤害作用不可忽视。为了实现低功率辐照下即可取得理想治疗效果,人们将各种小分子热休克蛋白抑制剂和光热试剂进行结合或者引入小干扰RNA下调热休克蛋白的表达量,来实现低温光热治疗。但是这类方法体系复杂,不具有临床转化价值。
发明内容
因此,本发明的目的在于提供一种新的化合物,以及由该化合物制得的纳米光热试剂,以提高光热治疗效果,乃至实现低温光热治疗。
本发明提供了一种化合物,所述化合物具有下式(I)所示的结构:
A1-A2-(A3)n(I)或者;
本发明涉及的光热单元或者光热试剂是一类发挥吸收光能转变成热能的作用的单元或者试剂,光热单元为光热试剂的端羧基去掉羟基或者端氨基去掉氢之后剩余的单元。
本发明涉及的环境响应单元或者环境响应试剂是指一类能够根据其所处的环境做出特定响应的单元或者试剂。这里的环境条件既包括温度、压力、电位、pH、氧化还原等物理化学环境,也包括酶、激素、细胞因子等生化学环境。而响应则包括降解、组装、释药、活化、粘附、蓄积等行为。
优选为细菌微环境响应单元或者细菌微环境响应试剂,细菌微环境是指在细菌新陈代谢中会分泌一些小分子或者酶等大分子,这些相对于正常组织来说过量的小分子或者酶就构成了细菌感染部位的特异性微环境。本设计中用到了细菌感染部位酸性微环境,还原性微环境(过量分泌的还原酶等),氧化性微环境(过氧化氢响应性),细菌分泌的磷酸酶、酯酶,耐药菌分泌的β-内酰胺酶,盘尼西林G酰胺酶等。
在本发明中,所述环境响应单元选自酸响应单元、还原环境响应单元、氧化环境响应单元或酶响应单元。响应指的是降解(或称水解)。
进一步地,所述光热单元选自如下结构:
进一步地,所述连接单元具有下述式(II)所示的结构:
-X1-R1-X2-(II),其中X1选自CO或者NH;X2选自NH或者R1选自取代或未取代的C1-C20的亚烷基,取代或未取代的C1-C20的亚烷氧基、取代或未取代的C5-C20的亚芳基;取代的是指亚烷基、亚烷氧基、亚芳基上至少1个氢原子被C1-C20的烷基,C1-C20的烷氧基所取代,优选地,R1选自亚己基、亚庚基、亚正十一烷基、亚正十三烷基、苯基、或者被 中的至少一种所取代的苯基。
其中对于取代的苯基来说,上述取代基的*端连接苯基,苯基与X1连接,取代基的#端连接X2。优选苯基上3个H原子被取代,取代基可以相同也可以不同。
进一步地,A1通过酰胺键与连接单元的X1连接,连接单元的X2与A3的酰基连接。
进一步地,所述连接单元选自如下结构:
其中,连接单元中*端连接光热单元,#端连接环境响应单元。
进一步地,所述化合物选自如下结构:
因上述光热单元具有疏水性,环境响应单元含有极性集团,具有亲水性,使得化合物具有两亲性,可以自组装形成纳米光热试剂,具有多价相互作用,进一步提高杀菌效果,可实现低功率杀菌。
本发明还提供了一种化合物的制备方法,包括如下步骤:
将含羧基的光热试剂与含有氨基且含有氨基保护基保护的氨基或胍基的连接试剂进行反应,脱保护,然后与含羧基或者酰氯基或酸酐的环境响应试剂反应,即得;或者,将含有氨基的光热试剂与含有羧基且含有氨基保护基保护的氨基或胍基的连接试剂进行反应,脱保护,然后与含有羧基或者酰氯基或酸酐的环境响应试剂反应,即得。
进一步地,所述氨基保护基为叔丁基氧基羰基。
进一步地,所述连接试剂的一端为氨基另一端为叔丁基氧基羰基保护氨基或者叔丁基氧基羰基保护胍基;或者所述连接试剂的一端为羧基另一端为叔丁基氧基羰基保护氨基或者叔丁基氧基羰基保护胍基。
进一步地,制备过程中可以通过柱层析等常规合成方法进行纯化。
进一步地,所述制备方法满足如下(1)-(5)中的至少一项:
(1)所述光热试剂、连接试剂以及环境响应试剂的摩尔比为1-1.2:1-1.2:1-4;
(5)所述氨基保护基为叔丁基氧基羰基。
本发明还提供了一种纳米光热试剂,其特征在于,包括任一所述的化合物或者所述的制备方法制得的化合物中的至少一种,还包括药学上可接受的载体。
进一步地,所述纳米光热试剂是以任一所述的化合物或者所述的制备方法制得的化合物中的至少一种为原料,采用药学上常规的纳米制剂的制备方法自组装而成。
例如化合物可以在选择性溶剂中自组装,选择性溶剂可以采用良溶剂(如DMSO)与水或者缓冲液的混合溶剂。优选地,可以采用良溶剂:缓冲液的体积比为4-6:1000。缓冲液可以采用磷酸盐缓冲液。制备时可以将化合物先溶解于良溶剂中(例如化合物的摩尔数与良溶剂的体积比可以是5-20毫摩尔:1升),再加入水中,搅拌或者振荡,即得。
本发明还提供了任一所述的化合物或者所述的制备方法制得的化合物或者所述的纳米光热试剂在制备杀菌剂或者成像剂中的用途。
本发明还提供了一种杀菌剂,包括任一所述的化合物或者所述的制备方法制得的化合物或者所述的纳米光热试剂。
所述杀菌剂的制备方法,包括如下步骤:将任一所述的化合物或者所述的制备方法制得的化合物溶于有机溶剂中,得到溶液,取溶液与水混合,即得杀菌剂。有机溶剂可以采用二甲亚砜等普通有机溶剂,可制成5-20mmol/L的溶液。有机溶剂与水的体积比为1:20-100。
本发明技术方案,具有如下优点:
附图说明
为了更清楚地说明本发明具体实施方式或现有技术中的技术方案,下面将对具体实施方式或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图是本发明的一些实施方式,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1是本发明实验例1中在pH 7.4水溶液中的纳米光热试剂的电镜照片;
图2是本发明实验例1中在pH 5.5水溶液中的的纳米光热试剂的电镜照片;
图3是本发明实验例1中分别在pH7.4、6.5和5.5的水溶液中在不同反应时间的水解反应比例;
图4是本发明实验例2激光照射纳米光热试剂对其温度的影响;
图5是本发明实验例3中以DBPC制备的纳米光热试剂的实验组(加样品光照)和对照组(空白对照)培养24小时之后的图片;
图6是实验例4中以DBPC制备的纳米光热试剂的实验组(加样品光照)和对照组(空白对照)培养24小时之后的图片;
图7是实验例5中以DBPC制备的纳米光热试剂的实验组(加样品光照)和对照组(空白对照)培养24小时之后的图片;
图8是实验例6中以DBPC制备的纳米光热试剂的实验组(加样品光照)和对照组(空白对照)培养24小时之后的图片;
图9是实验例7中荧光显微镜成像图。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明,并不局限于所述最佳实施方式,不对本发明的内容和保护范围构成限制,任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品,均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者,按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者,均为可以通过市购获得的常规试剂产品。
其中,各实施例所用主要原料均为商业渠道购买,结构式如下:
实施例1
化合物2-((7-(4-((9-(二乙基胺基)-5氢-苯并吩噻嗪-5-亚基)胺基)丁基酰胺基)正庚基)胺基甲酰基)环己基-1-烯-1-羧酸(DBPC)的制备
将40毫摩尔4-((9-(二乙基胺基)-5氢-苯并吩噻嗪-5-亚基)胺基)丁酸与50毫摩尔叔丁基(7-胺基庚基)胺基甲酸酯加入反应器中并用50毫升氮氮二甲基甲酰胺进行溶解,加入50毫摩尔1-(3-二甲胺基丙基)-3-乙基碳二亚胺和40毫摩尔1-羟基苯并三唑,室温反应12小时,加入200毫升二氯甲烷稀释反应液,用饱和食盐水洗涤三次,无水硫酸钠干燥,柱层析(洗脱剂采用体积比为10:1的二氯甲烷和甲醇)得到产物。接着将得到的产物20克溶解于100毫升甲醇溶液中,加入2毫升浓盐酸,并接着在室温下反应24小时。反应结束后,除掉甲醇,将得到的产物溶解于30毫升氮氮二甲基甲酰胺中,加入2毫升三乙胺和45毫摩尔4,5,6,7-四氢异苯并呋喃-1,3-二酮,在室温反应8小时,旋转蒸发除掉溶剂,柱层析(洗脱剂采用体积比为10:1的二氯甲烷和甲醇)纯化得到最终产物2-((7-(4-((9-(二乙基胺基)-5氢-苯并吩噻嗪-5-亚基)胺基)丁基酰胺基)正庚基)胺基甲酰基)环己基-1-烯-1-羧酸15克,产率为56%,纯度为95%。其结构式如下:
核磁氢谱(溶剂:氘代二甲基亚砜,频率:300兆赫兹):7.85(s,1H),7.79(d,1H),7.72(d,1H),7.64(t,2H),7.47(s,1H),6.98(d,1H),6.71(d,1H),6.56(t,1H),6.38(t,1H),3.71(t,2H),3.40(m,4H),3.19(m,2H),3.05(m,2H),2.34(m,2H),2.33(m,4H),2.04(m,2H),1.74(m,4H),1.50(m,2H),1.32(m,2H),1.28(m,4H),1.26(m,2H),1.12(m,t,6H).质谱分子离子峰:684.36
实施例2
化合物双(4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苄基)(((((((5-((5氢,氢-酞菁-23-基)胺基甲酰基)-2-((3-氧-1-(4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯基)-2,7,10-三氧-4-氮-十二烷-12-基)氧)-1,3-亚苯基)双(氧))双(乙烷-2,1-二基))双(氧))双(乙烷-2,1-二基))双(氧))双(乙烷-2,1-二基))二氨基甲酸酯(PTEB)的制备
将40毫摩尔5氢,氢-酞菁-23-胺与50毫摩尔3,4,5-三((2,2-二甲基-4-氧-3,8,11-三氧-5-氮十三烷-13-基)氧)苯甲酸加入反应器中并用50毫升氮氮二甲基甲酰胺进行溶解,加入50毫摩尔1-(3-二甲胺基丙基)-3-乙基碳二亚胺和40毫摩尔1-羟基苯并三唑,室温反应12小时,加入200毫升二氯甲烷稀释反应液,用饱和食盐水洗涤三次,无水硫酸钠干燥,柱层析(洗脱剂采用体积比为4:1的石油醚和乙酸乙酯)得到产物。接着将得到的产物45克溶解于100毫升甲醇溶液中,加入2毫升浓盐酸,并接着在室温下反应24小时。反应结束后,除掉甲醇,将得到的产物溶解于30毫升乙醇中,接着加入150毫摩尔4-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)苄基氯甲酸酯和60毫摩尔三乙胺,室温反应48小时,旋转蒸发除掉溶剂,柱层析(洗脱剂采用体积比为6:1的石油醚和乙酸乙酯)纯化得到最终产物双(4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苄基)(((((((5-((5氢,氢-酞菁-23-基)胺基甲酰基)-2-((3-氧-1-(4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)苯基)-2,7,10-三氧-4-氮-十二烷-12-基)氧)-1,3-亚苯基)双(氧))双(乙烷-2,1-二基))双(氧))双(乙烷-2,1-二基))双(氧))双(乙烷-2,1-二基))二氨基甲酸酯30克,产率为40%,纯度为97%,其结构式如下:
核磁氢谱(溶剂:氘代二甲基亚砜,频率:300兆赫兹):8.27(s,1H),7.99(d,1H),7.92(d,1H),7.89(d,1H),7.79(m,2H),7.78(d,6H),7.72(m,2H),7.64(m,4H),7.28(d,6H),7.17(s,2H),6.87(s,1H),6.76(t,3H),6.23(t,1H),6.20(d,1H),6.16(d,1H),6.05(d,1H),5.05(s,6H),4.31(t,6H),3.97(t,1H),3.77(t,6H),3.67(t,6H),3.52(t,12H),3.04(m,6H),1.26(s,48H)质谱分子离子峰:1857.86
实施例3
化合物(((5-((4-(10,15,20-三苯基卟啉-5-基)苯基)胺基甲酰基)苯-1,2,3-三基)三(氧))三(3-氧-2,7,10-三氧-4-氮十二烷-12,1-二基))三(苯-4,1-二基)三乙酯(TPBP)的制备
将40毫摩尔4-(10,15,20-三苯基卟啉-5-基)苯胺与50毫摩尔3,4,5-三((2,2-二甲基-4-氧-3,8,11-三氧-5-氮十三烷-13-基)氧)苯甲酸加入反应器中并用50毫升氮氮二甲基甲酰胺进行溶解,加入50毫摩尔1-(3-二甲胺基丙基)-3-乙基碳二亚胺和40毫摩尔1-羟基苯并三唑,室温反应12小时,加入200毫升二氯甲烷稀释反应液,用饱和食盐水洗涤三次,无水硫酸钠干燥,柱层析(洗脱剂采用体积比为3:1的石油醚和乙酸乙酯)得到产物。接着将得到的产物50克溶解于100毫升甲醇溶液中,加入2毫升浓盐酸,并接着在室温下反应24小时。反应结束后,除掉甲醇,将得到的产物溶解于二氯甲烷中,加入60毫摩尔三乙胺,冰水浴冷却下缓慢加入100毫摩尔4-(((氯羰基)氧)甲基)苯基乙酯,反应完成后,用饱和食盐水洗涤三遍,无水硫酸钠干燥,旋转蒸发除掉溶剂,柱层析(洗脱剂采用体积比为1:1的石油醚和乙酸乙酯)纯化得到最终产物(((5-((4-(10,15,20-三苯基卟啉-5-基)苯基)胺基甲酰基)苯-1,2,3-三基)三(氧))三(3-氧-2,7,10-三氧-4-氮十二烷-12,1-二基))三(苯-4,1-二基)三乙酯35克,产率为50%,纯度为98%,其结构式如下:
核磁氢谱(溶剂:氘代二甲基亚砜,频率:300兆赫兹):12.89(s,1H),10.20(s,1H),7.84(d,2H),7.59(d,2H),7.44(d,2H),7.37(m,6H),7.35(m,2H),7.34(d,2H),7.33(t,1H),7.17(m,6H),6.99(d,6H),6.76(s,3H),6.44(m,4H),6.24(m,2H),5.62(s,1H),5.05(s,6H),4.31(t,6H),3.77(t,6H),3.67(t,6H),3.52(s,12H),3.04(t,6H),2.31(s,9H)质谱分子离子峰:1751.69
实施例4
化合物2-(7-(3-(3-羟基丙基)-1,1-二甲基-1,3-二氢-2氢-苯并吲哚-2-亚基)七-1,3,5-三烯-1-基)-1,1-二甲基-3-(3-(3,4,5-三(2-(2-(2-苯甲酰胺基乙氧基)乙氧基)乙氧基)苯甲酰胺基)丙基)-1氢-苯并吲哚-3-盐(HHDB)的制备
将40毫摩尔3-(3-胺基丙基)-2-(7-(3-(3-羟基丙基)-1,1-二甲基-1,3-二氢-2氢-苯并吲哚-2-亚基)七-1,3,5-三烯-1-基)-1,1-二甲基-1氢-苯并吲哚3-盐与50毫摩尔3,4,5-三((2,2-二甲基-4-氧-3,8,11-三氧-5-氮十三烷-13-基)氧)苯甲酸加入反应器中并用50毫升氮氮二甲基甲酰胺进行溶解,加入50毫摩尔1-(3-二甲胺基丙基)-3-乙基碳二亚胺和40毫摩尔1-羟基苯并三唑,室温反应12小时,加入200毫升二氯甲烷稀释反应液,用饱和食盐水洗涤三次,无水硫酸钠干燥,柱层析(洗脱剂采用体积比为10:2的二氯甲烷和甲醇)得到产物。接着将得到的产物45克溶解于100毫升甲醇溶液中,加入2毫升浓盐酸,室温下反应24小时。反应结束后,除掉甲醇,将得到的产物溶解于二氯甲烷中,加入60毫摩尔三乙胺,冰水浴冷却下缓慢加入100毫摩尔苯甲酰氯,反应完成后,用饱和食盐水洗涤三遍,无水硫酸钠干燥,旋转蒸发除掉溶剂,柱层析纯化得到最终产物滤液进行柱层析(洗脱剂采用体积比为10:2的二氯甲烷和甲醇)纯化得到纯品2-(7-(3-(3-羟基丙基)-1,1-二甲基-1,3-二氢-2氢-苯并吲哚-2-亚基)七-1,3,5-三烯-1-基)-1,1-二甲基-3-(3-(3,4,5-三(2-(2-(2-苯甲酰胺基乙氧基)乙氧基)乙氧基)苯甲酰胺基)丙基)-1氢-苯并
吲哚-3-盐20克,产率为34%,纯度为98%。其结构式如下:
核磁氢谱(溶剂:氘代二甲基亚砜,频率:300兆赫兹):8.71(t,3H),8.44(t,1H),8.08(d,2H),7.93(d,1H),7.86(m,8H),7.72(d,2H),7.62(t,4H),7.49(d,6H),7.43(t,1H),7.32(t,1H),7.20(d,1H),7.17(s,2H),7.05(t,1H),6.25(t,2H),6.23(t,2H),4.89(t,1H),4.48(d,2H),4.31(t,6H),3.91(m,1H),3.77(m,14H),3.53(t,14H),3.42(m,3H),3.28(t,6H),2.55(m,2H),1.92(s,6H),1.75(m,2H),1.57(s,6H).质谱分子离子峰:1454.74
实施例5纳米光热试剂
分别以实施例1-4制备的化合物为原料进行纳米光热试剂的制备。制备方法相同,区别仅在于原料不同,以实施例1的DPBC为例,包括如下步骤:配制10毫摩尔每升的DBPC的二甲亚砜母液,取5微升上述DBPC的二甲亚砜母液,分别加到1mLpH 7.4磷酸盐缓冲溶中,振荡5分钟,即可得到纳米光热试剂。其中磷酸盐缓冲溶液的浓度为10毫摩尔每升。
实验例1pH依赖性
配制10毫摩尔每升的DBPC的二甲亚砜母液,分别取5微升上述母液,分别加入到1mLpH 7.4的水溶液(购自谱诺赛公司,货号:PB180327)、1mLpH6.5的水溶液(购自飞净生物科技有限公司,货号:200424)、1mLpH5.5的水溶液(购自飞净生物科技有限公司,货号:20210421)中,振荡5分钟,即可得到纳米光热试剂,分别记为样品1-3。将样品1-3置入37摄氏度的烘箱中培养。
对于样品1和3来说,培养8小时后,取样进行TEM表征纳米光热试剂的形貌。图1所示为在pH 7.4水溶液中的纳米光热试剂形貌,图2所示为在pH 5.5水溶液中的纳米光热试剂的形貌。
对于样品1-3来说,在特定的时间点分别取样,加入等体积的甲醇进行稀释后,用高效液相色谱法进行分析。测试仪器为安捷伦1260infinity II系统上进行,该系统配有四级泵(g7111b)和二极管阵列检测器wr(g7115a);色谱条件如下:Agilent ZORBAX 300SB-C18色谱柱,检测波长660纳米,流动相:甲醇/超纯水为7/3(体积比),柱温30℃。
结果见图3所示,这类化合物的水解特性具有明显的pH依赖性。
实验例2光热效果
配制10毫摩尔每升的DBPC的二甲亚砜母液,取5微升上述母液,稀释到1mLpH 7.4的水溶液,振荡5分钟,即可得到纳米光热试剂。
用660纳米激光分别辐照上述纳米光热试剂(样品溶液)和纯水,记录随光照时间温度上升的曲线,如图4所示,在180秒的照射时间内,样品溶液的温度迅速上升而纯水温度几乎不变。
实验例3杀菌测试-铜绿假单胞菌
分别以实施例1-4制备的化合物为原料按照实施例5的方法制备得到纳米光热试剂,共4组,分别以这4组纳米光热试剂为受试品,按照下述方法测定各组纳米光热试剂的杀菌效果,即对铜绿假单胞菌处理后的细菌存活率,具体方法如下:
将铜绿假单胞菌(ATCC 27853)置于肉汤中培养24小时,然后将细菌分散液在3000转每分钟的转速下离心3分钟,并用1毫升pH7.4浓度为10mM的磷酸盐缓冲溶液清洗3次,将细菌稀释到pH为5.5浓度为10mM的的磷酸盐缓冲溶液中,使细菌的浓度大约为107菌群每毫升,随机分为两组,一组加入纳米光热试剂,使纳光热试剂的浓度为50微摩尔每升,为试验组,一组不加入纳米光热试剂,为对照组,两组均于37℃下培养4小时后,然后用660纳米激光辐照180秒,设定激光功率为0.3瓦每平方厘米。辐照完成后,将没有加入纳米光热试剂辐照的对照组和加入样品辐照的试验组稀释涂板,37℃下培养24小时候后观察细菌生长情况,按照下式计算细菌存活率,细菌存活率=(试验组处理后菌落数除以对照组处理后的菌落数)乘以100%;杀菌率=100%-细菌存活率。
结果显示,24小时之后,对照组的菌落数分别为278、316、257和375,加入4组纳米光热试剂的试验组的细菌存活率均为0,4组纳米光热试剂的杀菌率均为100%。
如图5所示,为以实施例1制备的化合物DBPC为原料制备的纳米光热试剂的实验组和对照组培养24小时之后的图片。
实验例4杀菌测试-大肠杆菌
分别以实施例1-4制备的化合物为原料按照实施例5的方法制备得到纳米光热试剂,共4组,分别以这4组纳米光热试剂为受试品,分别按照下述方法测定各组纳米光热试剂的杀菌效果,即对大肠杆菌处理后的细菌存活率,具体方法如下:
将大肠杆菌(ATCC 8739)置于肉汤中培养24小时,然后将细菌分散液在3000转每分钟的转速下离心3分钟,并用1毫升pH7.4浓度为10mM的磷酸盐缓冲溶液清洗3次,将细菌稀释到pH为5.5浓度为10mM的的磷酸盐缓冲溶液中,使细菌的浓度大约为107菌群每毫升,随机分为两组,一组加入纳米光热试剂,使其浓度为50微摩尔每升,为试验组,另一组不加入纳米光热试剂,为对照组,两组均于37℃下培养4小时后,然后用660纳米激光辐照180秒,设定激光功率为0.3瓦每平方厘米。辐照完成后,将没有加入纳米光热试剂辐照(对照组)和加入纳米光热试剂辐照的试验组稀释涂板,37℃下培养24小时候后观察细菌生长情况,按照下式计算细菌存活率,细菌存活率=(试验组处理后菌落数除以对照组处理后的菌落数)乘以100%;杀菌率=100%-细菌存活率。
结果显示,24小时之后,对照组的菌落数分别为293、305、198和342,加入4组纳米光热试剂的试验组的细菌存活率均为0,4组纳米光热试剂的杀菌率均为100%。
如图6所示,为以实施例1制备的化合物DBPC制备的纳米光热试剂的实验组和对照组培养24小时之后的图片。
实验例5杀菌测试-金黄色葡萄球菌
分别以实施例1-4制备的化合物为原料按照实施例5的方法制备得到纳米光热试剂,共4组,分别以这4组纳米光热试剂为受试品,分别按照下述方法测定各实施例的纳米光热试剂的杀菌效果,即对金黄色葡萄球菌处理后的细菌存活率,具体方法如下:
将金黄色葡萄球菌(ATCC 25923)置于肉汤中培养24小时,然后将细菌分散液在3000转每分钟的转速下离心3分钟,并用1毫升pH7.4浓度为10mM的磷酸盐缓冲溶液清洗3次,将细菌稀释到pH为5.5浓度为10mM的磷酸盐缓冲溶液中,使细菌的浓度大约为107菌群每毫升,随机分为两组,一组加入纳米光热试剂,使其浓度为50微摩尔每升,为试验组,一组不加入纳米光热试剂,为对照组,两组均于37℃下培养4小时后,然后用660纳米激光辐照180秒,设定激光功率为0.3瓦每平方厘米。辐照完成后,将没有加入纳米光热试剂辐照(对照组)和加入纳米光热试剂辐照的试验组稀释涂板,37℃下培养24小时候后观察细菌生长情况,按照下式计算细菌存活率,细菌存活率=(试验组处理后菌落数除以对照组处理后的菌落数)乘以100%;杀菌率=100%-细菌存活率。
结果显示,24小时之后,对照组的菌落数分别为287、242、368和199,加入4组纳米光热试剂的试验组的细菌存活率均为0,4组纳米光热试剂的杀菌率均为100%。
如图7所示,为以实施例1制备的化合物DBPC制备的纳米光热试剂的实验组和对照组培养24小时之后的图片。
实验例6杀菌测试-耐甲氧西林金黄色葡萄球菌
分别以实施例1-4制备的化合物为原料按照实施例5的方法制备得到纳米光热试剂,共4组,分别以这4组纳米光热试剂为受试品,分别按照下述方法测定各实施例的纳米光热试剂的杀菌效果,即对耐甲氧西林金黄色葡萄球菌处理后的细菌存活率,具体方法如下:
将耐甲氧西林金黄色葡萄球菌(USA300LAC)置于肉汤中培养24小时,然后将细菌分散液在3000转每分钟的转速下离心3分钟,并用1毫升pH7.4浓度为10mM的磷酸盐缓冲溶液清洗3次,将细菌稀释到pH为5.5浓度为10mM的磷酸盐缓冲溶液中,使细菌的浓度大约为107菌群每毫升,随机分为两组,一组加入纳米光热试剂,使其浓度为50微摩尔每升,为试验组,一组不加入纳米光热试剂,为对照组,两组均于37℃下培养4小时后,然后用660纳米激光辐照180秒,设定激光功率为0.3瓦每平方厘米。辐照完成后,将没有加入纳米光热试剂辐照(对照组)和加入纳米光热试剂辐照的试验组稀释涂板,37℃下培养24小时候后观察细菌生长情况,按照下式计算细菌存活率,细菌存活率=(试验组处理后菌落数除以对照组处理后的菌落数)乘以100%;杀菌率=100%-细菌存活率。
结果显示,24小时之后,对照组的菌落数分别为414、398、405和277,加入4组纳米光热试剂的试验组的细菌存活率均为0,4组纳米光热试剂的杀菌率均为100%。
如图8所示,为以实施例1制备的化合物DBPC制备的纳米光热试剂的实验组和对照组培养24小时之后的图片。
实验例7
以实施例1制备的化合物为原料按照实施例5的方法制备得到纳米光热试剂,将大肠杆菌置于肉汤中37℃下培养24小时,然后将细菌分散液在3000转每分钟的转速下离心3分钟,并用1毫升pH7.4浓度为10mM的磷酸盐缓冲溶液清洗3次,将细菌稀释到pH为5.5浓度为10mM的磷酸盐缓冲溶液中,使细菌的浓度大约为107菌群每毫升,加入纳米光热试剂分散液,使其浓度为50微摩尔每升,37℃下培养1小时,用磷酸缓冲溶液洗涤3次,置于荧光显微镜下成像,细菌已被染色,可以清楚看到红色荧光,说明该体系还可以对病菌感染部位成像,参见图9。
显然,上述实施例仅仅是为清楚地说明所作的举例,而并非对实施方式的限定。对于所属领域的普通技术人员来说,在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (13)
2.根据权利要求1所述的化合物,其特征在于,所述环境响应单元选自酸响应单元、还原环境响应单元、氧化环境响应单元或酶响应单元。
8.一种化合物的制备方法,其特征在于,包括如下步骤:
将含羧基的光热试剂与含有氨基且含有氨基保护基保护的氨基或者氨基保护基保护的胍基的连接试剂进行反应,脱保护,然后与含有羧基或者酰氯基或酸酐的环境响应试剂反应,即得;或者,将含有氨基的光热试剂与含有羧基且含有氨基保护基保护的氨基或者氨基保护基保护的胍基的连接试剂进行反应,脱保护,然后与含有羧基或者酰氯基或酸酐的环境响应试剂反应,即得。
10.一种纳米光热试剂,其特征在于,包括权利要求1-7中任一所述的化合物或者权利要求8或9所述的制备方法制得的化合物中的至少一种,还包括药学上可接受的载体。
11.根据权利要求10所述的纳米光热试剂,其特征在于,所述纳米光热试剂是以权利要求1-7中任一所述的化合物或者权利要求8或9所述的制备方法制得的化合物中的至少一种为原料,采用药学上常规的纳米制剂的制备方法自组装而成。
12.权利要求1-7中任一所述的化合物或者权利要求8或9所述的制备方法制得的化合物或者权利要求10或11所述的纳米光热试剂在制备杀菌剂或者成像剂中的用途。
13.一种杀菌剂或者成像剂,其特征在于,包括权利要求1-7中任一所述的化合物或者权利要求8或9所述的制备方法制得的化合物或者权利要求10或11所述的纳米光热试剂。
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