CN116421568A - 一种利奈唑胺纳米给药系统及其制备方法和应用 - Google Patents
一种利奈唑胺纳米给药系统及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种利奈唑胺纳米给药系统及其制备方法和应用,所述纳米给药系统包括载体材料PCL‑b‑PArg‑DA,药物利奈唑胺和光热剂IR780,利奈唑胺和IR780包裹在合成的载体材料PCL‑b‑PArg‑DA中;在808nm近红外激光照射下,该纳米给药系统通过光热效应和药物抗菌的协同作用,杀灭金黄色葡萄球菌和大肠杆菌,并且具有很好的生物膜抑制和消融效果,避免细菌耐药性的产生。
Description
技术领域
本发明属于生物医药技术领域,涉及一种利奈唑胺纳米给药系统及其制备方法和应用。
背景技术
细菌感染一直是人类所面临的一大健康威胁,是世界范围内导致死亡的主要原因。目前临床上治疗细菌感染主要是抗生素,但随着抗生素的大量使用及滥用所导致的耐药细菌感染已构成了抗感染治疗的新挑战,是当今人类健康的重要威胁。
利奈唑胺是人工合成的噁唑烷酮类抗生素,2000年获得美国批准上市,2007年开始在中国上市,主要用于治疗革兰阳性球菌引起的感染,包括由MRSA引起的疑似或确诊院内获得性肺炎、社区获得性肺炎、复杂性皮肤或皮肤软组织感染。其属于细菌蛋白质合成抑制剂,作用于细菌50s核糖体亚单位,阻止细菌70S起始复合物的形成,从而在细菌翻译的早期阶段抑制细菌蛋白质的合成。具有独特的作用靶点,不易与其它基于抑制蛋白质合成的抗菌药物发生交叉耐药现象,在体外也不易诱导细菌耐药性的产生。但是利奈唑胺的水溶性不好以及在水溶液中不稳定性限制了其在临床上的使用。目前上市的利奈唑胺制剂只有静脉注射液和口服片剂两种剂型,均为全身性用药,均有不良反应的报道。并且随着使用量的增加,已经出现耐甲氧西林金黄色葡萄球菌对利奈唑胺产生耐药性。细菌产生耐药性的机制有很多,生物膜的形成就是机制之一,而且大多数细菌感染也都与生物膜的形成有关,所以生物膜的形成不仅会造成临床上细菌感染治疗难度的增加,也会致使细菌耐药性的产生。因此,寻找能够破坏生物膜形成的给药系统,将药物利奈唑胺递送到感染部位,减少药物全身分布,降低毒副作用,增加治疗效果以及对抗细菌耐药性,是目前急需解决的问题。
光热治疗(Photothermal Therapy,PTT)是利用光热剂在近红外光照射下产生的局部高温破坏细菌细胞壁和胞内蛋白,导致细菌菌体发生破裂、胞内蛋白发生变性而死亡,具有无创性、无耐药性以及深层组织穿透性和时空可控等优点,引起人们日益关注。
光热剂IR780是一种亲脂性小分子的碘化物,是光热治疗中常用的近红外荧光染料,但是IR780难溶于水,游离的IR780的光稳定性差,因此限制了其在临床的使用。
中国专利CN106580915公开了聚乳酸-羟基乙酸包裹利福喷丁和利奈唑胺制备而成的缓释微球给药系统用于局部给药治疗肺结核,可以减少药物产生的不良反应问题。CN111432800A公开了一种包含利奈唑胺的含泊洛沙姆407和碘海醇的热敏性水凝胶,将利奈唑胺递送到受感染的脊椎部位,其用于治疗、预防、改善和减轻与骨、关节、韧带或肌腱的临床状况同时发生的一种或多种类型的疼痛。CN108403624A公开了一种水和活性分子利奈唑胺包埋在由聚卡波菲和聚山梨酯制成的眼用凝胶中,用于治疗和预防包括结膜炎、角膜炎等眼局部细菌性感染,解决了利奈唑胺在单纯水溶液中溶解性和稳定性差的问题。国内在关于利奈唑胺的给药系统的研究上涉及的类型主要有脂质体、凝胶、缓释片等,但是关于利奈唑胺用于治疗细菌感染的纳米给药系统的报道却很少。
发明内容
针对现有技术的不足,本发明提供了一种利奈唑胺纳米给药系统及其制备方法和应用。该系统解决了利奈唑胺和IR780溶解性差的问题,并且能够在808nm的近红外光照射下通过光热效应和抗菌药物利奈唑胺作用协同杀灭细菌,抑制并破坏生物膜从而解决细菌耐药性的问题。
本发明的技术方案如下:
一种利奈唑胺纳米给药系统的制备方法,包括以下步骤:
步骤1:将ε-己内酯、N-Boc-乙醇胺和辛酸亚锡混合,氮气保护下,100~120℃反应4~8h,之后自然冷却至凝固状态,用CH2Cl2溶解后,加入到乙醚中进行沉淀,收集沉淀真空干燥,得到PCL-NH-Boc;将所得PCL-NH-Boc溶于CH2Cl2和CF3COOH的混合溶剂中,常温反应12~18h,然后加入到乙醚中进行沉淀(1~3次),收集沉淀加入到N(CH2CH3)3和CH2Cl2的混合溶剂中,常温下反应12~18h,之后加入到乙醚中沉淀(1~3次),收集沉淀真空干燥得到PCL-NH2;
其中,ε-己内酯,N-Boc-乙醇胺和辛酸亚锡的投料比例为6.18~12.39(mL):0.48~0.96(mL):0.01~0.96(mL);
CH2Cl2和CF3COOH的混合溶剂中,CH2Cl2和CF3COOH的体积比为1~3:1;
N(CH2CH3)3和CH2Cl2的混合溶液中,N(CH2CH3)3和CH2Cl2的体积比为1:1;
具体的,收集沉淀是用细的砂芯漏斗进行抽滤;
步骤2:将L-Orn(Z)-OH和三光气混合,在氮气保护下加入无水四氢呋喃,50~60℃反应至溶液变澄清,用旋转蒸发仪除去部分溶剂,在乙醚中沉淀(1~3次),真空干燥后得到L-Orn(Z)-NCA;
其中,L-Orn(Z)-OH、三光气和无水四氢呋喃的投料比例为0.05~6(g):0.22~2.448(g):6~60(mL);
步骤3:将PCL-NH2、L-Orn(Z)-NCA和无水二甲亚砜混合,在氮气保护下,50~60℃反应48~72h,之后反应液依次在DMF、去离子水中透析,冷冻干燥,得到PCL-b-POrn(Z);
其中,PCL-NH2、L-Orn(Z)-NCA和无水二甲亚砜的投料比例为0.096~0.64(g):0.42~2.78(g):5.8~38(mL);
步骤4:将PCL-b-POrn(Z)加入CF3COOH中,在室温下搅拌至完全溶解,然后加入HBr/乙酸溶液,搅拌2~8h后用碱溶液中和,经去离子水透析后冷冻干燥,得到PCL-b-POrn;
其中,PCL-b-POrn(Z)、CF3COOH和HBr/乙酸溶液的投料比例为0.1~1.5(g):2~30(mL):0.6~9(mL);
HBr/乙酸溶液中,HBr的浓度为33wt%;
优选碱溶液为1~20mol/L氢氧化钠溶液;
步骤5:将PCL-b-POrn、1H-吡唑-1-甲脒盐酸盐(胍基化试剂)和DIPEA混合,在25~60℃反应24~48h,之后用去离子水透析,冷冻干燥得到PCL-b-PArg;
其中,PCL-b-POrn、1H-吡唑-1-甲脒盐酸盐和DIPEA的投料比例为0.123~0.633(g):0.028~0.145(g):0.065~0.337(mL);
步骤6:将PCL-b-PArg、2,3-二甲基马来酸酐、DIPEA溶解在DMSO和DCM的混合溶剂中,室温下持续搅拌24~36h,然后用去离子水透析,冷冻干燥后得到PCL-b-PArg-DA;
其中,PCL-b-PArg、2,3-二甲基马来酸酐、DIPEA、DMSO和DCM的投料比例为0.094~0.338(g):0.07513~0.304(g):0.188~0.564(mL):0.939~3.29(mL):1.88~6.58(mL);
步骤7:将PCL-b-PArg-DA、IR780(光热剂)和利奈唑胺溶解在DMSO中,得到混合溶液,搅拌下将去离子水加入到所得混合溶液中,室温下避光搅拌30~60min,经去离子水透析,冷冻干燥后得到利奈唑胺纳米给药系统DL-PCL-b-PArg-DA;
其中,PCL-b-PArg-DA、IR780、利奈唑胺和DMSO的投料比例为8~20(mg):1~4(mg):0.5~2(mg):1~4(mL)。
本发明涉及上述制备方法制得的利奈唑胺纳米给药系统。
本发明所述的利奈唑胺纳米给药系统可应用于制备治疗细菌感染的药物。
相对于现有技术,本发明的有益效果在于:
本发明制备了一种利奈唑胺纳米给药系统DL-PCL-b-PArg-DA,其在808nm近红外激光照射下,可实现利奈唑胺和光热疗法协同作用,大大提高了对大肠杆菌和金黄色葡萄球菌抗菌效果,并且能够抑制和破坏生物膜,为治疗细菌感染和解决细菌耐药性问题提供了很有前景的策略。
附图说明
图1是本发明所涉及的利奈唑胺纳米给药系统的制备路线示意图。
图2是本发明所涉及的利奈唑胺纳米给药系统的TEM图。
图3是本发明所涉及的利奈唑胺纳米给药系统的粒径图。
图4是本发明所涉及的不同条件下利奈唑胺纳米给药系统的体外释放,(a)IR780释放曲线;(b)利奈唑胺释放曲线。
图5是本发明所涉及的利奈唑胺纳米给药系统对金黄色葡萄球菌(S.aureus)的杀灭效果图。
图6是本发明所涉及的利奈唑胺纳米给药系统对大肠杆菌(E.coli)的杀灭效果图。
图7是本发明所涉及的利奈唑胺纳米给药系统对金黄色葡萄球菌和大肠杆菌的生物膜抑制率效果图。
图8是本发明所涉及的利奈唑胺纳米给药系统对金黄色葡萄球菌和大肠杆菌的生物膜消融率效果图。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。下面通过实施例对本发明作进一步的阐述,其目的仅在于更好地理解本发明的内容。因此,所举之例并不限制本发明的保护范围。
实施例1
ε-己内酯、N-Boc-乙醇胺和辛酸亚锡按照12.39mL:0.96mL:0.02mL的体积比混合在一起后,在氮气保护下120℃加热反应8h,然后自然冷却至凝固状态,用少量CH2Cl2溶解后,乙醚沉淀3次,真空干燥后最终得到白色粉末状的产物PCL-NH-Boc 13.6g,收率为98%。
将上述获得产物PCL-NH-Boc称取13.6g溶于27mL的CH2Cl2和CF3COOH(V/V,1/1)混合溶剂中,常温反应12h,乙醚沉淀3次后,加入26mL的N(CH2CH3)3和CH2Cl2(1/1,V/V)的混合溶液常温反应12h,用乙醚沉淀3次,真空干燥后得到白色粉末状产物PCL-NH2 12g,收率为89%。
实施例2
将6g L-Orn(Z)-OH和2.448g三光气加入三颈烧瓶中,在氮气保护下加入60mL无水四氢呋喃,50℃加热反应4小时至溶液变澄清。用旋转蒸发仪除去部分溶剂,在乙醚中沉淀三次后真空干燥得到淡黄色产物L-Orn(Z)-NCA5.8g,收率为88%。
实施例3
将0.64g PCL-NH2和2.78g L-Orn(Z)-NCA加入到三颈烧瓶中,在氮气保护下加入38mL无水二甲亚砜,50℃加热反应72h,反应后溶液先在DMF溶液中透析24h,再经去离子水透析48h,冷冻干燥48h得到产物PCL-b-POrn(Z)0.45g,收率为70%。
实施例4
将1.5g PCL-b-POrn(Z)溶解在30mL CF3COOH中,在室温下搅拌至将聚合物完全溶解,然后加入9mL HBr/乙酸溶液搅拌4h后用20moL/L饱和氢氧化钠溶液中和,后用去离子水透析24h,冷冻干燥得到产物PCL-b-POrn 0.6g,收率为40%。
实施例5
将PCL-b-POrn(0.633g)和1H-吡唑-1-甲脒盐酸盐(0.145g,6.9mmoL),DIPEA(0.337mL,13.86mmoL)混合,在55℃加热反应24h,去离子水透析24h,冷冻干燥得到产物PCL-b-PArg 0.338g收率为52%。
实施例6
将PCL-b-PArg(0.338g)、2,3-二甲基马来酸酐(0.304g,0.37mmoL)和DIPEA(0.564mL,0.47mmoL)溶解在DMSO(3.29mL)和DCM(6.58mL)。将混合物在室温下持续搅拌24小时,然后用去离子水继续透析24小时来纯化产物,冷冻干燥后得到产物PCL-b-PArg-DA0.136g,收率为37%。
实施例7
将PCL-b-PArg-DA(20mg)和IR780(4.0mg)以及利奈唑胺(2.0mg)溶解在DMSO(4mL)中,然后在剧烈搅拌下缓慢加入去离子水(18mL),在室温下避光搅拌30min。然后用去离子水透析12h,冷冻干燥后得到产物DL-PCL-b-PArg-DA 12mg,收率为46%。
实施例8
选择金黄色葡萄球菌(S.aureus)和大肠杆菌(E.coli)为模型,在NIR和非NIR照射条件下,评价DL-PCL-b-PArg-DA纳米给药系统的细菌杀灭效果。在96孔板中每孔加入100μL细菌菌液,设置三个组分别为对照组、实验组和PBS组,对照组加入100μL培养基,实验组加入由TSB培养基配置的浓度为125μg/mL的纳米溶液100μL,PBS组加入100μL PBS溶液。然后放至37℃细菌培养箱中培养3h,然后用808nm(1W/cm2,10min)的近红外光照射,非光照组不做光照处理,随后将每孔细菌溶液用无菌PBS稀释102倍,取100μL稀释后的细菌溶液均匀地涂布在TSA琼脂平板上,并将其置于细菌培养箱,培养18-24h后进行菌落计数。以上每组平行重复三次。
本实施例中纳米给药系统抑制金黄色葡萄球菌和大肠杆菌生长的菌落数实验如图5和图6所示,图中显示对照组和PBS组长出大量菌落,并且近红外光照射并不会对PBS组和对照组产生影响,未经808nm近红外激光照射的纳米给药系统的菌落数相比与对照组和PBS组有所减少,说明DL-PCL-b-PArg-DA纳米给药系统抗菌效果有限,但经过808nm近红外激光照射后细菌菌落数显著降低,这归因于其光热效应和利奈唑胺的协同作用增强了抗菌效果,因此说明经近红外光照射的纳米给药系统对金黄色葡萄球菌和大肠杆菌具有良好的抗菌效果。
申请人声明,本发明通过上述实施例来说明本发明的一种利奈唑胺纳米给药系统及其制备方法和应用,但本发明并不局限于上述实施例,即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了,对本发明的任何改进,对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等均在本发明的保护范围和公开范围之内。
Claims (10)
1.一种利奈唑胺纳米给药系统的制备方法,其特征在于,包括以下步骤:
步骤1:将ε-己内酯、N-Boc-乙醇胺和辛酸亚锡混合,氮气保护下,100~120℃反应4~8h,之后自然冷却至凝固状态,用CH2Cl2溶解后,加入到乙醚中进行沉淀,收集沉淀真空干燥,得到PCL-NH-Boc;将所得PCL-NH-Boc溶于CH2Cl2和CF3COOH的混合溶剂中,常温反应12~18h,然后加入到乙醚中进行沉淀,收集沉淀加入到N(CH2CH3)3和CH2Cl2的混合溶剂中,常温下反应12~18h,之后加入到乙醚中沉淀,收集沉淀真空干燥得到PCL-NH2;
步骤2:将L-Orn(Z)-OH和三光气混合,在氮气保护下加入无水四氢呋喃,50~60℃反应至溶液变澄清,用旋转蒸发仪除去部分溶剂,在乙醚中沉淀,真空干燥后得到L-Orn(Z)-NCA;
步骤3:将PCL-NH2、L-Orn(Z)-NCA和无水二甲亚砜混合,在氮气保护下,50~60℃反应48~72h,之后反应液依次在DMF、去离子水中透析,冷冻干燥,得到PCL-b-POrn(Z);
步骤4:将PCL-b-POrn(Z)加入CF3COOH中,在室温下搅拌至完全溶解,然后加入HBr/乙酸溶液,搅拌2~8h后用碱溶液中和,经去离子水透析后冷冻干燥,得到PCL-b-POrn;
步骤5:将PCL-b-POrn、1H-吡唑-1-甲脒盐酸盐和DIPEA混合,在25~60℃反应24~48h,之后用去离子水透析,冷冻干燥得到PCL-b-PArg;
步骤6:将PCL-b-PArg、2,3-二甲基马来酸酐、DIPEA溶解在DMSO和DCM的混合溶剂中,室温下持续搅拌24~36h,然后用去离子水透析,冷冻干燥后得到PCL-b-PArg-DA;
步骤7:将PCL-b-PArg-DA、IR780和利奈唑胺溶解在DMSO中,得到混合溶液,搅拌下将去离子水加入到所得混合溶液中,室温下避光搅拌30~60min,经去离子水透析,冷冻干燥后得到利奈唑胺纳米给药系统DL-PCL-b-PArg-DA。
2.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(1)中,ε-己内酯,N-Boc-乙醇胺和辛酸亚锡的投料比例为6.18~12.39(mL):0.48~0.96(mL):0.01~0.96(mL)。
3.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(2)中,L-Orn(Z)-OH、三光气和无水四氢呋喃的投料比例为0.05~6(g):0.22~2.448(g):6~60(mL)。
4.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(3)中,PCL-NH2、L-Orn(Z)-NCA和无水二甲亚砜的投料比例为0.096~0.64(g):0.42~2.78(g):5.8~38(mL)。
5.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(4)中,PCL-b-POrn(Z)、CF3COOH和HBr/乙酸溶液的投料比例为0.1~1.5(g):2~30(mL):0.6~9(mL)。
6.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(5)中,PCL-b-POrn、1H-吡唑-1-甲脒盐酸盐和DIPEA的投料比例为0.123~0.633(g):0.028~0.145(g):0.065~0.337(mL)。
7.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(6)中,PCL-b-PArg、2,3-二甲基马来酸酐、DIPEA、DMSO和DCM的投料比例为0.094~0.338(g):0.07513~0.304(g):0.188~0.564(mL):0.939~3.29(mL):1.88~6.58(mL)。
8.如权利要求1所述的利奈唑胺纳米给药系统的制备方法,其特征在于,步骤(7)中,PCL-b-PArg-DA、IR780、利奈唑胺和DMSO的投料比例为8~20(mg):1~4(mg):0.5~2(mg):1~4(mL)。
9.如权利要求1~8任一项所述的制备方法制得的利奈唑胺纳米给药系统。
10.如权利要求9所述的利奈唑胺纳米给药系统在制备治疗细菌感染的药物中的应用。
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