CN116602920B - 一种透皮肽修饰、含有Ce6和CpG的脂质体及应用 - Google Patents
一种透皮肽修饰、含有Ce6和CpG的脂质体及应用 Download PDFInfo
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Abstract
本发明适用于生物医药技术领域，提供了一种透皮肽修饰、含有Ce6和CpG的脂质体，包括以下原料：DPPC、胆固醇、DDAB、DSPE‑PEG‑TD1、Ce6、CpG。本发明还提供了一种透皮肽修饰、含有Ce6和CpG的脂质体的制备方法、及其作为药物载体在药物透皮输运上的应用。本发明选用DDAB使得脂质体表面带阳离子，更有利于透皮，Ce6经脂质体包封后可通过在病变位置直接透皮给药，在生物体的药物残留更少，更容易在肿瘤部位累积，选用CpG可以增强光动力治疗的免疫原性反应，选用透皮肽TD共轭的磷脂DSPE‑PEG‑TD1，打开细胞旁通路，完全促进药物通过皮肤，减少皮肤刺激和损伤。
Description
技术领域
本发明属于生物医药技术领域，尤其涉及一种透皮肽修饰、含有Ce6和CpG的脂质体及应用。
背景技术
Ce6(Chlorine6，二氢卟吩e6)通常可由脱镁叶绿酸a合成而得，是一种良好的光敏剂，生物活性与脱镁叶绿酸a相近，Ce6产生单线态氧的效率很高，因此适合开发用于肿瘤的光动力治疗，但同迄今为止的大部分光敏剂一样，Ce6表现为疏水性，并在溶液中容易聚集，因此在实际应用中有一定困难。
而脂质体(Liposomes)作为一种新兴的药物载体，其能够将亲脂性的药物包裹于磷脂双分子层之间，可以解决脂溶性光敏剂的溶解性和稳定性问题。而且，脂质体具有良好的生物相容性，具有挤压变形能力，且其结构与细胞膜相似，可以促进药物透皮。然而，虽然载药柔性纳米脂质体已实现疫苗、胰岛素、非类固醇类(比如布洛芬)和抗炎症类药物(比如双氯芬酸)等药物的透皮输运，但是由于脂质体尺寸较大，透皮效率依然不高；而且将载有光敏剂Ce6和免疫佐剂的脂质体用于透皮给药尚未见文献报道。
发明内容
本发明实施例的目的在于提供一种透皮肽修饰、含有Ce6和CpG的脂质体，旨在解决上述背景技术中存在的问题。
本发明实施例是这样实现的，一种透皮肽修饰、含有Ce6和CpG的脂质体，包括以下重量份的原料：DPPC8-20份、胆固醇2-5份、DDAB1-3份、DSPE-PEG-TD12-10份、Ce60.1-2份、CpG0.01-0.1份。
优选地，包括以下重量份的原料：DPPC10份、胆固醇2.5份、DDAB1.5份、DSPE-PEG-TD14份、Ce60.5份、CpG0.06份。
本发明实施例的另一目的在于提供一种透皮肽修饰、含有Ce6和CpG的脂质体的制备方法，包括以下步骤：
S1、溶解：将DPPC、胆固醇、DDAB、DSPE-PEG-TD1、Ce6溶于有机溶剂中，超声溶解；
S2、旋蒸：在预设温度下，将S1得到的物料进行缓慢旋转蒸发除去有机溶剂；
S3、真空干燥：将S2得到的物料进行真空干燥，除去残留的少量有机溶剂，形成干燥膜；
S4、水化：配制CpG去离子水溶液，CpG去离子水溶液中添加有吐温80，向S3得到的干燥膜中添加CpG去离子水溶液，进行旋转水合，得到脂质体悬浮液；
S5、微细化处理：将S4得到的脂质体悬浮液进行超声微细化处理，即可得到所述透皮肽修饰、含有Ce6和CpG的脂质体。
优选地，S1中，所述有机溶剂为氯仿和甲醇的混合溶液，溶液为3:1，超声溶解时间为1-5min。
优选地，超声溶解时间为2min。
优选地，S2中，所述旋转蒸发在旋转蒸发仪中进行，旋转蒸发仪的转数为150-200rpm，旋转蒸发的温度为35-40℃。
优选地，旋转蒸发仪的转数为200rpm，旋转蒸发的温度为36℃。
优选地，S3中，所述真空干燥的时间为20～40min。
优选地，真空干燥的时间为30min.
优选地，S4中，所述旋转水合的时间为20～40min。
优选地，旋转水合的时间为30min。
优选地，S5中，所述超声微细化处理在细胞粉碎仪中进行，超声微细化处理的时间为5～10min。
优选地，超声微细化处理的时间为8min(超3s，停2s)。
本发明实施例的又一目的在于提供一种透皮肽修饰、含有Ce6和CpG的脂质体作为药物载体在药物透皮输运上的应用，使用DSPE-PEG-TD1修饰的阳离子脂质体作为载药载体来实现Ce6的透皮给药，DSPE-PEG-TD1通过打开皮肤细胞旁路来实现，可促使载药透皮脂质体完整、安全和高效地透过皮肤。
本发明实施例提供的一种透皮肽修饰、含有Ce6和CpG的脂质体，解决了现有技术中Ce6水溶性差，常规脂质体透皮效率不高等问题，首次制备了透皮肽TD修饰的、含有Ce6和CpG的阳离子脂质体制剂，制备的透皮脂质体粒径在80-200nm之间，分散性指数(PDI)在0.1-0.3之间，Ce6包封率可达到95％；
选用透皮肽TD共轭的磷脂DSPE-PEG-TD1，与传统的物理化学透皮方法相比，生物透皮肽TD通过暂时打开细胞旁通路，促进药物通过皮肤，减少皮肤刺激和损伤；Ce6包封于脂质体双分子层之间，透皮脂质体呈类球形，可通过在病变位置直接透皮给药，在生物体的药物残留更少，减少药物的毒副反应，并更容易在肿瘤部位累积；选用CpG作为免疫佐剂，可以增强光动力治疗的免疫原性反应；此外，选用阳离子脂质DDAB(双十二烷基二甲基溴化铵)，使得脂质体表面带阳离子，更有利于透皮；
将本发明实施例制备的透皮脂质体进行抗肿瘤实验，将含有Ce6和CpG的透皮脂质体涂抹在患处并进行激光照射后，可以明显抑制小鼠原位肿瘤的生长并抑制其转移。
附图说明
图1为实施例1提供的Ce6-Lip-TD1-CpG冷冻电镜形貌图；
图2a为实施例1提供的Ce6-Lip-TD1-CpG及对照组Ce6-Lip-CpG的粒径表征图；图2b为实施例1提供的Ce6-Lip-TD1-CpG及对照组(游离CpG、Ce6-Lip-TD1、Ce6-Lip-CpG)的电势表征图；
图3a为实施例1提供的Ce6-Lip-TD1-CpG及对照组(游离Ce6、Ce6-Lip-CpG)在B16F10细胞中的细胞摄取效果图；图3b为实施例1提供的Ce6-Lip-TD1-CpG及对照组(游离Ce6、Ce6-Lip-CpG)在4T1细胞中的细胞摄取效果图；
图4a为实施例1提供的Ce6-Lip-TD1-CpG及对照组(游离Ce6、Ce6-Lip-CpG)在B16F10细胞中的体外光毒性结果图；图4b为实施例1提供的Ce6-Lip-TD1-CpG及对照组(游离Ce6、Ce6-Lip-CpG)在4T1细胞中的体外光毒性结果图；
图5a为体外透皮装置示意图；图5b为实施例1提供的Ce6-Lip-TD1-CpG与Ce6-Lip-CpG的体外透皮效果对比图；图5c为用Ce6-Lip-FITC、Ce6-Lip-TD1-FITC体外透皮后小鼠皮肤组织的共聚焦图像(绿色荧光对应FITC)；
图6a为不同治疗组(n＝5)的原发肿瘤生长曲线；图6b为不同治疗组的远端肿瘤生长曲线；图6c为不同治疗组小鼠的体重变化曲线；图6d为21天后从小鼠中分离出的肿瘤(A：PBS(laseron)处理组；B：Lip-CpG(laseron)处理组；C：Ce6-Lip-TD1-CpG(laseroff)处理组；D:Ce6-Lip-CpG(laseron)处理组；E：Ce6-Lip-TD1(laseron)处理组；F：Ce6-Lip-TD1-CpG(laseron)处理组)尺寸图；
图7a为治疗后原位肿瘤组织中CD8T细胞(红色)的免疫荧光染色检测；图7b为治疗后原位肿瘤切片中钙网蛋白(Calreticulin，CRT)(免疫原性细胞死亡的典型标志)(绿色)暴露的免疫荧光成像；图7c为治疗后原位肿瘤组织切片的炎症相关因子免疫荧光图像，比例尺＝50μm(蓝色：DAPI，绿色：IL-6-Alexa Fluor488，红色：TNF-α-Cy3)。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
以下结合具体实施例对本发明的具体实现进行详细描述。
实施例1、一种透皮肽修饰、含有Ce6和CpG的脂质体，其制备方法包括以下步骤：
准确称取10mgDPPC，2.5mg胆固醇，1.5mgDDAB，4mgDSPE-PEG-TD1，500μgCe6于50mL烧瓶中，加入3mL氯仿和1mL甲醇，超声溶解1min后，置于36℃旋转蒸发仪下，真空条件下200rpm缓慢蒸发除去氯仿和甲醇，直至瓶壁上形成一层均匀薄膜，室温真空干燥30min后，加入1mL含0.5％吐温80的10μM的CpG去离子水溶液，旋转水合30min得到脂质体悬浮液，移至细胞粉碎仪下超声8min(超3s，停2s)，将所得的澄清溶液10000rpm离心5min后取上清液，即得均匀透明的含Ce6及免疫佐剂CpG的纳米透皮脂质体Ce6-Lip-TD1-CpG。
对实施例1制备得到的透皮脂质体Ce6-Lip-TD1-CpG进行外观、微观形态、粒径/电位表征、细胞摄取试验、体外光毒性试验、体外透皮试验、体内抗肿瘤试验以及体内免疫试验等，具体如下：
(1)形态表征：
实施例1制备的透皮脂质体Ce6-Lip-TD1-CpG，肉眼观察可见为绿色均一混悬液，以空白脂质体作为对照组，其为白色均一混悬液，两者均无分层、絮凝、沉淀等现象，图1为Ce6-Lip-TD1-CpG的冷冻电镜形貌图，可以看出，Ce6-Lip-TD1-CpG呈球形或近球形，粒径介于80-200nm之间；
(2)粒径及Zeta电位的测定：
利用动态光散射仪(Malvern，英国)对Ce6-Lip-TD1-CpG进行分析，结果如图2所示，根据图2a可以看出，Ce6-Lip-TD1-CpG的平均水合粒径为130.1±4.06nm，根据图2b可以看出，平均Zeta电位为25±0.88mV；
(3)细胞摄取试验：
将B16F10细胞、4T1细胞分别按照1×104细胞/孔接种于含有新鲜细胞培养基(含有10％胎牛血清和1％抗生素的DMEM)的共聚焦小皿中，并在一定条件(37℃；5％的二氧化碳)下将其在细胞培养箱中培养24h，然后将含有10μM游离Ce6等效物的Ce6、Ce6-Lip-TD1-CpG和Ce6-Lip-CpG溶液加入皿中，细胞和样品共同培养2h后用PBS洗涤细胞两次，并用4％多聚甲醛溶液固定，20min后将固定液洗去，细胞用DAPI染料染色10min，然后用PBS洗3次，最后，在共聚焦显微镜下对处理后的B16F10细胞和4T1细胞进行观察和拍照记录，得到结果分别为如图3a、图3b所示，根据图3可以看出，相较于游离的Ce6，包封在脂质体的Ce6更易被细胞摄取；
(4)体外光毒性试验：
在试验(3)的基础上，对处理后的B16F10细胞和4T1细胞进行激光照射，得到结果分别为如图4a、图4b所示，根据图4可以看出，游离的Ce6由于未能被细胞摄取，在激光照射下不存在细胞杀伤效果，而同样浓度下包封在脂质体的Ce6在激光照射下具有很好的肿瘤细胞杀伤效果；
(5)体外透皮试验：
体外透皮装置如图5a所示；Ce6-Lip-TD1-CpG与Ce6-Lip-CpG的体外透皮效果对比如图5b所示，可以看出，Ce6-Lip-TD1-CpG与Ce6-Lip-CpG都随着时间逐渐穿透皮肤，但前者的穿透效率明显高于后者，表明共轭的TD肽可以增强脂质体的皮肤渗透性；24小时后，制备皮肤切片并通过荧光显微镜观察，结果如图5c所示，可以看出，Ce6-Lip-TD1-FITC和Ce6-Lip-FITC处理的皮肤组织均显示FITC荧光，这可能归因于阳离子柔性脂质体本身具有一定的透皮能力；然而，在Ce6-Lip-TD1-FITC处理组中观察到的荧光强度显著强于Ce6-Lip-FITC处理组，这进一步证实了TD肽的皮肤渗透增强，这些结果表明，具有TD功能化的Ce6-Lip-TD1-CpG脂质体显示出高的经皮渗透性；
(6)体内抗肿瘤试验：
采用双侧皮下肿瘤模型进行小鼠体内抗肿瘤研究：
双侧皮下肿瘤模型的建立：通过将B16F10细胞(1×106)皮下注射入C57BL/6小鼠的左背部来建立原发性肿瘤，在第6天，将B16F10细胞(2×105)皮下注入同一只小鼠的右背部建立远端肿瘤，肿瘤体积根据下式计算：宽度2×长度×0.5；
将B16F10荷瘤小鼠随机分为六组(n＝5)，一组660nm激光照射的PBS，二组660nm激光照射的空脂质体，三组660nm激光照射的Ce6-Lip-CpG，四组660nm激光照射的Ce6-Lip-TD1，五组无光照射的Ce6-Lip-TD1-CpG，六组660nm激光照射的Ce6-Lip-TD1-CpG，然后，将等分试样的治疗剂涂抹于小鼠肿瘤表面，在治疗期间每两天记录一次肿瘤大小和体重，并且当肿瘤体积超过伦理体积时对小鼠实施安乐死；
记录结果如图6所示，可以看出，两周后，660nm激光照射Ce6-Lip-TD1和660nm激光照射Ce6-Lip-TD1-CpG组原位皮下肿瘤的大小和重量要明显小于660nm激光照射PBS组、660nm激光照射空脂质体组、660nm激光照射Ce6-Lip-CpG组和无光照射Ce6-Lip-TD1-CpG组，而660nm激光照射Ce6-Lip-TD1-CpG组对远端肿瘤的抑制效果又要好于660nm激光照射Ce6-Lip-TD1组，表明免疫佐剂CpG增强了免疫反应效果；
(7)体内免疫相关试验：
对试验(6)治疗后的小组进行原位肿瘤组织切片与免疫荧光染色，得到结果如图7所示，可以看出，660nm激光照射Ce6-Lip-TD1和Ce6-Lip-TD1-CpG组的淋巴细胞浸润、CRT暴露及肿瘤相关炎症因子的增加均强于其他对照组，且后者的增强效果优于前者，表明光动力治疗本身可以诱导免疫原性细胞死亡，且CpG的存在增强了这一免疫反应。
实施例2、一种透皮肽修饰、含有Ce6和CpG的脂质体，其制备方法包括以下步骤：
准确称取8mgDPPC，2mg胆固醇，1mgDDAB，2mgDSPE-PEG-TD1，100μgCe6于50mL烧瓶中，加入3mL氯仿和1mL甲醇，超声溶解2min后，置于35℃旋转蒸发仪下，真空条件下150rpm缓慢蒸发除去氯仿和甲醇，直至瓶壁上形成一层均匀薄膜，室温真空干燥20min后，加入1mL含0.5％吐温80的10μM的CpG去离子水溶液，旋转水合20min得到脂质体悬浮液，移至细胞粉碎仪下超声5min(超3s，停2s)，将所得的澄清溶液10000rpm离心5min后取上清液，即得均匀透明的含Ce6及免疫佐剂CpG的纳米透皮脂质体Ce6-Lip-TD1-CpG。
实施例3、一种透皮肽修饰、含有Ce6和CpG的脂质体，其制备方法包括以下步骤：
准确称取20mgDPPC，5mg胆固醇，3mgDDAB，10mgDSPE-PEG-TD1，2mgCe6于50mL烧瓶中，加入3mL氯仿和1mL甲醇，超声溶解5min后，置于40℃旋转蒸发仪下，真空条件下150rpm缓慢蒸发除去氯仿和甲醇，直至瓶壁上形成一层均匀薄膜，室温真空干燥40min后，加入1mL含0.5％吐温80的10μM的CpG去离子水溶液，旋转水合40min得到脂质体悬浮液，移至细胞粉碎仪下超声10min(超3s，停2s)，将所得的澄清溶液10000rpm离心5min后取上清液，即得均匀透明的含Ce6及免疫佐剂CpG的纳米透皮脂质体Ce6-Lip-TD1-CpG。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (8)
1.一种透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，包括以下重量份的原料：DPPC 8-20份、胆固醇2-5份、双十二烷基二甲基溴化铵1-3份、DSPE-PEG-TD1 2-10份、Ce60.1-2份、CpG 0.01-0.1份；
所述透皮肽修饰、含有Ce6和CpG的脂质体的制备方法，包括以下步骤：
S1、溶解：将DPPC、胆固醇、双十二烷基二甲基溴化铵、DSPE-PEG-TD1、Ce6溶于有机溶剂中，超声溶解；
S2、旋蒸：在预设温度下，将S1得到的物料进行缓慢旋转蒸发除去有机溶剂；
S3、真空干燥：将S2得到的物料进行真空干燥，除去残留的少量有机溶剂，形成干燥膜；
S4、水化：配制CpG去离子水溶液，CpG去离子水溶液中添加有吐温80，向S3得到的干燥膜中添加CpG去离子水溶液，进行旋转水合，得到脂质体悬浮液；
S5、微细化处理：将S4得到的脂质体悬浮液进行超声微细化处理，即可得到所述透皮肽修饰、含有Ce6和CpG的脂质体。
2.根据权利要求1所述的透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，包括以下重量份的原料：DPPC 10份、胆固醇2.5份、双十二烷基二甲基溴化铵1.5份、DSPE-PEG-TD1 4份、Ce6 0.5份、CpG 0.06份。
3.根据权利要求1所述的透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，S1中，所述有机溶剂为氯仿和甲醇的混合溶液，溶液为3:1，超声溶解时间为1-5min。
4.根据权利要求1所述的透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，S2中，所述旋转蒸发在旋转蒸发仪中进行，旋转蒸发仪的转数为150-200rpm，旋转蒸发的温度为35-40℃。
5.根据权利要求1所述的透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，S3中，所述真空干燥的时间为20～40min。
6.根据权利要求1所述的透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，S4中，所述旋转水合的时间为20～40min。
7.根据权利要求1所述的透皮肽修饰、含有Ce6和CpG的脂质体，其特征在于，S5中，所述超声微细化处理在细胞粉碎仪中进行，超声微细化处理的时间为5～10min。
8.一种如权利要求 1 或 2 所述的透皮肽修饰、含有 Ce6 和 CpG 的脂质体在制备药物透皮输运的载体中的应用。
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| CN1665531A (zh) * | 2002-05-10 | 2005-09-07 | 伊内克斯药物公司 | 甲基化的免疫刺激性寡核苷酸和利用这些寡核苷酸的方法 |
| CN114272211A (zh) * | 2021-12-30 | 2022-04-05 | 安徽医科大学第一附属医院 | 一种td-1修饰的脂质体载药系统、制备方法及其应用 |
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| US20080274169A1 (en) * | 2007-05-04 | 2008-11-06 | Ceramoptec Industries Inc. | Photosensitizer formulations for topical applications |
| TWI442945B (zh) * | 2011-05-18 | 2014-07-01 | Univ Nat Taiwan | 雙效微脂體用於治療的方法 |
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| CN114272211A (zh) * | 2021-12-30 | 2022-04-05 | 安徽医科大学第一附属医院 | 一种td-1修饰的脂质体载药系统、制备方法及其应用 |
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