CN105561306A - 一种含有单线态氧保护剂的组合物及其制备方法 - Google Patents
一种含有单线态氧保护剂的组合物及其制备方法 Download PDFInfo
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- CN105561306A CN105561306A CN201610028413.XA CN201610028413A CN105561306A CN 105561306 A CN105561306 A CN 105561306A CN 201610028413 A CN201610028413 A CN 201610028413A CN 105561306 A CN105561306 A CN 105561306A
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- photosensitizer
- preparation
- emulsifying agent
- singlet oxygen
- protective agent
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Abstract
本发明涉及一种利用保护剂可以使得单线态氧孵育在其中并能明显延长单线态氧的寿命的特性,提供大量的持久性的单线态氧,进而增强光动力治疗疗效。组合物是由具有延长单线态氧寿命的功能性物质、乳化剂和光敏剂组成,通过乳化剂将功能性物质制成乳剂,与光敏剂协同递送到肿瘤组织内,由此光动力疗法将可以利用具有延长单线态氧寿命的功能性物质中所孵育的大量单线态氧进行光动力治疗,从而提高光动力治疗的药效。
Description
技术领域
本发明的技术目的在于利用1O2保护剂大幅提高单线态氧的寿命用于增效光动力治疗的方法,属于光动力疗法的增效及其临床应用领域。具体来说,本发明是一种利用保护剂的延长单线态氧能力,以及用乳化的方法将保护剂、光敏剂和乳化剂制备成纳米粒或微米粒以增效光动力治疗的方法。
背景技术
光动力治疗是一种具有时空选择性的肿瘤治疗方案,它通过递送光敏剂至肿瘤组织,进一步利用可见/近红外激光对肿瘤部位进行辐照,此时光敏剂吸收光子跃迁至激发态,激发态光敏剂可以将能量传递给处于基态的氧气(三线态氧气),将其激发到激发态(单线态氧)。单线态氧具有很高的氧化性和反应活性,可以迅速地氧化肿瘤组织里的核酸、蛋白质、脂质,导致肿瘤坏死凋亡,但单线态氧的寿命也极短(0.1-20μs)。因此,光动力治疗的疗效与肿瘤组织内的单线态氧寿命密切相关,肿瘤组织内单线态氧寿命越长,光动力治疗的疗效也就越高。
单线态氧在溶液中的寿命与光敏剂种类相关性较小,而主要取决于溶剂的种类。保护剂是可以延长单线态氧寿命的物质,此类材料一般是但不限于是不溶于水、不溶解光敏剂的惰性材料,并且拥有孵育单线态氧并大幅提高其寿命的能力。可以有效地提高单线态氧的寿命从而提高药效。
发明内容
本发明的技术目的在于提供一种包含光敏剂、乳化剂和保护剂组合物及其制备方法,所述保护剂可有效延长单线态氧寿命用于增效光动力治疗,以解决目前光敏剂分子在肿瘤介质中产生的单线态氧寿命太短导致光动力疗效十分有限的问题。
为了实现本发明的技术目的,本发明的技术方案为:
一种含有单线态氧保护剂的组合物的制备方法,包括以下步骤:
(a)用一种溶剂溶解光敏剂、乳化剂获得混合溶液;
(b)向获得的混合溶液中加入适量保护剂,并在冰浴的情况下用适当的方法乳化保护剂,形成纳米粒者微米粒。
具体地,所述步骤(a)操作中的溶剂是二氯甲烷、三氯甲烷、乙醇、甲醇、丙醇或它们的混合中的一种或几种。
具体地,所述步骤(b)中的乳化方法是挤出法、超声法、或者高速分散法等。
本发明技术方案中所述的脂质体纳米粒的平均粒径为20nm-2000nm,优化的粒径为35-800nm,最优的是为50-300nm。
本发明技术方案中所述的脂质体纳米粒中保护剂所占体积比为1%-35%。
本发明技术方案中所述的步骤(a)中的光敏剂其特征在于所述光敏物质为安全无毒的能被光激活产生光化学反应的所有物质,这些光敏剂可为亲水性、亲油性、两亲性的。所述的光敏剂选自卟啉及其衍生物如ICG、Ce6、5-ALA、叶绿素及其衍生物如脱镁叶绿素和二氢卟酚及紫红素18、蒽醌及其衍生物;酞菁及其衍生物如锌酞菁和酞菁铝;内源性光敏剂如5-氨基乙酰丙酸、藻胆蛋白如藻红蛋白和藻蓝蛋白、五氮齿类衍生物如镥III五氮齿、醌类化合物、玫瑰红、富勒烯、聚乙炔类如苯庚三炔、噻吩类化合物如α噻吩;无机光敏剂如氧化钛(TiO2)、氧化锌;或选自中草药类光敏剂的竹红菌素衍生物、补骨脂素、姜黄素、金丝桃素、假金丝桃素、大黄素、核黄素、芦荟大黄素;七甲川菁类如IR780、IR775等。这些光敏剂或近红外染料都适用于本发明。
其中,优选的光敏剂是IR780、IR775、酞菁等.
本发明技术方案中所述的步骤(a)中的乳化剂是脂质类:DSPE-PEG2000,卵磷脂,胆固醇,DSPC,DPPC,DSPE等;蛋白类:人血白蛋白、血红蛋白、转铁蛋白、免疫球蛋白、胰岛素、血管内皮抑制素、肌红蛋白、纤维连接蛋白、胶原蛋白、明胶、人造多肽和蛋白,或者他们的组合等;高分子类:聚乙烯醇PVA,泊洛沙姆、吐温、司盘、苄泽,卖泽、聚氧乙烯、蓖麻油等。
其中优选的载体乳化剂是磷脂、DSPE-PEG2000和白蛋白。
另外,为了使本发明的组合物可以靶向特定的肿瘤组织或病变部位如肝肿瘤、肾肿瘤、骨肿瘤、乳腺癌和子宫肌瘤等,还可在该组合物中加入对所述的肿瘤组织或病灶部位有特异亲和性的物质,如识别肿瘤的抗体、肽、配体、适体(aptamcr)等而形成的靶向物质;为使本发明的高效光敏剂具有生物膜穿透功能,还可加入具有生物膜穿透功能的物质对其进行修饰而得的各种具有生物膜穿透功能的组合物。所述具有生物膜穿透功能的物质衍生自(但不仅限于)流感病毒、VSV、SFV、仙台病毒和HIV病毒,或选自人工合成的穿膜肽。
在本发明中,所述含具有延长单线态氧寿命的保护剂、光敏剂和乳化剂的组合物可以是通过保护剂、乳化剂和光敏物质混和而成的组合物,也可以是通过(但不仅限于)化学方法或物理方法使含有延长单线态氧寿命的保护剂、乳化剂和光敏物质构建成一个整体而形成的组合物,可以是微泡、微囊、微粒、微乳以及纳米粒和纳米乳。光敏物质包裹或粘附于微泡、微囊、微粒、微乳以及纳米粒和纳米乳内部或表面。微泡、微囊、微粒、微乳以及纳米粒和纳米乳可为(但不仅限于)直接市场现有的产品,也可为自制的,其膜材料可为脂类、多聚物、白蛋白、多糖。其芯材料所采用具有携氧功能的气体、液体或纳米级生物相容性固体中的一种或几种。
下面是对本发明技术方案进一步描述:
除上述总的技术方案以外,本发明进一步提出了一种利用保护剂有效延长单线态氧寿命用于增效光动力治疗的方法,所述方法包括以下步骤:(a)在温度是10-35℃,pH3-10的条件下,用一种溶剂溶解光敏剂、乳化剂获得混合溶液;利用两亲性脂质同时作为携载疏水性光敏剂的载体和保护剂的乳化剂;有机溶剂同时溶解脂溶性光敏剂和两亲性乳化剂(b)将以上混合溶液置于合适的圆底烧瓶中并抽真空恒温水浴锅内除去溶剂,可使光敏剂均匀分散到乳化剂的疏水端中乳化剂和光敏剂在圆底烧瓶底部形成一层均匀的薄膜。(c)向上述圆底烧瓶内加入适量溶剂,并用超声水化10-15min,可使乳化剂脱落,分散于水中形成胶束、囊泡等结构使脂质薄膜完全从瓶壁脱落,并均匀分散在溶剂中;(d)在温度是2-35℃,pH3-9的条件下向步骤(c)获得的混合溶液中加入适量保护剂,并用高速分散器进行高速分散,可利用亲水-疏水相互作用,使得乳化剂包裹保护剂,形成纳米或微米乳滴。通过乳化时间、输出功率、转速等因素的控制,可以制得粒径均一的纳米或微米乳剂。这种纳米乳同时携带保护剂和光敏剂,并可以通过静脉注射后的EPR效应蓄积到肿瘤部位。进行光动力治疗时,由于保护剂可进一步有效延长单线态氧寿命,进而产生高效的光动力疗效。
本技术方案中形成的纳米粒或微米粒的平均粒径为20nm-2000nm,其中保护剂的体积比约为1%-35%。
本技术方案步骤(a)中的溶剂包括但不局限于二氯甲烷、三氯甲烷、乙醇、甲醇、丙醇或它们的混合。本技术方案步骤本技术方案步骤(b)中的除去溶剂的方法包括但不局限于喷雾干燥、水浴干燥、减压干燥和水浴减压干燥等。
本技术方案步骤(c)中的溶剂包括但不局限于是水、生理盐水、醋酸盐、生理葡萄糖、磷酸盐缓冲液或TRIS缓冲液。本技术方案步骤(c)中的溶解瓶壁上光敏剂和乳化剂形成的薄膜的操作方法包括但不局限于是超声水化法、涡旋振荡法、水洗法。本发明技术方案中所述的步骤(d)中的保护剂包括但不局限于是石蜡、碘油、大豆油、二氯甲烷、氯仿、全氟化物、重水,其中全氟化物包括但不限于是全氟烷烃类、全氟胺类、全氟冠醚类、溴代全氟烷烃。其中优选的全氟化物是全氟己烷和全氟三丁胺。其中文献报道单线态氧在各种溶剂中的寿命,水:2μs,重水20μs,甲醇7μs,乙醇12μs,己烷17μs,氯仿60±15μs,全氟己烷600±200μs,二硫化碳200±60μs,Freon111000±200μs。保护剂在本技术方案步骤(d)中的乳化方法包括但不局限于是挤出法、超声法、高速分散法等。其中,优选的操作是超声法和高速分散法法。
本发明的另一目的是提供上述方法制备出的组合物,该组合物可有效延长单线态氧寿命用于增效光动力治疗。
本领域技术人员能够意识到本发明的范围和精髓是变动的。同时可以溶解光敏剂和乳化剂的有机溶剂是多种的,许多种光敏剂和乳化剂都是可使用的,同时许多类保护剂是可以用来增加单线态氧寿命的,多重操作方法都是可行的。本发明将会在下面的实施例中得到更加明确的和清晰的描述。
本发明的有益效果在于:
首先,经本发明提供的方法形成的纳米或者微米粒子中的保护剂体积比最高可以达到35%,形成了一种高效低耗的方法;其次,保护剂不仅可以十分有效的提高单线态氧的寿命,也可以提高单线态氧的产率。由于以上优势,在较小的剂量给药情况下极大地提高的光动力的疗效。
附图说明
图1.为本发明中脂质体-全氟己烷-IR780纳米粒的粒径分布图(30%全氟己烷体积比)。
图2.为本发明中白蛋白-全氟三丁胺-IR780纳米粒的粒径分布图(30%全氟三丁胺体积比)。
图3.本发明中脂质体-全氟己烷-IR780纳米粒与其他不同组样品在持续近红外光照射条件下产生单线态氧折线图。
图4.为为本发明中白蛋白-全氟三丁胺-IR780纳米粒与其他不同组样品在持续近红外光照射条件下产生单线态氧折线图。
图5.为本发明中脂质体-石蜡-IR780纳米粒与其他不同组样品在梯度稀释相同近红外光照射条件下产生单线态氧柱状图。
图6.为本发明中脂质体-碘油-IR780纳米粒与脂质体-IR780纳米粒在乏氧条件下持续近红外光照射条件下产生单线态氧折线图。
图7.为本发明中脂质体-全氟己烷-IR780纳米粒、脂质体-IR780纳米粒和IR780溶液的紫外吸收图。
图8.为本发明中不同浓度的脂质体-全氟己烷-IR780纳米粒和IR780溶液产生单线态氧的折线图。
具体实施方式
以下均是基于本发明的代表性实施例,但下述实施例不会在任何方面限制本发明的保护范围。
实施例1.含50ug/mlIR780,30v/v%脂质体-全氟己烷-IR780纳米粒的制备
在pH值为6,温度24℃下,向25ml圆底烧瓶中加入24.65mg卵磷脂,4.28mg胆固醇,3.79mgDSPE-PEG2000以及100ugIR780,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.4ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分六次加入共0.6ml全氟己烷(每次0.1ml),每次加入全氟己烷高速分散2min。0.6ml全氟己烷加完后,再继续高速分散冰浴下10~15min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,而且载光敏剂的粒子平均粒径为50-2000nm,(BIC90plusParticleSizeAnalyzer)。
实施例2.含50ug/mlIR775,30v/v%脂质体-石蜡-IR780纳米粒的制备
在25ml圆底烧瓶中加入24.65mg卵磷脂,4.28mg胆固醇,3.79mgDSPE-PEG2000以及100ugIR780,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR775的脂质薄膜。加入1.4ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分六次加入共0.6ml石蜡(每次0.1ml),每次石蜡加入后高速分散2min。0.6ml石蜡加毕后,再继续高速分散冰浴下8~10min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,而且载光敏剂的粒子平均粒径为200-2000nm,(BIC90plusParticleSizeAnalyzer)。
实施例3.含50ug/mlIR780,30v/v%脂质体-全氟三丁胺-IR780纳米粒的制备
在25ml圆底烧瓶中加入24.65mg卵磷脂,4.28mg胆固醇,3.79mgDSPE-PEG2000以及100ugIR780,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.4ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分六次加入共0.6ml全氟三丁胺(每次0.1ml),每次全氟三丁胺加入后高速分散2min。0.6ml全氟己烷加毕后,再继续高速分散冰浴下10~15min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,而且载光敏剂的粒子平均粒径为300-1200nm,(BIC90plusParticleSizeAnalyzer)。
实施例4.含50ug/mlIR780,30v/v%脂质体-碘油-IR780纳米粒的制备
在25ml圆底烧瓶中加入24.65mg卵磷脂,4.28mg胆固醇,3.79mgDSPE-PEG2000以及100ugIR780,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.4ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分六次加入共0.6ml碘油(每次0.1ml),每次碘油加入后高速分散2min。0.6ml碘油加毕后,再继续高速分散冰浴下10~15min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,而且载光敏剂的粒子平均粒径为300-1200nm,(BIC90plusParticleSizeAnalyzer)。
实施例5.含50ug/mlIR780,30v/v%白蛋白-大豆油-IR780纳米粒的制备
向3mlEP管中加入1.4ml的20mg/ml人血白蛋白水溶液以及100ugIR780,在常温下使用涡旋仪混合30min。在冰浴下,利用超声乳化,300W。分六次加入共0.6ml大豆油(每次0.1ml),每次大豆油加入后超声乳化1min。0.6ml大豆油加毕后,在冰浴下继续超声乳化2-5min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,用BIC90plusParticleSizeAnalyzer分析,载光敏剂的粒子平均粒径为170-250nm。
实施例6.含50ug/mlIR780,30v/v%白蛋白-全氟三丁胺-IR775纳米粒的制备
向3mlEP管中加入1.4ml的20mg/ml人血白蛋白水溶液以及100ugIR775,在常温下使用涡旋仪混合30min。在冰浴下,利用超声乳化,300W。分六次加入共0.6ml全氟三丁胺(每次0.1ml),每次全氟三丁胺-加入后超声乳化1min。0.6ml全氟三丁胺加毕后,在冰浴下继续超声乳化2-5min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,用BIC90plusParticleSizeAnalyzer分析,载光敏剂的粒子平均粒径为30-300nm。
实施例7.含50ug/mlIR780,30v/v%白蛋白-重水-IR780纳米粒的制备
向3mlEP管中加入1.4ml的20mg/ml人血白蛋白水溶液以及100ugIR780,在常温下使用涡旋仪混合30min。在冰浴下,利用超声乳化,300W。分六次加入共0.6ml重水(每次0.1ml),每次重水加入后超声乳化1min。0.6ml重水加毕后,在冰浴下继续超声乳化2-5min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,用BIC90plusParticleSizeAnalyzer分析,载光敏剂的粒子平均粒径为300-1500nm。
实施例8.含50ug/mlIR780,30v/v%脂质体-氯仿-IR780纳米粒的制备
在25ml圆底烧瓶中加入24.65mg卵磷脂,4.28mg胆固醇,3.79mgDSPE-PEG2000以及100ugIR780,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.4ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分六次加入共0.6ml氯仿(每次0.1ml),每次氯仿加入后高速分散2min。0.6ml氯仿加毕后,再继续高速分散冰浴下10~15min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,而且载光敏剂的粒子平均粒径为100-2000nm,(BIC90plusParticleSizeAnalyzer)。
实施例8.含50ug/mlIR780,30v/v%脂质体-氯仿-IR780纳米粒的制备
在25ml圆底烧瓶中加入24.65mg卵磷脂,4.28mg胆固醇,3.79mgDSPE-PEG2000以及100ugIR780,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.4ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分六次加入共0.6ml氯仿(每次0.1ml),每次氯仿加入后高速分散2min。0.6ml氯仿加毕后,再继续高速分散冰浴下10~15min直至粒径均一,溶液稳定。得到的悬液迎光呈光亮透明,而且载光敏剂的粒子平均粒径为550-5000nm,(BIC90plusParticleSizeAnalyzer)。
实施例9.含50ug/mlIR780,20v/v%,泊洛沙姆-全氟己烷-酞菁锌纳米粒的制备
在25ml圆底烧瓶中加入35mg泊洛沙姆以及100ugIR780,用5ml三氯甲烷完全溶解。之后通过旋转减压蒸发,除去三氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.6ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分4次加入共0.4ml全氟己烷(每次0.1ml),每次全氟己烷加入后高速分散2min。0.4ml全氟己烷加毕后,再继续高速分散冰浴下3-5min直至粒径均一,溶液稳定。载光敏剂的粒子平均粒径为150-1000nm,(BIC90plusParticleSizeAnalyzer)。
实施例10.含50ug/mlIR780,20v/v%,吐温-全氟己烷-金丝桃素纳米粒的制备
在25ml圆底烧瓶中加入47mg吐温以及100ug金丝桃素,用5ml二氯甲烷完全溶解。之后通过旋转减压蒸发,除去二氯甲烷,在圆底烧瓶上形成携载了IR780的脂质薄膜。加入1.6ml生理盐水,并用超声水化10min,使脂质薄膜完全从瓶壁脱落,并均匀分散在生理盐水中。在冰浴下,利用高速分散器对溶液进行高速分散。分4次加入共0.4ml全氟己烷(每次0.1ml),每次全氟己烷加入后高速分散2min。0.4ml全氟己烷加毕后,再继续高速分散冰浴下10-15min直至粒径均一,溶液稳定。载光敏剂的粒子平均粒径为550-5000nm,(BIC90plusParticleSizeAnalyzer)。
附加实验表明脂质体、蛋白和大分子等均能作为乳化剂,且用脂质体和白蛋白做载体乳化剂得到的粒径较小。
在制备过程中,我们考察了不同的缓冲液(水、生理盐水、生理葡萄糖、磷酸盐缓冲液、醋酸缓冲液和TRIS缓冲液等)对粒子粒径的影响,结果表明,生理盐水较好。
Claims (11)
1.一种含有单线态氧保护剂的组合物的制备方法,所述组合物由乳化剂、光敏剂和保护剂组成,其特征在于,制备方法包括以下步骤:
(a)用溶剂溶解光敏剂、乳化剂获得混合溶液;
(b)向上述的混合溶液中加入1O2保护剂,在冰浴下乳化保护剂制成组合物。
2.根据权利要求1所述的制备方法,其特征在于,所述的步骤(a)操作中的溶剂是二氯甲烷、三氯甲烷、乙醇、甲醇、丙醇中的一种或几种。
3.根据权利要求1所述的制备方法,其特征在于,步骤(b)中的乳化方法是挤出法、超声法或者高速分散法。
4.根据权利要求1所述的制备方法,其特征在于,所述的步骤(a)中的光敏剂光敏剂为亲水性、亲油性或者两亲性的,选自卟啉及其衍生物中的ICG、Ce6、5-ALA;叶绿素及其衍生物中的脱镁叶绿素、二氢卟酚及紫红素18、蒽醌及其衍生物;酞菁及其衍生物中的锌酞菁、酞菁铝;内源性光敏剂中的5-氨基乙酰丙酸、藻胆蛋白中的藻红蛋白、藻蓝蛋白、五氮齿类衍生物中的镥III五氮齿、醌类化合物、玫瑰红、富勒烯;聚乙炔类中的苯庚三炔、噻吩类化合物中的α噻吩;无机光敏剂中的氧化钛(TiO2)、氧化锌;或选自中草药类光敏剂中的的竹红菌素衍生物、补骨脂素、姜黄素、金丝桃素、假金丝桃素、大黄素、核黄素、芦荟大黄素;七甲川菁类中的IR780、IR775中的一种或几种。
5.根据权利要求4所述的制备方法,其特征在于,所述的光敏剂为IR780、IR775、酞菁中的一种或几种。
6.根据权利要求1所述的制备方法,其特征在于,所述的步骤(a)操作中的乳化剂为脂质类:DSPE-PEG2000,卵磷脂,胆固醇,DSPC,DPPC,DSPE;蛋白类:人血白蛋白、血红蛋白、转铁蛋白、免疫球蛋白、胰岛素;高分子类:聚乙烯醇PVA,泊洛沙姆、吐温、司盘、苄泽,卖泽、聚氧乙烯、蓖麻油中的一种或几种。
7.根据权利要求6所述的制备方法,其特征在于,所述的乳化剂是磷脂、DSPE-PEG2000、白蛋白中的一种或几种。
8.根据权利要求1所述的制备方法,其特征在于所述的步骤(b)操作中的单线态氧保护剂包括石蜡、碘油、大豆油、二氯甲烷、氯仿、全氟化物、重水、Freon11中的一种或几种。
9.根据权利要求1所述的制备方法,其特征在于所述保护剂作为微泡、微囊、微粒、微乳以及纳米粒和纳米乳的芯材料,或者作为其成膜材料组分,或者粘附于成膜材料之上。
10.根据权利要求1-9任一项所述的制备方法,其特征在于,具体制备方法如下:
(a)在温度是10-35℃,pH3-10的条件下,用溶剂溶解光敏剂、乳化剂获得混合溶液;利用两亲性脂质同时作为携载疏水性光敏剂的载体和保护剂的乳化剂;有机溶剂同时溶解脂溶性光敏剂和两亲性乳化剂;
(b)将以上混合溶液置于合适的圆底烧瓶中并抽真空恒温水浴锅内除去溶剂,使光敏剂均匀分散到乳化剂的疏水端中乳化剂和光敏剂在圆底烧瓶底部形成一层均匀的薄膜;
(c)向上述圆底烧瓶内加入溶剂,并用超声水化10-15min,使乳化剂脱落,分散于水中形成胶束、囊泡等结构使脂质薄膜完全从瓶壁脱落,并均匀分散在溶剂中;
(d)在温度是2-35℃,pH3-9的条件下向步骤(c)获得的混合溶液中加入保护剂,并用高速分散器进行分散,利用亲水-疏水相互作用,使得乳化剂包裹保护剂,形成纳米或微米乳滴。
11.权利要求1所述方法制备出的组合物,其特征在于,所述组合物用于增效光动力治疗。
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WO2017121246A1 (zh) * | 2015-01-16 | 2017-07-20 | 南京大学 | 一种含有单线态氧保护剂的组合物及其制备方法 |
CN108114273A (zh) * | 2018-02-02 | 2018-06-05 | 南京大学 | 一种全氟化碳白蛋白纳米粒及其制备方法与应用 |
CN108245484A (zh) * | 2017-12-27 | 2018-07-06 | 国家纳米科学中心 | 一种纳米药物组合物及其制备方法与应用 |
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