CN114983940B - 一种生物活性纳米胶束及其合成方法 - Google Patents
一种生物活性纳米胶束及其合成方法 Download PDFInfo
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- CN114983940B CN114983940B CN202210750351.9A CN202210750351A CN114983940B CN 114983940 B CN114983940 B CN 114983940B CN 202210750351 A CN202210750351 A CN 202210750351A CN 114983940 B CN114983940 B CN 114983940B
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
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- C08G65/335—Polymers modified by chemical after-treatment with organic compounds containing phosphorus
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- C—CHEMISTRY; METALLURGY
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Abstract
本发明公开了一种生物活性纳米胶束及其合成方法,该纳米胶束由功能性修饰的六氯磷腈或三聚氯氰两亲聚合物自组装形成。该功能性两亲聚合物是以六氯磷腈或三聚氯氰化合物为母核,通过逐步亲和取代反应连接不同比例的亲水性聚乙二醇链、过氧化氢清除/响应性基团苯硼酸酯衍生物以及超氧化物歧化酶样的2,2,6,6‑四甲基哌啶‑1‑氧自由基所构成。该两亲聚合物的制备方法简单,结构和功能便于调控,且易于规模化合成。此外,该两亲聚合物可通过分子间作用在水溶液中自组装形成纳米胶束,且具有炎症和氧化应激微环境调节功能,从而可用于治疗炎症或氧化应激损伤相关疾病,且具有良好的体内安全性。
Description
技术领域
本发明涉及一种生物活性纳米胶束,具体是一种炎症微环境调节功能纳米胶束的组成、合成及其在治疗炎症或氧化应激损伤相关疾病中的应用。
背景技术
活性氧(ROS)是一类高活性的分子。在正常生理条件下,细胞内活性氧处于氧化还原稳态的一个狭小的范围内,通过内源性抗氧化剂如超氧化物歧化酶(SOD)、过氧化氢酶(CAT)、过氧化物酶(POD)、谷胱甘肽(GSH)、维生素C、维生素E等维持着细胞内ROS产生和消除之间的平衡,且对血管调节、免疫功能、氧感知、基因激活和细胞生长等生理过程起到关键性作用。然而,ROS的过量产生会诱导氧化应激,它是体内氧化作用和抗氧化作用之间的一种不平衡状态。在氧化应激状态下,ROS的生成显著增加,内源性抗氧化剂不能有效清除所有的ROS,从而导致严重的生物分子损伤,包括DNA、脂质和蛋白质。在炎症组织中,过量的ROS生成会进一步加剧组织损伤,引起创伤性败血症、炎性肠病、肝/肾损伤、肝纤维化等急性/慢性炎症性疾病。临床上,治疗炎症性疾病的代表性药物包括糖皮质激素和非甾体抗炎药,但它们可能导致严重的副作用,包括心血管疾病风险增加、胃肠道出血、骨质疏松和慢性肾病等。
近年来,随着ROS调控研究取得的进展,许多抗氧化分子如维生素、类胡萝卜素和类黄酮,或天然酶如超氧化物歧化酶(SOD)、过氧化氢酶(CAT)和谷胱甘肽过氧化物酶(GPx)被引入到生物系统中,用于防止或抑制炎症疾病中的氧化应激损伤。然而,传统抗氧化分子仍面临稳定性差、毒性高、生物利用度低等问题。同时,天然酶也存在诸多局限性,如对环境条件的敏感、功能稳定性差、大批量生产困难等问题。随着纳米技术和纳米科学快速和显著的发展,大量基于ROS调控策略的新型多功能纳米材料被广泛应用,为炎症疾病的治疗提供了新的机遇。在这里,这些基于ROS调控的纳米治疗模式或纳米药物不仅可以提高小分子ROS清除剂的稳定性和生物利用度,还可以实现靶向,可控制药物递送到组织、细胞或细胞器。同时,纳米载体的使用也可以减少给药剂量,降低药物的副作用。
尽管在国内外的研究中,抗氧化剂载体纳米平台能有效改善抗氧化剂的药代动力学,增强抗氧化作用。然而,这些输送平台的缺点是明显的,例如过早释放抗氧化剂,纳米载体的载药能力有限。而已知的药物与载体相结合的复合纳米药物合成工艺复杂,体内安全性、结构和治疗可控性也存在诸多问题。因此,在本领域中开发一种既能够提高药物与载体的稳定结合又能够保证药物负载效率,并具有简便合成方法和良好炎症微环境调节效果的纳米胶束是本领域研究的重点。
发明内容
针对上述现有技术的不足,本发明的第一目的在于提供一种生物活性纳米胶束,由功能性修饰的六氯磷腈或三聚氯氰两亲聚合物自组装形成,该两亲聚合物是以六氯磷腈或三聚氯氰化合物为母核,连接亲水性聚乙二醇链、过氧化氢清除/响应性基团苯硼酸酯衍生物以及超氧化物歧化酶样的2,2,6,6-四甲基哌啶-1-氧自由基所组成的。另一目的是提供所述生物活性纳米胶束的合成方法。
为了实现上述目的本发明的技术方案是:一种生物活性纳米胶束的组成,由功能性修饰的六氯磷腈或三聚氯氰两亲聚合物自装形成,其化学结构组成为:
其中:
R为含有活性端基(氨基、羟基或巯基)的聚乙二醇衍生物(包含且不仅限于 且每种两亲聚合物结构中至少含有一个该类基团;R1为含有活性端基(氨基、羟基、巯基或酚羟基)的苯硼酸酯衍生物(包含且不仅限于 且每种两亲聚合物结构中可含有0-5个该类基团;R2为含有活性端基(氨基或羟基)的2,2,6,6-四甲基哌啶-1-氧自由基(包含且不仅限于/>和/>且每种两亲聚合物结构中可含有0-5个该类基团。在六氯磷腈中R、R1和R2取代基的总数为6,在三聚氯氰中R、R1和R2取代基的总数为3。
在上述生物活性纳米胶束的结构组成中,功能性修饰六氯磷腈或三聚氯氰两亲聚合物,其母核分子除六氯磷腈或三聚氯氰外,亦可为具有亲和取代反应活性的其它卤代环磷腈或卤代1,3,5-三嗪,如六溴环三磷腈或2,4,6-三溴-1,3,5-三嗪。
在上述生物活性纳米胶束的结构组成中,含有活性端基的聚乙二醇衍生物,其平均分子量可选500Da、1000Da、2000Da、5000Da或10000Da。
为实现本发明的第二目的,本发明提供一种生物活性纳米胶束的合成方法,包括以下步骤:
(1)氮气或氩气保护下,六氯磷腈或三聚氯氰,加入无机或有机碱作为缚酸剂,分别与不同比例聚乙二醇衍生物、不同比例含有活性端基的苯硼酸酯衍生物,和不同比例含有活性端基的2,2,6,6-四甲基哌啶-1-氧自由基在超干有机溶剂中逐步亲和取代反应,每步取代反应时间为0.5-48h,反应温度为-80-100℃。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液,最后在冰乙醚中沉淀,过滤后得到产物,即功能性修饰六氯磷腈或三聚氯氰两亲聚合物;
(2)将步骤(1)所得的功能性修饰六氯磷腈或三聚氯氰两亲聚合物,置于水溶液中,超声处理5-30min后常温静置5-60min,最后即得生物活性纳米胶束溶液。
在上述合成方法中,所述步骤(1)中无机或有机碱缚酸剂,选自金属钠、金属钾、氢化钠、氢化钙、氢氧化钠、氢氧化钾、碳酸钠、碳酸铯、碳酸钾、三乙胺和N,N-二异丙基乙胺中的一种或任意两种组合,加入可一次加入亦可分次加入。
在上述合成方法中,所述步骤(1)中有机溶剂,选自二氯甲烷、四氢呋喃或1,4-二氧六环。
在上述合成方法中,所述步骤(1)中六氯磷腈和三聚氯氰在有机溶剂中的浓度范围为0.01mmol/mL-1mmol/mL。
在上述合成方法中,所述步骤(1)中六氯磷腈和三聚氯氰与无机或有机碱缚酸剂的用量比,分别为摩尔比1:6到1:24之间和1:3到1:12之间。
在上述合成方法中,所述步骤(1)中六氯磷腈和三聚氯氰与聚乙二醇衍生物的用量比,分别为摩尔比1:1到1:3和1:1到1:2。
在上述合成方法中,所述步骤(1)中六氯磷腈和三聚氯氰与含有活性端基的苯硼酸酯衍生物的用量比,分别为摩尔比1:0到1:6和1:0到1:3。
在上述合成方法中,所述步骤(1)中六氯磷腈和三聚氯氰与含有活性端基的2,2,6,6-四甲基哌啶-1-氧自由基的用量比,分别为摩尔比1:0到1:6和1:0到1:3。
在上述合成方法中,所述步骤(1)中六氯磷腈或三聚氯氰分别与不同比例聚乙二醇衍生物、不同比例含有活性端基的苯硼酸酯衍生物和不同比例含有活性端基的2,2,6,6-四甲基哌啶-1-氧自由基的亲和取代反应顺序,可根据各取代基的亲和取代反应活性进行先后调整。
在上述合成方法中,所述步骤(1)中在冰乙醚中沉淀,采用的乙醚温度一般为-40℃到0℃,浓缩后的反应液与乙醚体积比为1:20到1:9。
本发明所具有的有益技术效果如下:
(1)本发明所设计的生物活性纳米胶束,由六氯磷腈或三聚氢氰两亲聚合物组成,该两亲聚合物通过逐步亲和取代反应制备,合成方法简单、易于放大、且成本较低。
(2)本发明所设计的生物活性纳米胶束,在活性氧簇或炎症环境中最终水解为聚乙二醇以及频哪醇、硼酸、磷酸离子和铵离子等有机/无机小分子水解产物,具有良好的体内外生物相容性,保证了该纳米胶束的体内安全性。
(3)本发明所设计的生物活性纳米胶束,通过六氯三聚磷腈或三聚氢氰两亲聚合物在水相中自组装快速形成,制备方法简单易行,保证了该纳米胶束在使用中的便利性和可靠性。
(4)本发明所制备的生物活性纳米胶束,其功能修饰基团通过化学键相连,既保证药物的高效负载,又避免了负载药物在体内的提前释放。
(5)本发明所设计的生物活性纳米胶束,采用六氯磷腈或三聚氢氰母核与功能基团的化学组合,亦可与其它小分子药物、多肽和小干扰RNA结合,便于实现纳米胶束性能和功能的调控。
(6)本发明所制备的生物活性纳米胶束,自身具有亲水性外壳和疏水性内腔,亦可负载疏水性治疗药物,从而进一步增强纳米胶束的功能性和实用性。
(7)本发明所制备的生物活性纳米胶束具有活性氧簇清除性能/炎症微环境调节功能,且粒径在5-100nm范围易于病灶部位高效靶向富集,治疗炎症或氧化应激损伤相关疾病,且治疗效果明显优于小分子抗氧化剂。
附图说明
图1为1个甲氧基聚乙二醇2000-氨基和5个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物的1H NMR图谱;
图2为1个甲氧基聚乙二醇2000-氨基和5个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物的MADLI-TOF图谱。
图3为1个甲氧基聚乙二醇2000-氨基和5个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束的透射电镜图片;
图4为1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束在不同浓度过氧化氢存在条件下的水解曲线;
图5为1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束对DPPH自由基的清除曲线;
图6为1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束在不同浓度过氧化氢存在条件下的降解曲线;
图7为1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束降低急性肾损伤小鼠血清中肌酐含量;
图8为1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束缓解急性肾损伤症状的H&E染色切片;
图9为1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物,所形成的纳米胶束在小鼠急毒实验中对体重的影响。
具体实施方式
下面结合具体实施方式对本发明的发明内容作进一步的详细描述。应理解,本发明的实施例只用于说明本发明而非限制本发明,在不脱离本发明技术思想的情况下,根据本领域普通技术知识和惯用手段,做出的各种替换和变更,均应包括在本发明的范围内。
下面结合非限定性的实施例对本发明做详细说明。
实施例1
在氮气保护下,0.1mmol六氯磷腈溶于10mL超干四氢呋喃,加入2.4mmol三乙胺,先与0.1mmol甲氧基聚乙二醇氨基(MW=2000)在-80℃下反应6h,接着与0.6mmol甘氨酸化4-羟甲基苯硼酸酯在75℃下反应48h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在45mL温度为-40℃冰乙醚中沉淀,过滤后得到产物,即1个甲氧基聚乙二醇2000-氨基和5个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物。
取1mg所得两亲聚合物,置于1mL去离子水中超声处理30min后常温静置60min,最后即得1mg/mL生物活性纳米胶束溶液。
实施例2
在氩气保护下,10mmol六氯磷腈溶于10mL超干1,4-二氧六环,加入10mmol氢化钠,与10mmol 4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基在-20℃下反应3h,再加入50mmol N,N-二异丙基乙胺,与10mmol甲氧基聚乙二醇氨基(MW=2000)在40℃下反应0.5h,随后与50mmol甘氨酸化4-羟甲基苯硼酸酯在100℃下反应48h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在100mL温度为0℃冰乙醚中沉淀,过滤后得到产物,即1个甲氧基聚乙二醇2000-氨基、1个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基和4个甘氨酸化4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物。
取1mg所得两亲聚合物,置于1mL PBS中超声处理5min后常温静置5min,最后即得1mg/mL生物活性纳米胶束溶液。
实施例3
在氩气保护下,0.1mmol六氯磷腈溶于10mL超干二氯甲烷,加入2.4mmol金属钠,与0.3mmol甲氧基聚乙二醇羟基(MW=500)在40℃下反应24h,随后与0.3mmol 4-羟甲基苯硼酸酯在40℃下反应36h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在60mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即3个甲氧基聚乙二醇500-羟基和3个4-羟甲基苯硼酸酯修饰的六氯磷腈两亲聚合物。
取2mg所得两亲聚合物,置于1mL生理盐水中超声处理5min后常温静置10min,最后即得2mg/mL生物活性纳米胶束溶液。
实施例4
在氮气保护下,0.1mmol六氯磷腈溶于10mL超干四氢呋喃,加入1.2mmol碳酸铯,与0.5mmol 4-氨基苯硼酸酯在70℃下反应12h,再与1.2mmol甲氧基聚乙二醇巯基(MW=1000)在70℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至2mL,最后在30mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即1个甲氧基聚乙二醇1000-巯基和5个4-氨基苯硼酸酯修饰的六氯磷腈两亲聚合物。
取0.5mg所得两亲聚合物,置于10mL HBSS中超声处理20min后常温静置30min,最后即得0.05mg/mL生物活性抗炎纳米胶束溶液。
实施例5
在氮气保护下,0.1mmol六氯磷腈溶于10mL超干四氢呋喃,加入1.2mmol碳酸钾,与0.1mmol羟基聚乙二醇氨基(MW=5000)在0℃下反应6h,再加入0.6mmol 4-氨基-2,2,6,6-四甲基哌啶-1-氧自由基在50℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在50mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即1个羟基聚乙二醇5000-氨基和5个4-氨基-2,2,6,6-四甲基哌啶-1-氧自由基修饰的六氯磷腈两亲聚合物。
取0.5mg所得两亲聚合物,置于50mL细胞培养基中超声处理5min后常温静置30min,最后即得0.01mg/mL生物活性纳米胶束溶液。
实施例6
在氩气保护下,0.1mmol六氯磷腈溶于10mL超干1,4-二氧六环,加入0.6mmol碳酸钠,与0.5mmol 4-氨甲基苯硼酸酯在60℃下反应3h,再加入1.2mmol氢氧化钠,与0.1mmol氨基聚乙二醇氨基(MW=10000)在50℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在50mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即1个氨基聚乙二醇10000-氨基和5个4-氨甲基苯硼酸酯修饰的六氯磷腈两亲聚合物。
取100mg所得两亲聚合物,置于1mL胎牛血清中超声处理30min后常温静置30min,最后即得100mg/mL生物活性纳米胶束溶液。
实施例7
在氮气保护下,0.1mmol三聚氯氰溶于10mL超干二氯甲烷,加入1.2mmol氢氧化钾,与0.1mmol马来酰亚胺聚乙二醇氨基(MW=2000)在-20℃下反应12h,再与0.3mmol 4-羟基苯硼酸酯在25℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至1mL,最后在9mL温度为0℃冰乙醚中沉淀,过滤后得到产物,即1个马来酰亚胺聚乙二醇2000-氨基和2个4-羟基苯硼酸酯修饰的三聚氯氰两亲聚合物。
取100mg所得两亲聚合物,置于1mL HBSS中超声处理20min后常温静置60min,最后即得100mg/mL生物活性纳米胶束溶液。
实施例8
在氮气保护下,10mmol三聚氯氰溶于10mL超干四氢呋喃,加入30mmol氢化钙,与10mmol甲氧基聚乙二醇羟基(MW=1000)在0℃下反应24h,再加入30mmol 4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基在40℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至2mL,最后在40mL温度为-20℃冰乙醚中沉淀,过滤后得到产物,即1个甲氧基聚乙二醇1000-羟基和2个4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基修饰的三聚氯氰两亲聚合物。
取1mg所得两亲聚合物,置于10mL生理盐水中超声处理5min后常温静置30min,最后即得0.1mg/mL生物活性纳米胶束溶液。
实施例9
在氮气保护下,0.1mmol 2,4,6-三溴-1,3,5-三嗪溶于10mL超干四氢呋喃,加入1.2mmol N,N-二异丙基乙胺,与0.2mmol甲氧基聚乙二醇羟基(MW=500)在25℃下反应24h,再与0.3mmol 4-氨基-2,2,6,6-四甲基哌啶-1-氧自由基在70℃下反应48h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在50mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即1个甲氧基聚乙二醇500-羟基和2个4-氨基-2,2,6,6-四甲基哌啶-1-氧自由基修饰的2,4,6-三溴-1,3,5-三嗪两亲聚合物。
取10mg所得两亲聚合物,置于1mL PBS中超声处理5min后常温静置30min,最后即得10mg/mL生物活性纳米胶束溶液。
实施例10
在氩气保护下,1.0mmol六溴环三磷腈溶于10mL超干1,4-二氧六环,加入6.0mmolN,N-二异丙基乙胺,与1.0mmol甲氧基聚乙二醇羟基(MW=2000)在40℃下反应12h,随后与6.0mmol 4-氨甲基苯硼酸酯在70℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在50mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即1个甲氧基聚乙二醇2000-羟基和5个4-氨甲基苯硼酸酯修饰的六溴环三磷腈两亲聚合物。
取5mg所得两亲聚合物,置于50mL去离子水中超声处理5min后常温静置30min,最后即得0.1mg/mL生物活性纳米胶束溶液。
实施例11
在氮气保护下,1.0mmol三聚氯氰溶于10mL超干四氢呋喃,加入6.0mmol金属钾,与2.0mmol甲氧基聚乙二醇羟基(MW=2000)在-20℃下反应12h,再与1.0mmol 4-羟基苯硼酸酯在25℃下反应24h。反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液至5mL,最后在50mL温度为-10℃冰乙醚中沉淀,过滤后得到产物,即2个甲氧基聚乙二醇2000-羟基和1个4-羟基苯硼酸酯修饰的三聚氯氰两亲聚合物。
取0.5mg所得两亲聚合物,置于50mL胎牛血清中超声处理5min后常温静置30min,最后即得0.01mg/mL生物活性纳米胶束溶液。
图1和图2结果显示,实施例1中所合成的两亲聚合物为1个甲氧基聚乙二醇2000-氨基和5个甘氨酸化4-羟甲基苯硼酸酯修饰产物。图3结果显示所得的溶液为球形纳米胶束溶液。图4-6结果显示,实施例2所纳米胶束在活性氧可逐步分解,且在体外可有效的清除DPPH自由基,同时能释放出所连接的4-甲基苯甲醇和四甲基哌啶氮氧化物等功能性小分子。图7和图8结果显示,实施例2所得纳米胶束在顺铂诱导的急性肾损伤模型中,可有效缓解血清肌酐水平的异常升高和组织病变。图9结果显示,尾静脉注射高浓度纳米胶束后14天内,小鼠体内未出现明显变化,初步证明所得纳米胶束在体内具有良好的生物安全性。
Claims (5)
1.一种生物活性纳米胶束,其特征在于:包括功能性修饰的六氯磷腈两亲聚合物,化学结构为:
其中/>为甲氧基聚乙二醇2000-氨基-。
2.一种权利要求1所述生物活性纳米胶束的合成方法,其特征在于,包括以下步骤:
(1)氮气或氩气保护下,六氯磷腈,加入无机或有机碱作为缚酸剂,分别与10mmol 4-羟基-2,2,6,6-四甲基哌啶-1-氧自由基、10mmol甲氧基聚乙二醇氨基MW=2000和50mmol甘氨酸化4-羟甲基苯硼酸酯在超干有机溶剂中逐步亲和取代反应,每步取代反应的时间为0.5-48h,反应温度为-80-100℃;反应完成后,真空抽滤除去产生的盐,旋蒸浓缩反应液,最后在冰乙醚中沉淀,过滤后得到产物,即功能性修饰的六氯磷腈两亲聚合物;
(2)将步骤(1)所得的产物,置于水溶液中,超声处理5-30min后室温静置5-60min,最后即得生物活性纳米胶束溶液。
3.根据权利要求2所述生物活性纳米胶束的合成方法,其特征在于:所述缚酸剂选自金属钠、金属钾、氢化钠、氢化钙、氢氧化钠、氢氧化钾、碳酸钠、碳酸铯、碳酸钾、三乙胺和N,N-二异丙基乙胺中的一种或任意两种组合。
4.根据权利要求2所述生物活性纳米胶束的合成方法,其特征在于:所述有机溶剂选自二氯甲烷、四氢呋喃或1,4-二氧六环。
5.根据权利要求2所述生物活性纳米胶束的合成方法,其特征在于:步骤(1)中所述六氯磷腈在有机溶剂中的浓度范围为0.01mmol/mL-1.0mmol/mL。
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