CN111084763A - 一种聚多巴胺多层级纳米药物载体、制备方法及其应用 - Google Patents
一种聚多巴胺多层级纳米药物载体、制备方法及其应用 Download PDFInfo
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Abstract
本发明提供了一种聚多巴胺多层级纳米药物载体、制备方法及其应用，包括以下步骤：S1：将乙醇、超纯水、氨水混合均匀后，再加入多巴胺盐酸盐溶液，在室温下搅拌25～35h，离心收集沉淀，制得粒径约为120nm～350nm的PDA微球；S2：将步骤S1制备的PDA微球溶于乙醇，随后加入乙酰丙酮铁和多元醇，在真空条件下将溶液温度升至65～75℃并保持15～30min以除去乙醇，充入氮气后升温至200～220℃并搅拌2h；继续升至280～290℃并搅拌50～70min，冷却至室温后，加入等体积丙酮后用磁铁分离，再用乙醇洗涤，得到PDA@IOs微球；S3：将步骤S3中得到的PDA@IOs微球分散至pH为8～9的Tris‑HCl缓冲液中，搅拌22～26h，得到所述聚多巴胺多层级纳米药物载体，表示为PDA@IOs@PDA纳米微球。该纳米微球具备金属亲和性，磁响应好，光热转换效率高。
Description
技术领域
本发明涉及一种聚多巴胺多层级纳米药物载体、制备方法及其应用，属于纳米材料技术领域。
背景技术
目前，超顺磁氧化铁纳米颗粒(IOs)具备优良的生物相容性以及多种在体诊断-治疗模式：包括磁共振成像、外加磁场作用下的靶向富集以及交变磁场作用下的肿瘤热疗等，在疾病的分子影像学诊断与靶向治疗等方面有着巨大的应用潜力。但是，现有技术的超顺磁氧化铁纳米颗粒存在以下缺点：模板不具备金属亲和性，导致纳米颗粒包覆度低，磁响应差；稳定性差，光热转换效率低；大多数方案需额外进行模板的表面基团改性才能连上化疗药物。
发明内容
本发明提供了一种聚多巴胺多层级纳米药物载体的制备方法，可以有效解决上述问题。
本发明提供一种聚多巴胺多层级纳米药物载体的制备方法，包括以下步骤：
S1：将乙醇、超纯水、氨水混合均匀后，再加入多巴胺盐酸盐溶液，在室温下搅拌25～35h，离心收集沉淀，制得粒径约为120nm～350nm的PDA微球；
S2：将步骤S1制备的PDA微球溶于乙醇，随后加入乙酰丙酮铁和多元醇，在真空条件下将溶液温度升至65～75℃并保持15～30min以除去乙醇，充入氮气后升温至200～220℃并搅拌2h；继续升至280～290℃并搅拌50～70min，冷却至室温后，加入等体积丙酮后用磁铁分离，再用乙醇洗涤，得到PDA@IOs微球；
S3：将步骤S3中得到的PDA@IOs微球分散至pH为8～9的Tris-HCl缓冲液中，搅拌22～26h，得到所述聚多巴胺多层级纳米药物载体，表示为PDA@IOs@PDA(PIP)纳米微球。
作为进一步改进的，在步骤S1中，所加入的乙醇、超纯水、氨水、多巴胺盐酸盐溶液的体积比为70～90：160～200：1～5：10～30。
作为进一步改进的，在步骤S1中，所述多巴胺盐酸盐溶度的浓度为0.04～0.06g/ml。
作为进一步改进的，在步骤S2中，所用的PDA微球、乙醇、乙酰丙酮铁、多元醇的质量体积比为35～45ml：0.5～1.5ml：120～240mg：15～25ml。
作为进一步改进的，所述多元醇为为三甘醇或四甘醇中的至少一种。
作为进一步改进的，在步骤S3中，PDA@IOs微球分散在Tris-HCl缓冲液中的浓度为0.3～1mg/ml。
本发明还提供一种上述的聚多巴胺多层级纳米药物载体制备抗肿瘤药物释放多功能载体的方法：包括以下步骤：
A：将DTDP溶于乙酰氯中，在60～70℃下回流1.5～2h，旋转蒸发除去多余的乙酰氯，随后用过量的乙醚沉淀产物，真空干燥，得到DTDPA；
B：将含有氨基官能团的抗肿瘤药物X溶于无水DMF中，随后加入TEA和步骤S1制备的DTDPA，在室温下避光搅拌过夜，再加入EDC和NHS，继续搅拌3.5～4.5h，得到X-DTDPA溶液；
C：将步骤S2所制备的X-DTDPA溶液加入到NH2-PEG-NH2的DMF溶液中，其中NH2-PEG-NH2的分子量为2000或4000，室温避光反应10～14h，最后在超纯水中透析三天得到X-SS-PEG-NH2前药；
D：将步骤C得到的X-SS-PEG-NH2前药逐滴加入到所述PIP纳米微球的Tris-HCl溶液中，室温搅拌10～14h后，产物离心并用超纯水清洗几次，即得到所述的抗肿瘤药物释放多功能载体，表示为PIP-X。
作为进一步改进的，含有氨基官能团的抗肿瘤药物X为DOX·HCl。
作为进一步改进的，在步骤A中，所述DTDP和乙酰氯的体积质量比为1g：2.5～3.5ml；在步骤B中，所述含有氨基官能团的抗肿瘤药物X、DMF、TEA、DTDPA、EDC和NHS的质量体积比为4～6mg：0.8～1.2ml：3～5ml：1.5～2mg：6～7mg：3.5～4.2mg。
作为进一步改进的，在步骤C中，NH2-PEG-NH2在DMF溶液中的浓度为10～15mg/ml；在步骤D中，所述PIP纳米微球在Tris-HCl溶液中的浓度为1.5～2.5mg/ml。
本发明还提供一种上述的方法制备的聚多巴胺多层级纳米药物载体PDA@IOs@PDA纳米微球。
本发明的有益效果是：
1.本发明的PIP纳米微球的制备方法以聚多巴胺为天然铁亲和模板，原位生长高密度负载氧化铁颗粒，进一步包覆聚多巴胺层，相比单个的IOs和IO/PDA核壳结构，具备粒径高度均一以及尺寸可调控以及磁响应快速的优势。
2.本发明的聚多巴胺模板表面具有金属亲和性，可直接原位生长超顺磁氧化铁纳米颗粒，纳米颗粒包覆度高，磁响应性能好。
3.本发明的PIP纳米微球为三明治结构，由于聚多巴胺在近红外区的强吸收，PIP纳米微球光稳定性好，无散射，光热转换效率相对其他光热试剂如金纳米棒，荧光染料等要高。
4.本发明的PIP纳米微球的聚多巴胺表面的邻苯二酚基团可与氨基官能团之间发生加成反应，可以方便地在聚多巴胺表面共价连接含有氨基官能团的有机分子，因而不需额外进行模板的表面基团改性，就可以直接连上还原响应性的化疗前药DOX-SS-PEG-NH2。
5.本发明的PIP纳米微球整合了各材料的优点，最终赋予材料MRI/PA成像及光热/化疗功能。
6.本发明的PIP纳米微球聚多巴胺模板具有生物相容性，可通过类
反应大量可控合成。
附图说明
为了更清楚地说明本发明实施方式的技术方案，下面将对实施方式中所需要使用的附图作简单地介绍，应当理解，以下附图仅示出了本发明的某些实施例，因此不应被看作是对范围的限定，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相关的附图。
图1是本发明的聚多巴胺多层级纳米药物载体的制备方法示意图。
图2是本发明的实施例1的PDA微球、PDA@IOs微球及PIP纳米微球的电镜图。其中，(a)PDA微球；(b)PDA@IOs微球；(c)PDA@IOs纳米微球局部放大；(d)PIP纳米微球。
图3是本发明的实施例1的PIP纳米粒子室温磁滞回线图。
具体实施方式
为使本发明实施方式的目的、技术方案和优点更加清楚，下面将结合本发明实施方式中的附图，对本发明实施方式中的技术方案进行清楚、完整地描述，显然，所描述的实施方式是本发明一部分实施方式，而不是全部的实施方式。基于本发明中的实施方式，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施方式，都属于本发明保护的范围。因此，以下对在附图中提供的本发明的实施方式的详细描述并非旨在限制要求保护的本发明的范围，而是仅仅表示本发明的选定实施方式。基于本发明中的实施方式，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施方式，都属于本发明保护的范围。
实施例1
(1)量取40mL乙醇、90mL超纯水以及2.2mL氨水，倒入250mL反应瓶中。称取0.5g多巴胺盐酸盐并溶解于10mL水中，在剧烈搅拌下快速加入上述混合溶液中，在室温下磁力搅拌30h。将溶液离心收集沉淀并水洗数次，得到PDA微球。
(2)将上述制备的PDA微球(干重约40mg)溶于1mL乙醇并加入50mL两口反应瓶中。随后加入240mg Fe(acac)3和20mL TEG。在真空条件下将溶液温度升至70℃并保持15min以上以除去乙醇。向瓶中充入氮气后升温至210℃并磁力搅拌2h；继续升至285℃并搅拌1h。将溶液冷却至室温后，加入等体积丙酮后用磁铁分离，用乙醇洗涤三次以上，得到PDA@IOs微球。
(3)将20mg PDA@IOs纳米球的粗溶液离心后分散至20mL多巴胺的Tris-HCl缓冲液中，温和搅拌24h，然后水洗几次，得到PDA@IOs@PDA(PIP)纳米微球。Tris-HCl缓冲液的浓度为10mM，pH为8.5。
(4)5g DTDP溶于15mL乙酰氯中，在65℃下回流2h。旋转蒸发除去多余的乙酰氯。随后用过量的乙醚沉淀产物，清洗4遍，真空干燥，得到DTDPA。称取15mg DOX·HCl溶于3mL无水DMF中，随后加入12μL TEA和5.4mg DTDPA。混合物在室温下避光搅拌过夜。19.8mg EDC和11.88mg NHS加入到上述溶液中，继续搅拌4h。将上述得到的DOX-DTDPA溶液加入NH2-PEG2000-NH2(104mg)的DMF(8mL)中，室温避光反应12h。最后在超纯水中透析三天，得到DOX-SS-PEG-NH2前药。
(5)将上述得到的DOX-SS-PEG-NH2前药逐滴加入到PIP(2mg/mL)的Tris-HCl溶液中(pH＝8.0)。室温搅拌12h后，产物离心并用超纯水清洗几次，得到所述抗肿瘤药物释放多功能载体，表示为PIP-DOX。
其电镜图如图2所示。PIP纳米粒子室温磁滞回线图如图3所示。
实施例2
(1)量取40mL乙醇、90mL超纯水以及2.2mL氨水，倒入250mL反应瓶中。称取0.5g多巴胺盐酸盐并溶解于10mL水中，在剧烈搅拌下快速加入上述混合溶液中，在室温下磁力搅拌30h。将溶液离心收集沉淀并水洗数次，得到PDA微球。
(2)将上述制备的湿沉淀(干重约40mg)溶于1mL乙醇并加入50mL两口反应瓶中。随后加入120mg Fe(acac)3和20mL TEG。在真空条件下将溶液温度升至70℃并保持15min以上以除去乙醇。向瓶中充入氮气后升温至210℃并磁力搅拌2h；继续升至285℃并搅拌1h。将溶液冷却至室温后，加入等体积丙酮后用磁铁分离，将PDA@IOs微球用乙醇洗涤三次以上，得到PDA@IOs微球。
(3)将20mg PDA@IOs纳米球的粗溶液离心后分散至20mL多巴胺的Tris-HCl缓冲液中，温和搅拌24h。然后水洗几次，得到PDA@IOs@PDA(PIP)纳米微球。Tris-HCl缓冲液的浓度为10mM，pH为8.5。
(4)5g DTDP溶于15mL乙酰氯中，在65℃下回流2h。旋转蒸发除去多余的乙酰氯。随后用过量的乙醚沉淀产物，清洗4遍，真空干燥，得到DTDPA。称取15mg DOX·HCl溶于3mL无水DMF中，随后加入12μL TEA和5.4mg DTDPA。混合物在室温下避光搅拌过夜。19.8mg EDC和11.88mg NHS加入到上述溶液中，继续搅拌4h。将上述得到的DOX-DTDPA溶液加入NH2-PEG2000-NH2(104mg)的DMF(8mL)中，室温避光反应12h。最后在超纯水中透析三天，得到DOX-SS-PEG-NH2前药。
(5)将上述得到的DOX-SS-PEG-NH2前药逐滴加入到PIP(2mg/mL)的Tris-HCl溶液中(pH 8.0)。室温搅拌12h后，产物离心并用超纯水清洗几次，得到所述抗肿瘤药物释放多功能载体，表示为PIP-DOX。
实施例3
(1)量取40mL乙醇、90mL超纯水以及0.7mL氨水，倒入250mL反应瓶中。称取0.5g多巴胺盐酸盐并溶解于10mL水中，在剧烈搅拌下快速加入上述混合溶液中，在室温下磁力搅拌30h。将溶液离心收集沉淀并水洗数次，得到PDA微球。
(2)将上述制备的湿沉淀(干重约40mg)溶于1mL乙醇并加入50mL两口反应瓶中。随后加入240mg Fe(acac)3和20mL TEG。在真空条件下将溶液温度升至70℃并保持15min以上以除去乙醇。向瓶中充入氮气后升温至210℃并磁力搅拌2h；继续升至285℃并搅拌1h。将溶液冷却至室温后，加入等体积丙酮后用磁铁分离，将PDA@IOs微球用乙醇洗涤三次以上，得到PDA@IOs微球。
(3)将20mg PDA@IOs纳米球的粗溶液离心后分散至20mL多巴胺的Tris-HCl缓冲液中，温和搅拌24h。然后水洗几次，得到PDA@IOs@PDA(PIP)纳米微球。Tris-HCl缓冲液的浓度为10mM，pH为8.5。
(4)5g DTDP溶于15mL乙酰氯中，在65℃下回流2h。旋转蒸发除去多余的乙酰氯。随后用过量的乙醚沉淀产物，清洗4遍，真空干燥，得到DTDPA。称取15mg DOX·HCl溶于3mL无水DMF中，随后加入12μL TEA和5.4mg DTDPA。混合物在室温下避光搅拌过夜。19.8mg EDC和11.88mg NHS加入到上述溶液中，继续搅拌4h。将上述得到的DOX-DTDPA溶液加入NH2-PEG2000-NH2(104mg)的DMF(8mL)中，室温避光反应12h。最后在超纯水中透析三天，得到DOX-SS-PEG-NH2前药。
(5)将上述得到的DOX-SS-PEG-NH2前药逐滴加入到PIP(2mg/mL)的Tris-HCl溶液中(pH 8.0)。室温搅拌12h后，产物离心并用超纯水清洗几次，得到所述抗肿瘤药物释放多功能载体，表示为PIP-DOX。
实施例4
(1)量取40mL乙醇、90mL超纯水以及2.2mL氨水，倒入250mL反应瓶中。称取0.5g多巴胺盐酸盐并溶解于10mL水中，在剧烈搅拌下快速加入上述混合溶液中，在室温下磁力搅拌30h。将溶液离心收集沉淀并水洗数次，得到PDA微球。
(2)将上述制备的湿沉淀(干重约40mg)溶于1mL乙醇并加入50mL两口反应瓶中。随后加入240mg Fe(acac)3和20mL TEG。在真空条件下将溶液温度升至70℃并保持15min以上以除去乙醇。向瓶中充入氮气后升温至210℃并磁力搅拌2h；继续升至285℃并搅拌1h。将溶液冷却至室温后，加入等体积丙酮后用磁铁分离，将PDA@IOs微球用乙醇洗涤三次以上，得到PDA@IOs微球。
(3)将20mg PDA@IOs纳米球的粗溶液离心后分散至30mL多巴胺的Tris-HCl缓冲液中，温和搅拌24h。然后水洗几次，得到PDA@IOs@PDA(PIP)纳米微球。Tris-HCl缓冲液的浓度为10mM，pH为8.5。
(4)5g DTDP溶于15mL乙酰氯中，在65℃下回流2h。旋转蒸发除去多余的乙酰氯。随后用过量的乙醚沉淀产物，清洗4遍，真空干燥，得到DTDPA。称取15mg DOX·HCl溶于3mL无水DMF中，随后加入12μL TEA和5.4mg DTDPA。混合物在室温下避光搅拌过夜。19.8mg EDC和11.88mg NHS加入到上述溶液中，继续搅拌4h。将上述得到的DOX-DTDPA溶液加入NH2-PEG2000-NH2(104mg)的DMF(8mL)中，室温避光反应12h。最后在超纯水中透析三天，得到DOX-SS-PEG-NH2前药。
(5)将上述得到的DOX-SS-PEG-NH2前药逐滴加入到PIP(2mg/mL)的Tris-HCl溶液中(pH 8.0)。室温搅拌12h后，产物离心并用超纯水清洗几次，得到所述抗肿瘤药物释放多功能载体，表示为PIP-DOX。
实施例5
(1)量取40mL乙醇、90mL超纯水以及2.2mL氨水，倒入250mL反应瓶中。称取0.5g多巴胺盐酸盐并溶解于10mL水中，在剧烈搅拌下快速加入上述混合溶液中，在室温下磁力搅拌30h。将溶液离心收集沉淀并水洗数次，得到PDA微球。
(2)将上述制备的湿沉淀(干重约40mg)溶于1mL乙醇并加入50mL两口反应瓶中。随后加入240mg Fe(acac)3和20mL TEG。在真空条件下将溶液温度升至70℃并保持15min以上以除去乙醇。向瓶中充入氮气后升温至210℃并磁力搅拌2h；继续升至285℃并搅拌1h。将溶液冷却至室温后，加入等体积丙酮后用磁铁分离，将PDA@IOs微球用乙醇洗涤三次以上，得到PDA@IOs微球。
(3)将20mg PDA@IOs纳米球的粗溶液离心后分散至20mL多巴胺的Tris-HCl缓冲液中，温和搅拌24h。然后水洗几次，得到PDA@IOs@PDA(PIP)纳米微球。Tris-HCl缓冲液的浓度为10mM，pH为8.5。
(4)5g DTDP溶于15mL乙酰氯中，在65℃下回流2h。旋转蒸发除去多余的乙酰氯。随后用过量的乙醚沉淀产物，清洗4遍，真空干燥，得到DTDPA。称取15mg DOX·HCl溶于3mL无水DMF中，随后加入12μL TEA和5.4mg DTDPA。混合物在室温下避光搅拌过夜。19.8mg EDC和11.88mg NHS加入到上述溶液中，继续搅拌4h。将上述得到的DOX-DTDPA溶液加入NH2-PEG4000-NH2(104mg)的DMF(8mL)中，室温避光反应12h。最后在超纯水中透析三天，得到DOX-SS-PEG-NH2前药。
(5)将上述得到的DOX-SS-PEG-NH2前药逐滴加入到PIP(2mg/mL)的Tris-HCl溶液中(pH为8.0)。室温搅拌12h后，产物离心并用超纯水清洗几次，得到所述抗肿瘤药物释放多功能载体，表示为PIP-DOX。
以上所述仅为本发明的优选实施方式而已，并不用于限制本发明，对于本领域的技术人员来说，本发明可以有各种更改和变化。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种聚多巴胺多层级纳米药物载体的制备方法，其特征在于：包括以下步骤：
S1：将乙醇、超纯水、氨水混合均匀后，再加入多巴胺盐酸盐溶液，在室温下搅拌25～35h，离心收集沉淀，制得粒径约为120nm～350nm的PDA微球；
S2：将步骤S1制备的PDA微球溶于乙醇，随后加入乙酰丙酮铁和多元醇，在真空条件下将溶液温度升至65～75℃并保持15～30min以除去乙醇，充入氮气后升温至200～220℃并搅拌2h；继续升至280～290℃并搅拌50～70min，冷却至室温后，加入等体积丙酮后用磁铁分离，再用乙醇洗涤，得到PDA@IOs微球；
S3：将步骤S3中得到的PDA@IOs微球分散至pH为8～9的Tris-HCl缓冲液中，搅拌22～26h，得到所述聚多巴胺多层级纳米药物载体，表示为PDA@IOs@PDA纳米微球。
2.根据权利要求1所述的聚多巴胺多层级纳米药物载体的制备方法，其特征在于：在步骤S1中，所加入的乙醇、超纯水、氨水、多巴胺盐酸盐溶液的体积比为70～90：160～200：1～5：10～30。
3.根据权利要求1所述的聚多巴胺多层级纳米药物载体的制备方法，其特征在于：在步骤S1中，所述多巴胺盐酸盐溶度的浓度为0.04～0.06g/ml。
4.根据权利要求1所述的聚多巴胺多层级纳米药物载体的制备方法，其特征在于：在步骤S2中，所用的PDA微球、乙醇、乙酰丙酮铁、多元醇的质量体积比为35～45ml：0.5～1.5ml：120～240mg：15～25ml。
5.根据权利要求1所述的聚多巴胺多层级纳米药物载体的制备方法，其特征在于：所述多元醇为为三甘醇或四甘醇中的至少一种。
6.根据权利要求1所述的聚多巴胺多层级纳米药物载体的制备方法，其特征在于：在步骤S3中，PDA@IOs微球分散在Tris-HCl缓冲液中的浓度为0.3～1mg/ml。
7.一种应用权利要求1至6任一权利要求所述的聚多巴胺多层级纳米药物载体制备抗肿瘤药物释放多功能载体的方法：其特征在于：包括以下步骤：
A：将DTDP溶于乙酰氯中，在60～70℃下回流1.5～2h，旋转蒸发除去多余的乙酰氯，随后用过量的乙醚沉淀产物，真空干燥，得到DTDPA；
B：将含有氨基官能团的抗肿瘤药物X溶于无水DMF中，随后加入TEA和步骤S1制备的DTDPA，在室温下避光搅拌过夜，再加入EDC和NHS，继续搅拌3.5～4.5h，得到X-DTDPA溶液；
C：将步骤S2所制备的X-DTDPA溶液加入到NH2-PEG-NH2的DMF溶液中，其中NH2-PEG-NH2的分子量为2000或4000，室温避光反应10～14h，最后在超纯水中透析三天得到X-SS-PEG-NH2前药；
D：将步骤C得到的X-SS-PEG-NH2前药逐滴加入到所述PDA@IOs@PDA纳米微球的Tris-HCl溶液中，室温搅拌10～14h后，产物离心并用超纯水清洗几次，即得到所述的抗肿瘤药物释放多功能载体，表示为PDA@IOs@PDA-X。
8.根据权利要求7所述的方法，其特征在于：含有氨基官能团的抗肿瘤药物X为DOX·HCl。
9.根据权利要求7所述的方法，其特征在于：在步骤A中，所述DTDP和乙酰氯的体积质量比为1g：2.5～3.5ml；在步骤B中，所述含有氨基官能团的抗肿瘤药物X、DMF、TEA、DTDPA、EDC和NHS的质量体积比为4～6mg：0.8～1.2ml：3～5ml：1.5～2mg：6～7mg：3.5～4.2mg。
10.一种权利要求1至6任一项所述的方法制备的聚多巴胺多层级纳米药物载体PDA@IOs@PDA纳米微球。
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