CN111012909A - 肿瘤光热-免疫联合治疗dna纳米制剂的方法 - Google Patents

肿瘤光热-免疫联合治疗dna纳米制剂的方法 Download PDF

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CN111012909A
CN111012909A CN201911330328.9A CN201911330328A CN111012909A CN 111012909 A CN111012909 A CN 111012909A CN 201911330328 A CN201911330328 A CN 201911330328A CN 111012909 A CN111012909 A CN 111012909A
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郑斌
彭文畅
明东
刘爽
甘霖
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Abstract

本发明公布一种肿瘤光热‑免疫联合治疗DNA纳米制剂的方法，主要步骤包括:1)DNA‑A与核酸适配体聚合物链的制备；2)CPG‑ODN聚合物链的制备；3)DNA‑A聚合物链与CPG‑ODN聚合物链与Linker DNA碱基互补，可交联形成DNA微凝胶纳米颗粒。同时加入吲哚菁绿(ICG)光热剂，交联形成包裹ICG的微凝胶颗粒；4)化疗药物DOX的装载。其中DNA‑A溶液中混合核酸适配体，形成了具有核酸配适体的DNA‑A聚合物链。该微凝胶纳米颗粒将化学治疗与免疫治疗联合，极大地增强肿瘤治疗的效果，使肿瘤治疗更加彻底。

Description

肿瘤光热-免疫联合治疗DNA纳米制剂的方法
技术领域
本发明涉及纳米制剂制备技术领域，具体为利用DNA碱基互补配对的原理，使DNA-A和CpG-ODN与连接DNA相连，从而合成肿瘤治疗纳米制剂的方法。
背景技术
微凝胶是尺寸在微米或纳米级别的聚合物胶体颗粒，它具有负载效率高、生物相容性好以及生物稳定性优异等特点。而且微凝胶对外界刺激的灵敏度更高，能够通过较大的形变快速响应外界环境的变化。这些特点都使微凝胶在药物输送领域具有很大的优势和潜力。现在大多采用化学试剂作为微凝胶颗粒的交联剂，而化学试剂的潜在毒性限制了凝胶颗粒在人体内的应用。
本发明采用碱基互补配对的机理，使DNA-A和CpG-ODN与Linker DNA相连，从而交联形成微凝胶颗粒。生物相容性优异，对人体无毒无害，开辟了交联剂应用的新思路。
核酸适配体是一段DNA序列。通常是利用体外筛选技术--指数富集的配体***进化技术从核酸分子文库中得到的寡核苷酸片段。核酸适配体能与多种目标物质高特异性、高选择性地结合，因此被广泛应用于生物传感器领域。本发明合成的微凝胶的粒径在100nm以下，通过静脉注射后会聚集在肿瘤部位，具有对肿瘤的被动靶向作用。且DNA-A聚合物链上的靶向4T1肿瘤表面的核酸适配体，可以实现对肿瘤的主动靶向，从而更高效地把化疗药物输送至肿瘤部位，并且减少对正常组织的伤害。
细菌DNA具有广谱的免疫刺激作用,有实验证明人工合成的CpG-ODN可以模拟细菌DNA诱发机体产生强烈的Th1型免疫应答,CpG-ODN作为一种新型的免疫佐剂已成为分子免疫学研究的热点之一。该微凝胶纳米颗粒将化学治疗与免疫治疗联合，极大地增强肿瘤治疗的效果，使肿瘤治疗更加彻底。
发明内容
本发明涉及一种利用DNA碱基互补配对的原理，使DNA-A和CpG-ODN与连接DNA相连，从而合成肿瘤治疗纳米制剂的方法。
本发明的技术方案是肿瘤光热-免疫联合治疗DNA纳米制剂的方法，通过DNA碱基互补配对合成包裹化疗药物的微凝胶纳米颗粒,具体步骤如下：
1)DNA-A@核酸适配体聚合物链的制备；
2)CpG-ODN聚合物链的制备；
3)ICG@DNA微凝胶的制备及收集。
4)将微凝胶粉末溶于3ml 20-40mg/ml的DOX溶液中透析，以300r/min速度搅拌过夜，1000r/min十分钟离心收集。
2、根据权利要求1所述的肿瘤光热-免疫联合治疗DNA纳米制剂的方法，其特征是，所述步骤1)具体如下：
(1)室温下，将4uL 10-12mg/ml的DNA-A水溶液，3uL 5-8mg/ml的核酸适配体水溶液，2uL 1-2mg/mL的N-异丙基丙烯酰胺，1uL 1％2-羧基-40-(2-羧乙氧基)-2-甲基-苯丙酮引发剂水溶液，10-15uL的Tris缓冲液(pH＝8.0)和25-30uL的超纯水混合，以400rpm速度搅拌；
(2)随后该混合溶液在波长为365nm的紫光灯下照射5min。
所述步骤2)具体如下：
(1)室温下，将10uL 10-12mg/ml的CpG-ODN水溶液，1uL 0.5-1mg/mL的N-异丙基丙烯酰胺，1uL 1％2-羧基-40-(2-羧乙氧基)-2-甲基-苯丙酮引发剂水溶液，20-25uL的Tris缓冲液(pH＝8.0)和25-30uL的超纯水混合，以400rpm速度搅拌；
(2)随后该混合溶液在波长为365nm的紫光灯下照射5min。
所述步骤3)具体如下：
(1)室温下，将50uL DNA-A溶液，5uLCpG-ODN溶液，2uLICG和5u 3-4mg/ml的连接DNA水溶液充分混合，得到混合溶液。
(2)将混合溶液在80℃水浴锅中孵育5min，随后缓慢冷却至室温。
(3)将得到的微凝胶溶液装入截留分子量为8000的透析袋中在Tris缓冲液中透析2-3天，最后离心收集，清水洗涤三次。
(4)将收集到的微凝胶颗粒放在-55℃真空干燥箱中冷冻干燥至粉末状态。
本发明的优势在于：
1)DNA互补配对作为交联原理，避免了化学交联剂的潜在毒性，提高了微凝胶的生物相容性。
2)微凝胶纳米级的粒径对肿瘤区域具有被动靶向作用，药物能够在肿瘤区域聚集。
3)核酸适配体对肿瘤区域具有主动靶向作用，更加精准作用于肿瘤区域，避免了对正常组织的伤害。
4)微凝胶在肿瘤区域酸性条件下能够灵敏感应，体积缩小，从而释放药物。
5)CpG-ODN以模拟细菌DNA可以诱发机体产生强烈的Th1型免疫应答，将化学治疗与免疫治疗联合，极大地增强肿瘤治疗的效果，使肿瘤治疗更加彻底。
6)ICG的光热效应杀伤肿瘤细胞，增强了肿瘤治疗效果。
附图说明
图1：微凝胶作用机理示意图。
具体实施方式
实施例1：
DNA-A@核酸适配体聚合物链的制备
(1)室温下，将4uL 15mg/ml的DNA-A水溶液，3uL 5mg/ml的核酸适配体水溶液，2uL1mg/mL的N-异丙基丙烯酰胺，1uL 1％2-羧基-40-(2-羧乙氧基)-2-甲基-苯丙酮引发剂水溶液，15uL的Tris缓冲液(pH＝8.0)和25uL的超纯水混合，以400rpm速度搅拌；
(2)随后该混合溶液在波长为365nm的紫光灯下照射5min。
实施例2：
CpG-ODN聚合物链的制备
(1)室温下，将10uL 10mg/ml的CpG-ODN水溶液，1uL 1mg/mL的N-异丙基丙烯酰胺，1uL 1％2-羧基-40-(2-羧乙氧基)-2-甲基-苯丙酮引发剂水溶液，25uL的Tris缓冲液(pH＝8.0)和25uL的超纯水混合，以400rpm速度搅拌；
(2)随后该混合溶液在波长为365nm的紫光灯下照射5min。
实施例3：
DNA微凝胶的制备及收集
(1)室温下，将50uL DNA-A聚合物链溶液，5uL CpG-ODN聚合物链溶液和5u 5mg/ml的连接DNA水溶液充分混合，得到混合溶液。
(2)将混合溶液在80℃水浴锅中孵育5min，随后缓慢冷却至室温。
(3)将得到的微凝胶溶液装入截留分子量为8000的透析袋中在Tris缓冲液中透析2-3天，最后离心收集，清水洗涤三次。
(4)将收集到的微凝胶颗粒放在-55℃真空干燥箱中冷冻干燥至粉末状态。
实施例4：
微凝胶的载药
(1)将微凝胶粉末溶于3ml 40mg/ml的DOX溶液中透析，以300r/min速度搅拌过夜.
(2)以1000r/min的速度进行十分钟离心收集。
吲哚菁绿(ICG)的荧光效应使肿瘤清除的过程可视化，其产生的光热效应也可清除肿瘤细胞。核酸适配体是一段DNA。通常是利用体外筛选技术--指数富集的配体***进化技术从核酸分子文库中得到的寡核苷酸片段。核酸适配体能与多种目标物质高特异性、高选择性地结合，因此被广泛应用于生物传感器领域。本发明合成的微凝胶的粒径在100nm以下，通过静脉注射后会聚集在肿瘤部位，具有对肿瘤的被动靶向作用。且DNA-A聚合物链上的靶向4T1肿瘤表面的核酸适配体，可以实现对肿瘤的主动靶向，从而更高效地把化疗药物输送至肿瘤部位，并且减少对正常组织的伤害。细菌DNA具有广谱的免疫刺激作用,有实验证明人工合成的CpG-ODN可以模拟细菌DNA诱发机体产生强烈的Th1型免疫应答,CpG-ODN作为一种新型的免疫佐剂已成为分子免疫学研究的热点之一。该微凝胶纳米颗粒将化学治疗与免疫治疗联合，极大地增强肿瘤治疗的效果，使肿瘤治疗更加彻底。
序列表
<110> 天津大学
<120> 肿瘤光热-免疫联合治疗DNA纳米制剂的方法
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<213> 人工序列(Artificial Sequence)
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<213> 人工序列(Artificial Sequence)
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aggtactgca aggactgcaa ggagagagac 30
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cctgacagtc gagaccgtgg cggtggctta aaccgacggc cgggccaccg gggtcctagg 60

Claims (3)

1.肿瘤光热-免疫联合治疗DNA纳米制剂的方法，其特征是，通过DNA碱基互补配对合成包裹化疗药物的微凝胶纳米颗粒,具体步骤如下：
1)DNA-A@核酸适配体聚合物链的制备；
2)CpG-ODN聚合物链的制备；
3)ICG@DNA微凝胶的制备及收集；
4)将微凝胶粉末溶于3ml 20-40mg/ml的DOX溶液中透析，以300r/min速度搅拌过夜，1000r/min十分钟离心收集。
2.根据权利要求1所述的肿瘤光热-免疫联合治疗DNA纳米制剂的方法，所述步骤1)具体如下：
(1)室温下，将4uL 10-12mg/ml的DNA-A水溶液，3uL 5-8mg/ml的核酸适配体水溶液，2uL1-2mg/mL的N-异丙基丙烯酰胺，1uL 1％2-羧基-40-(2-羧乙氧基)-2-甲基-苯丙酮引发剂水溶液，10-15uL的Tris缓冲液(pH＝8.0)和25-30uL的超纯水混合，以400rpm速度搅拌；
(2)随后该混合溶液在波长为365nm的紫光灯下照射5min；
所述步骤2)具体如下：
(1)室温下，将10uL 10-12mg/ml的CpG-ODN水溶液，1uL 0.5-1mg/mL的N-异丙基丙烯酰胺，1uL 1％2-羧基-40-(2-羧乙氧基)-2-甲基-苯丙酮引发剂水溶液，20-25uL的Tris缓冲液(pH＝8.0)和25-30uL的超纯水混合，以400rpm搅拌；
(2)随后该混合溶液在波长为365nm的紫光灯下照射5min；
所述步骤3)具体如下：
(1)室温下，将50uL DNA-A溶液，5uL CpG-ODN溶液，2uLICG和5uL 3-4mg/ml的连接DNA水溶液充分混合，得到混合溶液；
(2)将混合溶液在80℃水浴锅中孵育5min，随后缓慢冷却至室温；
(3)将得到的微凝胶溶液装入截留分子量为8000的透析袋中在Tris缓冲液中透析2-3天，最后离心收集，清水洗涤三次；
(4)将收集到的微凝胶颗粒放在-55℃真空干燥箱中冷冻干燥至粉末状态。
3.根据权利要求1所述的肿瘤光热-免疫联合治疗DNA纳米制剂的方法，所述碱基序列具体如下：
DNA-A:5'-Acrydite-GTCTCTCTCC-3'
CpG-ODN:5'-Acrydite-TCCATGACGTTCCTGACGTT-3'
Linker DNA:5'-Acrydite-AGGTACTGCAAGGACTGCAAGGAGAGAGAC-3'
Aptamer:
5'-Acrydite-
CCTGACAGTCGAGACCGTGGCGGTGGCTTAAACCGACGGCCGGGCCACCGGGGTCCTAGG-3'。
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