CN114191410A - 一种诊疗一体化双亲微球缓释微球的制备方法 - Google Patents
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Abstract
本发明公开了一种用于诊疗一体化双亲微球缓释微球的研究领域的制备技术,具体地说,是以壳聚糖为原料,通过微流控方法制成具有诊疗一体化双亲微球缓释微球。该方法特征在于,以PEOz‑CS嵌段共聚物为基本骨架构建微球缓释体基材。再利用微流控方式,盐析、透析法精制缓释微球。整个制备过程中,缓释微球损失少、变性小、得率高。
Description
技术领域
本发明涉及一种用于诊疗一体化双亲微球缓释微球的研究领域的制备技术,具体地说,是以壳聚糖为原料,通过微流控方法制成具有诊疗一体化双亲微球缓释微球。
背景技术
近年来我国癌症发病形势严峻,发病率与死亡率呈持续上升趋势。近期,国家癌症中心发布了2017中国城市癌症数据最新报告,该报告汇总了全国347家癌症登记点的数据。数据显示,全国每天约1万人确诊癌症,肺癌为发病率、死亡率双率第一。
本申请项目的研究针对淋巴管畸形微环境,集中于逆转肿瘤耐药作用的微球缓释体系的构建,核心目标是实现药物的靶向治疗和可控释放行为;以及在近红外光作用下实现成像/治疗的双重目的。实现这些目标的关键是设计和筛选对于肿瘤细胞器和细胞内环境具有特异性和响应性给药能力的高分子复合体系。设计合成一系列结构明确、功能可预期,在肿瘤组织微环境中具有响应递药性能的两亲性高分子,获得具有抑制跨膜转运蛋白外排功能的微球缓释体系。因此,我们以壳聚糖为原料,通过微流控方法制成具有诊疗一体化双亲微球缓释微球。其具有广阔的市场前景。
发明内容
本发明的目的是克服现有缓释微球的不足,采用微流控方法获取具有诊疗一体化双亲微球缓释微球。这种制备方法可以癌症治疗需要。
本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。基于针对肿瘤细胞器酸性环境作出响应的目标,将具有促内涵体逃逸功能的PBAE引入聚合物主链,预期可降低抗肿瘤药物在溶酶体中的代谢。通过选择不同的PBAE主链和侧链,考察不同结构的高分子载体对内涵体的逃逸能力和对亚细胞环境进行响应性传递药物的性能。为提高细胞毒药物治疗肿瘤的效果和特异性,将肿瘤靶向基元叶酸等分子结合到聚合物上。
设计结合有淋巴管畸形细胞靶向信号分子的聚膦腈两亲高分子,其主链由氮磷双键构成,侧链分别为可在酸性环境下质子化的DPA、EAB等和亲水性的PEG,PEG末端修饰靶向性基元。利用该高分子制备的胶束共装载抗肿瘤药物,微球胶束在进入细胞内涵体后由于聚合物侧基DPA和/或EAB的质子化得以逃逸,载药胶束在淋巴管畸形细胞靶向信号介导下定位于淋巴管细胞内部,释放出的细胞毒药物以不同作用机制诱导细胞凋亡,实现联合治疗肿瘤的目的。
具体实施方式
本发明通过以下实例作进一步阐述,但并不限制本发明的范围。这种制造技术的生产工艺对于本专业的人员来说是容易实施的。
例1本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。在pH2的酸性环境下质子化的0.5mol/LDPA和亲水性的1.5mol/L PEG。通过微流控模板,按每次1.5分钟。按溶胀比为1:15-30加入0.5mol/L的乙酸溶液,从而获得改性后的缓释微球。将粗提液和NaCl溶液按重量配比混合,以3500-5500r/min转速离心5-30min,弃去上清液,沉淀用10倍体积的0.5mol/L的乙酸溶解,以3500-5500r/min转速离心5-30min。重复此步3次左右。将透析过后的微球溶液用真空冷冻干燥机进行干燥,即可得诊疗一体化双亲微球缓释微球。
例2本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。在pH2的酸性环境下质子化的0.5mol/L EAB和亲水性的1.5mol/L PEG。通过微流控模板,按每次1.5分钟。按溶胀比为1:15-30加入0.5mol/L的乙酸溶液,从而获得改性后的缓释微球。将粗提液和NaCl溶液按重量配比混合,以3500-5500r/min转速离心5-30min,弃去上清液,沉淀用10倍体积的0.5mol/L的乙酸溶解,以3500-5500r/min转速离心5-30min。重复此步3次左右。将几次盐析过后得到的上清液透析三天,每半天换一次蒸馏水。透析袋孔径为7000。将透析过后的微球溶液用真空冷冻干燥机进行干燥,即可得诊疗一体化双亲微球缓释微球。
Claims (3)
1.一种用于诊疗一体化双亲微球缓释微球的研究领域的制备技术,具体地说,是以壳聚糖为原料,通过微流控方法制成具有诊疗一体化双亲微球缓释微球。
2.一种用于诊疗一体化双亲微球缓释微球的方法,其特征在于:该方法特征在于,以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材。再利用微流控方式,盐析、透析法精制缓释微球。整个制备过程中,缓释微球损失少、变性小、得率高。
3.一种用于诊疗一体化双亲微球缓释微球的方法,其特征在于包含如下步骤:包括以下工艺步骤:
(1)本发明首先是以PEOz-CS嵌段共聚物为基本骨架构建微球缓释体基材;
(2)在pH2的酸性环境下质子化的0.5mol/LDPA和亲水性的1.5mol/LPEG;
(3)通过微流控模板,按每次1.5分钟,备用;
(4)按溶胀比为1:15-30加入0.5mol/L的乙酸溶液,从而获得改性后的缓释微球;
(5)将粗提液和NaCl溶液按重量配比混合,以3500-5500r/min转速离心5-30min,弃去上清液,沉淀用10倍体积的0.5mol/L的乙酸溶解,以3500-5500r/min转速离心5-30min。重复此步3次左右;
(6)干燥样品:将透析过后的微球溶液用真空冷冻干燥机进行干燥,即诊疗一体化双亲微球缓释微球。
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JPH10273447A (ja) * | 1997-01-29 | 1998-10-13 | Takeda Chem Ind Ltd | 徐放性マイクロスフィア、その製造法および用途 |
WO2010062678A2 (en) * | 2008-10-30 | 2010-06-03 | David Liu | Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same |
CN103371974A (zh) * | 2012-04-25 | 2013-10-30 | 中国科学院大连化学物理研究所 | 一种基于微流控技术制备的药物缓释聚合物微球及应用 |
WO2018028058A1 (zh) * | 2016-08-08 | 2018-02-15 | 江南大学 | 一种表面功能化可载药洗脱微球的制备方法 |
US20180221503A1 (en) * | 2015-07-31 | 2018-08-09 | Tarveda Therapeutics, Inc. | Compositions and methods for immuno-oncology therapies |
US20190117799A1 (en) * | 2016-04-01 | 2019-04-25 | The Brigham And Women's Hospital, Inc. | Stimuli-responsive nanoparticles for biomedical applications |
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Patent Citations (6)
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JPH10273447A (ja) * | 1997-01-29 | 1998-10-13 | Takeda Chem Ind Ltd | 徐放性マイクロスフィア、その製造法および用途 |
WO2010062678A2 (en) * | 2008-10-30 | 2010-06-03 | David Liu | Micro-spherical porous biocompatible scaffolds and methods and apparatus for fabricating same |
CN103371974A (zh) * | 2012-04-25 | 2013-10-30 | 中国科学院大连化学物理研究所 | 一种基于微流控技术制备的药物缓释聚合物微球及应用 |
US20180221503A1 (en) * | 2015-07-31 | 2018-08-09 | Tarveda Therapeutics, Inc. | Compositions and methods for immuno-oncology therapies |
US20190117799A1 (en) * | 2016-04-01 | 2019-04-25 | The Brigham And Women's Hospital, Inc. | Stimuli-responsive nanoparticles for biomedical applications |
WO2018028058A1 (zh) * | 2016-08-08 | 2018-02-15 | 江南大学 | 一种表面功能化可载药洗脱微球的制备方法 |
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