物理化学学报 >> 2021, Vol. 37 >> Issue (10): 1912053.doi: 10.3866/PKU.WHXB201912053

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光交联固化的聚合物囊泡用于降温触发的药物释放

廖雨瑶1,2, 范震2,3,(), 杜建忠1,2,4,*()   

  1. 1 同济大学附属上海市第十人民医院骨科，同济大学医学院，上海 200072
    2 同济大学材料科学与工程学院高分子材料系，上海 201804
    3 同济大学高等研究院，上海 200092
    4 先进土木工程材料教育部重点实验室，同济大学，上海 201804
  • 收稿日期:2019-12-23 录用日期:2020-02-18 发布日期:2020-03-02
  • 通讯作者: 范震,杜建忠 E-mail:fanzhen2018@tongji.edu.cn;jzdu@tongji.edu.cn
  • 基金资助:
    国家自然科学基金(21674081);国家自然科学基金(21925505);国家自然科学基金(51803152);上海市自然科学基金(19ZR1478800)

Photocrosslinking-Immobilized Polymer Vesicles for Lowering Temperature Triggered Drug Release

Yuyao Liao1,2, Zhen Fan2,3,(), Jianzhong Du1,2,4,*()   

  1. 1 Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China
    2 Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
    3 Institute for Advanced Study, Tongji University, Shanghai 200092, China
    4 Key Laboratory of Advanced Civil Engineering Materials of Ministry of Education, Tongji University, Shanghai 201804, China
  • Received:2019-12-23 Accepted:2020-02-18 Published:2020-03-02
  • Contact: Zhen Fan,Jianzhong Du E-mail:fanzhen2018@tongji.edu.cn;jzdu@tongji.edu.cn
  • About author:Email: jzdu@tongji.edu.cn, Tel.: +86-21-69580239 (J.D.)
    Email: fanzhen2018@tongji.edu.cn (Z.F.)
  • Supported by:
    the National Natural Science Foundation of China(21674081);the National Natural Science Foundation of China(21925505);the National Natural Science Foundation of China(51803152);the Natural Science Foundation of Shanghai, China(19ZR1478800)

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摘要：

光交联固化可以使聚合物囊泡保持稳定的结构，从而使其在生物医学领域具有应用前景。升温是常用的控制药物释放的触发手段，但是其可能会导致细胞损伤，而通过降温进行药物可控释放则能够避免该问题。本文通过可逆加成断裂链转移(RAFT)聚合制备了一种两亲性嵌段共聚物聚氧乙烯-嵌段-聚[(N-异丙基丙烯酰胺-无规-7-(2-甲基丙烯酰氧基乙氧基)-4-甲基香豆素)-嵌段-聚丙烯酸] [PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13]。该共聚物能够在水溶液中自组装形成囊泡。其中，P(NIPAM71-stat-CMA8)嵌段形成囊泡的非均相膜，而PEO链和PAA链形成囊泡的混合冠，囊泡的内部空腔可用于包载亲水性药物。可光交联的CMA基团可增强囊泡的稳定性，而PNIPAM链段赋予了囊泡温度响应特性。温度降低时，囊泡溶胀并响应性释放所包载的药物。通过动态光散射、扫描电子显微镜和透射电子显微镜表征了囊泡的尺寸分布和形貌。为了验证囊泡载药和释药的能力，将一种水溶性抗生素包载在囊泡的空腔内，其在水溶液中释放12 h后，抗生素释放率在25 ℃时比在37 ℃时高近35%。总体而言，这种具有温度响应特性的光交联囊泡为降温触发的药物释放提供了一个范例，有望应用于降温触发药物释放领域。

关键词: 聚合物囊泡, 温敏, 光交联, 可控释药, 可逆加成断裂链转移聚合

Abstract:

The stability of nanocarriers in physiological environments is of importance for biomedical applications. Among the existing crosslinking approaches for enhancing the structural integrity and stability, photocrosslinking has been considered to be an ideal crosslinking chemistry, as it is non-toxic and cost-effective, and does not require an additional crosslinker or generate by-products. Meanwhile, most current temperature-responsive nanocarriers are designed and synthesized for drug release by increasing temperature. However, heating may induce cell damage during triggered drug release. Therefore, lowering temperature-triggered nanocarriers need to be developed for drug delivery and safe drug release during therapeutic hypothermia. In this study, we prepared an amphiphilic block copolymer, poly(ethylene oxide)-block-poly[N-isopropyl acrylamide-stat-7-(2-methacryloyloxyethoxy)-4-methylcoumarin]-block-poly(acrylic acid) [PEO43-b-P(NIPAM71-stat-CMA8)-b-PAA13], by reversible addition fragmentation chain transfer (RAFT) polymerization. Successful synthesis of the polymer was verified by proton nuclear magnetic resonance (1H NMR) and size exclusion chromatography (SEC). The copolymers self-assembled into vesicles in aqueous solution, with the P(NIPAM-stat-CMA) block forming an inhomogeneous membrane and the PEO chains and PAA chains forming mixed coronas. The cavity of this vesicle could be utilized to load hydrophilic drugs. The CMA groups could undergo photocrosslinking and enhance the stability of vesicles in biological applications, and the PNIPAM moiety endowed the vesicle with temperature-responsive properties. Upon decreasing the temperature, the vesicles swelled and released the loaded drugs. The size distribution and morphology of the vesicles were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) experiments. After staining with phosphotungstic acid, the hollow morphology of the vesicles with a phase-separated inhomogeneous membrane was observed by TEM and SEM. The DLS results showed that the hydrodynamic diameter of the vesicles was 208 nm and the polydispersity was 0.075. The size of the vesicles observed by TEM was between 180 and 200 nm, which was in accordance with that measured by DLS. To verify the drug loading capacity and controlled release ability of the vesicle, a water-soluble antibiotic was encapsulated in the vesicles. The experimental results showed that the drug loading content was 10.4% relative to the vesicles and the drug loading efficiency was approximately 32.7%. For vesicles containing the same amount of antibiotics, the release rate at 25 ℃ was 35% higher than that at 37 ℃ after 12 h in aqueous solution. Overall, this photocrosslinked vesicle with temperature-responsive properties facilitates lowering temperature-triggered drug release during therapeutic hypothermia.

Key words: Polymer vesicle, Temperature-sensitive, Photocrosslinking, Controlled drug release, Reversible addition fragmentation chain transfer (RAFT) polymerization

MSC2000: 

  • O648