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化学进展 2022, Vol. 34 Issue (8): 1723-1733 DOI: 10.7536/PC220414 前一篇   后一篇

• 综述 •

酶响应性线形-树枝状嵌段共聚物的合成、性能及应用

宝利军, 危俊吾, 钱杨杨, 王雨佳, 宋文杰, 毕韵梅*()   

  1. 云南师范大学化学化工学院 昆明 650500
  • 收稿日期:2022-04-14 修回日期:2022-06-06 出版日期:2022-07-20 发布日期:2022-07-20
  • 通讯作者: 毕韵梅
  • 作者简介:

    作者简介：毕韵梅 教授,云南省中青年学术技术带头人。2001年,在中国科学院兰州化学物理研究所获博士学位。曾在美国宾夕法尼亚州立大学和加州大学戴维斯分校做访问学者。致力于药用高分子材料研究,设计合成出多种具有酶、pH和温度响应性的线形、线形-树枝状、环形等聚合物,在药物的主动和靶向释放系统具有应用价值。主持科研项目15项,其中国家自然科学基金4项。获授权发明专利9件。发表学术论文90余篇。

  • 基金资助:
    国家自然科学基金项目(21564017)
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Synthesis, Properties and Applications of Enzyme-Responsive Linear-Dendritic Block Copolymers

Lijun Bao, Junwu Wei, Yangyang Qian, Yujia Wang, Wenjie Song, Yunmei Bi()   

  1. College of Chemistry and Chemical Engineering, Yunnan Normal University,Kunming 650500, China
  • Received:2022-04-14 Revised:2022-06-06 Online:2022-07-20 Published:2022-07-20
  • Contact: Yunmei Bi
  • Supported by:
    National Natural Science Foundation of China(21564017)

酶响应性线形-树枝状嵌段共聚物(LDBCs)能对内源性酶产生特异性响应,与只能对外源性刺激信号(如温度、光等)产生响应的聚合物相比,酶响应性LDBCs具有高选择性和更好的生物相容性,作为生物医用材料更适合在人体内使用。通过变换LDBCs的酶响应基团、线形链和树枝化基元,可调控酶响应性两亲LDBCs的自组装和酶响应性解组装性能。由于其独特的酶响应性能和优良的生物相容性,在药物递送和生物医学影像等方面有广阔的应用前景。本文总结归纳了酶响应性LDBCs的合成方法、LDBCs的结构(如线形链长度和结构、树枝化基元的疏水性)对其自组装性能和酶响应性能的影响以及应用,并对酶响应性LDBCs的发展方向进行了展望。

关键词： 酶响应, 线形-树枝状嵌段共聚物, 合成方法, 结构与性能, 药物载体

Linear-dendritic block copolymers (LDBCs) are composed of a linear polymer and dendrimers (dendrons). They not only combine the characteristics of the two types of polymers, but also have unique structures and properties. Furthermore, stimuli-responsive LDBCs can be generated through the selection and structural modification of their linear chains and dendrons. Stimuli-responsive LDBCs have attracted much attention in recent years because of combining the ability to respond to a specific stimulus and different polymeric architectures for a broad range of applications, including drug delivery, gene therapy and materials science. Among them, enzyme responsive LDBCs are able to specifically respond to endogenous enzymes. Compared with the polymers that are able to only respond to exogenous stimuli such as temperature, light, etc, enzyme responsive LDBCs have high selectivity and better biocompatibility. Therefore, they are more suitable for application in in vivo as biomedical materials. Amphiphilic enzyme responsive LDBCs are capable of self-assembling in aqueous solution into nano-aggregates and disassembling to release payloads upon enzymatic stimuli. Additionally, the self-assembly and enzyme responsive disassembly properties of amphiphilic enzyme responsive LDBCs can be adjusted by changing the enzyme-responsive groups, linear chains and dendrons of LDBCs. Due to their unique enzyme response properties and excellent biocompatibility, enzyme responsive LDBCs have broad application prospects in drug delivery, biomedical imaging, etc. Herein, this review summarizes the synthetic approaches of enzyme responsive LDBCs, the effect of the structures such as the length and structure of linear chain, and hydrophobicity of dendrons of the LDBCs on their self-assembly properties and enzyme-responsive properties. The applications of these copolymers are also introduced. Finally, the research prospect of enzyme responsive LDBCs are proposed.

Contents

1 Introduction

2 Synthetic approaches for enzyme responsive linear-dendritic block copolymers (LDBCs)

2.1 The divergent approach

2.2 The convergent approach

2.3 The coupling approach

3 Effect of LDBCs structures and enzyme concentration on the properties of enzyme responsive LDBCs

3.1 The effect of different enzyme responsive groups in the LDBCs

3.2 The effect of linear chain length of the LDBCs

3.3 The effect of linear chain structure and type of the LDBCs

3.4 The effect of hydrophobicity of dendrons in the LDBCs

3.5 The effect of enzyme concentration

4 Application of enzyme responsive LDBCs

4.1 As a drug carrier

4.2 Application in the field of fluorescent imaging probes

5 Conclusion and outlook

Key words: enzyme responsiveness, linear-dendritic block copolymers (LDBCs), synthetic approaches, structures and properties, drug carriers
()
图1 酶响应性LDBCs的结构[11,22,23]
Fig. 1 Structures of enzyme responsive LDBCs[11,22,23]
图2 发散法合成PNVP-b-dendr(Phe-Lys)n (n =1~3) 酶响应性LDBCs的合成路线[11]
Fig. 2 Synthesis of enzyme responsive LDBCs PNVP-b-dendr(Phe-Lys)n (n =1~3) by a chain-first approach[11]
图3 收敛法合成酶响应性LDBCs(bis-MPA-Gn-b-PHEG (n = 1, 2)[23]
Fig. 3 Synthesis of enzyme responsive LDBCs (bis-MPA-Gn-b-PHEG (n = 1, 2) ) by a dendron-first approach[23]
图4 偶合法合成酶响应性LDBCs[35]
Fig. 4 Synthesis of enzyme responsive LDBCs by a coupling approach[35]
表1 LDBCs中的酶响应性基团
Table 1 Enzyme responsive groups in LDBCs
LDBCs Response groups Enzyme ref
PEG-Dendron phenyl acetamide groups Penicillin G acylase (PGA) 22,37
PEG-Dendron ester groups Porcine liver esterase (PLE) 38
PEG、PEtOx or PAA-Dendron 35
PEG10kDa-dend-(Hex)4 and (PEG5 kDa)2-dend-(Hex)4 36
LD-DOX/Ce6 peptide bonds Cathepsin B 39
PNVCLn-b-D(Phe-Lys)1-3 (n=66,100) amide bonds and ester groups Papain 40
G-b-PHEG and PHEG-Gn-bis-MPA 23
PNVCL-b-Gn-Fmoc-Gly (n=1,2) 12
图5 LDBCs胶束在酶作用下解组装的机理[22]
Fig. 5 Mechanism of disassembly of LDBCs micelles upon enzymatic activation[22]
图6 亲水性线形链的结构对LDBCs胶束酶响应性自组装的影响[36]
Fig. 6 Effect of linear and V-shaped hydrophilic blocks on enzyme responsive disassembly properties of LDBC micelles[36]
图7 以共价方式或非共价方式搭载疏水性小分子的LDBCs胶束的酶响应性释放[52]
Fig. 7 Enzyme-responsive release of LDBCs micelles loaded with hydrophobic small molecules in a covalent or non-covalent manner[52]
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