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化学进展 2020, Vol. 32 Issue (2/3): 331-343 DOI: 10.7536/PC190332 前一篇   后一篇

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基于PHPMA的生物医用功能高分子

张芬铭1,2,3, 田语舒3, 郑绩3, 陈堃3, 冯岸超1,2,3,**(), 张立群1,2,3   

  1. 1. 北京化工大学 有机无机复合材料国家重点实验室 北京 100029
    2. 北京化工大学 北京新型高分子材料制备与加工重点实验室 北京 100029
    3. 北京化工大学 材料科学与工程学院 北京 100029
  • 收稿日期:2019-03-26 出版日期:2020-03-15 发布日期:2019-10-15
  • 通讯作者: 冯岸超

Biomedical Functional Polymer Based on PHPMA

Fenming Zhang1,2,3, Yushu Tian3, Ji Zheng3, Kun Chen3, Anchao Feng1,2,3,**(), Liqun Zhang1,2,3   

  1. 1. State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijng 100029, China
    2. Beijing Key Laboratory of preparation and processing of new polymer materials, Beijing University of Chemical Technology, Beijing 100029, China
    3. College of Materials Science and Engineering, Beijing University of Chemical Technology, Beijing 100029, China
  • Received:2019-03-26 Online:2020-03-15 Published:2019-10-15
  • Contact: Anchao Feng
  • About author:

聚(N-(2-羟丙基)甲基丙烯酰胺) (PHPMA)作为一种应用较广的水溶性聚合物,具有结构稳定性、非免疫原性以及良好的亲水性,可在人体中代谢,因此这种药物载体在过去几十年中被广泛运用于抗癌药物载药体系的研究。将PHPMA作为药物载体,连接不同功能基团,可使药物准确地在特定区域表达或释放,由此完成对疾病的检测或治疗。科学家进一步改进了载体的可降解性,降低了系统的细胞毒性,使这一体系获得更广阔的应用前景。目前为止只有少数的综述论文对这一领域进行了总结,几乎全部是从材料的生物功能方面进行阐述,而忽视了对材料制备方法的关注。为了弥补这一空白,本文从聚合物键合药物方式的独特分类视角,分别从共价键键合以及非共价键合的角度进行归纳整理,同时对于外界刺激可断裂型的材料进行了详细的论述,以期为科研工作者提供更多的启示。

Poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA), a water soluble polymer bearing a stable structure, can be metabolized in the human body. Because of that, PHPMA is widely used in anticancer drug’s delivery systems. The drug delivery systems based on the PHPMA have been extensively studied over the past few decades. Scientists use different kinds of functional groups to modify the polymer, which can deliver drugs to targeted tissue or detect pathogenic tissue. In recent studies, scientists enhance the degradability of the polymer and decrease the cytotoxicity, which makes the delivery system based on PHPMA more suitable to be utlized in human body. In this paper, we summarize the recent works about PHPMA and studies of different methods to modify the polymer with drugs or functional groups.

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图式1 含硫醇末端基团的HPMA基聚合物的合成[10]
Scheme 1 Scheme 1 Synthesis of HPMA based polymers bearing thiol end groups for radioactive labeling with 72/74As [10]
图式1 用RAFT合成方法制备带有硫醇末端官能团的HPMA与AMA共聚物[16]
Scheme 2 Scheme 2 Synthesis of copolymer of HPMA and allyl methacrylate (AMA) via RAFT and subsequent conjugation with thiolated α(1,2)-trimannoside using thiol-ene chemistry [16]
图1 PBS/PRDL共聚物(左)、PHPMA-chol(中)和PHPMA-chol-DOX(右)的分子结构。纳米颗粒的结构示意图(PBS/PBDL-黑色,PHPMA-蓝色,胆固醇-黄色,DTXL-绿色,DOX-红色)[20]
Fig.1 Molecular structure of the PBS/PBDL copolyester-left, PHPMA-chol-middle and PHPMA-chol-DOX-right (top) and schematic representation of the prepared NPs (bottom) (PBS/PBDL-black, PHPMA-blue, cholesterol anchor-yellow, DTXL-green, and DOX-red) [20]
图2 细胞内聚合物主链的降解,将DOX从含有β-SITO的HPMA交联胶束中释放[22]
Fig.2 Illustration of acid-specific intracellular backbone degradation and release of doxorubicin (DOX) from cross-linked micelles of HPMA copolymers containing β-sitosterol (β-SITO) [22]
图3 多功能胶束纳米颗粒的制备[23]
Fig.3 Schematic illustration for the fabrication of multifunctional micellar nanoparticles [23]
图式3 HPMA共聚物- PTX缀合物的合成:(A)合成传统的HPMA共聚物-紫杉醇缀合物(P-PTX);(B)合成多块主干生物可降解的HPMA共聚物-紫杉醇缀合物(mP-PTX)[25]
Scheme 3 Scheme 3 Synthetic scheme of HPMA copolymer-PTX conjugates. (A) Synthesis of traditional HPMA copolymer-paclitaxel conjugate (P-PTX). (B) Synthesis of multiblock backbone biodegradable HPMA copolymer-paclitaxel conjugate (mP-PTX) [25]
图4 (A)经125I标记的P-PTX/mP-PTX的药物,静脉注射后,移植A2780人体卵巢癌的小鼠SPECT/CT成像结果。异体移植卵巢癌的小鼠分别感染P-PTX和mP-PTX的情况。L:肝S:脾B:膀胱T:肿瘤。(B) 经不同PTX的药物治疗后,癌组织的照片[25]
Fig.4 (A) SPECT/CT imaging of mice bearing orthotopic A2780 human ovarian carcinoma after intravenous injection of 125I-labeled P-PTX or mP-PTX. L, liver; S, spleen; B, bladder; T, tumor. (B) Photographs of tumors after treatment with different PTX formulations [25]
图式4 HPMA共聚物和TAT的缀合物的结构示意图[27]
Scheme 4 Scheme 4 Structures of HPMA copolymer TAT conjugates [27]
图5 DOX在血液和肿瘤中的动力学研究:(A)DOX在肿瘤组织中的蓄积情况; (B) DOX在血液中的清除情况; (C)瘤血比[37]
Fig.5 Kinetics of DOX in the blood and tumour after i.v. administration of HPMA copolymer-DOX conjugates. (A) Accumulation of DOX in tumour tissue; (B) Blood clearance of DOX; (C) Tumour to blood ratio[37]
图式5 P-SS-Mce 6的合成[39]
Scheme 5 Scheme 5 Synthetic scheme for P-SS-Mce6 [39]
图式6 RAFT聚合法制备还原性HPMA-共聚物[41]
Scheme 6 Synthesis of reducible HPMA-co-oligolysine copolymers via reversible-addition fragmentation chain transfer (RAFT) polymerization [41]
图6 以金纳米颗粒为牺牲模板合成纳米胶囊:(1)纳米颗粒组装;(2)交联;(3)GNP核心移除。[42]
Fig.6 Synthesis of nano-capsules using gold nanoparticles, (1) assembly of nanoparticles, (2) crosslinking, (3) removal of GNP cores [42]
图7 反微乳液边缘聚合(IMEPP)合成空心纳米颗粒[43]
Fig.7 Using miniemulsion periphery RAFT polymerization (IMEPP) approach to prepare hollow polymeric nanoparticles [43]
图8 通过互补肽链过二聚作用形成分子,(A)非共价的基于PHPMA的聚合物治疗药物,(B)该非共价聚合物治疗药物的细胞内吞途径及其细胞内释放[45]
Fig.8 (A) Schematic illustration of the structure of the proposed noncovalent poly(N-(2-hydroxypropyl)methacrylamide) (PHPMA)- based polymer therapeutics. (B) Envisioned pathway for the cell uptake of the proposed noncovalent polymer therapeutics and subsequent intracellular release of the cargo. In this illustration, the drug is represented by a red star [45]
图9 (a) (CCK)-Polymer的合成 (b) Fab’-(CCE)的合成[46]
Fig.9 (a) synthesis of (CCK)-Polymer; (b) synthesis of Fab’-(CCE) [46]
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