聚磷酸酯-紫杉醇前药合成及其还原响应药物释放研究

doi:10.11949/0438-1157.20240513

摘要/Abstract

摘要：

用单甲氧基聚乙二醇（mPEG）大分子引发剂引发2-丁烯氧基-2-氧代-1，3，2-二氧磷杂环戊烷（BenEP）开环聚合制备了嵌段共聚物mPEG₄₄-b-PBenEP₄₄，通过点击反应、酯化反应等聚合后改性方法，将二硫键与紫杉醇引入PBenEP链段的侧链，制备了一种还原响应性聚磷酸酯基紫杉醇前药mPEG₄₄-b-（PBenEP₃₄-g-SS-PTX₃）（PEBSP），其载药量为14.57%。PEBSP的自组装行为研究表明：PEBSP在水中能形成平均直径约为71 nm的球形纳米颗粒，其临界胶束浓度是60 mg∙L^-1；PEBSP球形纳米颗粒在正常条件下能稳定存在，在还原性介质中（10 mmol·L^-1谷胱甘肽）会因为二硫键断裂，可控、持续地释放药物紫杉醇。

关键词: 聚磷酸酯, 前药, 还原响应释放, 聚合物, 纳米材料, 合成

Abstract:

The block copolymer mPEG₄₄-b-PBenEP₄₄ was prepared by the ring-opening polymerization of BenEP with monomethoxy polyethylene glycol (mPEG) as macroinitiator. A reduction-responsive polyphosphate-based paclitaxel prodrug mPEG₄₄-b-(PBenEP₃₄-g-SS-PTX₃) (PEBSP) was prepared by introducing the disulfide bond and paclitaxel into the pendant groups of PBenEP block, and the drug loading content (DLC) is 14.57%. The self-assembly behavior of PEBSP was studied by transmission electron microscopy (TEM), dynamic light scattering (DLS) and fluorescent analyses. The results show that PEBSP can form spherical particles with an average size of 71 nm in aqueous solution, and its critical micelle concentration is determined to be 60 mg∙L^-1. PEBSP spherical nanoparticles can exist stably under normal conditions, and in a reducing medium (10 mmol·L^-1 glutathione), the disulfide bond breaks and the drug paclitaxel is released in a controllable and continuous manner.

Key words: polyphosphoester, prodrug, reduction-responsive release, polymers, nanomaterials, synthesis

中图分类号:

TQ 323.9

陈旭东, 付伟东, 李锦锦, 赵玲, 奚桢浩. 聚磷酸酯-紫杉醇前药合成及其还原响应药物释放研究[J]. 化工学报, 2024, 75(12): 4815-4824.

Xudong CHEN, Weidong FU, Jinjin LI, Ling ZHAO, Zhenhao XI. Synthesis of amphiphilic polyphosphoester-PTX prodrug and its potential in reduction-responsive drug release[J]. CIESC Journal, 2024, 75(12): 4815-4824.

图/表 10

图1 还原响应性聚磷酸酯基紫杉醇前药的合成路线

Fig.1 Synthetic routes of reduction-responsive polyphosphoester based PTX prodrug

图2 PEB(a)、PEBO(b)、PEBS(c)的1H NMR谱图（DMSO-d6）

Fig.2 1H NMR spectra (DMSO-d6) of PEB (a), PEBO (b), and PEBS (c)

图3 大分子引发剂PEG和嵌段共聚物PEB的GPC曲线

Fig.3 GPC traces of macroinitiator PEG and block copolymer PEB

图4 PTX(a)和PEBSP(b)的1H NMR谱图（CDCl3）

Fig.4 1H NMR spectra (CDCl3) of PTX (a) and PEBSP (b)

图5 芘的荧光发射光谱强度与PEBSP水溶液浓度对数的函数关系

Fig.5 Intensity of the fluorescence emission spectrum of pyrene as a function of logarithm concentration of PEBSP in aqueous solution

图6 PEBSP纳米颗粒的TEM粒径分布（插图：TEM图像）(a)，DLS粒径分布(b)

Fig.6 Particle size distribution of PEBSP nanoparticles analyzed from the corresponding TEM image (inset) (a) and measured by DLS (b)

图7 PEBSP纳米颗粒在pH 7.4 (a)， pH 7.4+10 mmol·L -1 GSH (b)中粒径分布随时间的变化

Fig.7 Particle size distribution of PEBSP nanoparticles at various time intervals under different conditions: (a) pH 7.4； (b) pH 7.4+10 mmol·L-1 GSH

图8 PEBSP 纳米颗粒在不同PBS（pH 7.4）中的PTX体外药物释放曲线

Fig.8 In vitro drug release profiles of PTX from PEBSP nanoparticles in PBS (pH 7.4)

图9 PEBSP的自组装及其还原响应性紫杉醇药物释放机理

Fig.9 Schematic illustration of the self-assembly of PEBSP and its reduction-responsive PTX release

图10 不同浓度的聚合物PEBS培养48 h后L929细胞和HepG2细胞的细胞存活率

Fig.10 Cell viability of L929 and HepG2 cells treated with PEBS at different concentrations for 48 h incubation

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