叶酸修饰的pH响应共聚物混合胶束用于抗癌药物递送

doi:10.11949/0438-1157.20240965

摘要/Abstract

摘要：

对聚乙二醇（PEG）进行末端溴化、酯化等聚合前改性，然后引发甲基丙烯酸-2-羟乙酯（HEMA）、甲基丙烯酸N，N-二乙氨基乙酯（DEAEMA）进行原子转移自由基聚合（ATRP）反应合成含叶酸的pH响应共聚物P1（FA-PEG-PHEMA-PDEAEMA）。通过开环、溴化和ARGET ATRP反应合成共聚物聚己内酯-聚甲基丙烯酸-2-羟乙酯-聚甲基丙烯酸单甲氧基聚乙二醇酯P2（PCL-PHEMA-PEGMA）。通过¹H NMR、FTIR和GPC表征了共聚物的结构、分子量及分子量分布。共聚物P1、P2和混合共聚物P1/P2的CMC值分别为5.02、1.58与2.51 mg/L，说明共聚物能够在溶液中形成稳定的胶束。通过透析法制备各载药胶束，形貌均呈球状，混合共聚物胶束MM综合载药性能和药物控制释放性能均优于单共聚物胶束。含叶酸载药胶束对HepG2细胞有更好的抑制作用。

关键词: 共聚物, 混合胶束, 药物递送, 合成

Abstract:

Folate-modified pH-sensitive copolymer P1 (FA-PEG-PHEMA-PDEAEMA) was prepared by end-bromination, esterification, and atom transfer radical polymerization (ARGET ATRP) reaction. Copolymer P2 (PCL-PHEMA-PEGMA) was synthesized by ring-opening, bromination, and ATRP reactions. The structure, molecular weight, and molecular weight distribution of the copolymers were tested by ¹H NMR, FTIR, and GPC. The CMC values of copolymers P1, P2, and mixed copolymer P1/P2 were 5.02, 1.58 and 2.51 mg/L, respectively, indicating that the copolymers could form stable micelles in solution. The drug-loaded micelles were prepared by dialysis method, and the morphology was spherical. The comprehensive drug loading performance and drug controlled release performance of mixed copolymer micelles MM were better than those of single copolymer micelles. Folate-modified drug-loaded micelles exhibited better inhibitory effects on HepG2 cells.

Key words: copolymer, mixed micelles, drug delivery, synthesis

中图分类号:

TQ 323.9

赵海钎, 陈方, 陈涛, 郭建维, 林文静, 杨楚芬. 叶酸修饰的pH响应共聚物混合胶束用于抗癌药物递送[J]. 化工学报, 2025, 76(4): 1702-1710.

Haiqian ZHAO, Fang CHEN, Tao CHEN, Jianwei GUO, Wenjing LIN, Chufen YANG. Folate-modified pH-responsive copolymer mixed micelles for anticancer drug delivery[J]. CIESC Journal, 2025, 76(4): 1702-1710.

图/表 9

图1 P1(a)和P2(b)的合成路线

Fig.1 Synthesis routes of P1 (a) and P2 (b)

图2 PEG、PEG-i-BuBr、FA、FA-PEG-i-BuBr、P1、PCL、PCL-i-BuBr和P2的1H NMR谱图[图（d）、（e）的溶剂为CDCl3，其他溶剂为DMSO-d6]

Fig.2 1H NMR spectra of PEG, PEG-i-BuBr, FA, FA-PEG-i-BuBr, P1, PCL, PCL-i-BuBr and P2[The solvent of Figs.(d) and (e) was CDCl3, while the solvent of others was DMSO-d6]

图3 共聚物P1和P2及其前体的FTIR谱图

Fig.3 FTIR spectra of polymer P1, P2 and their precusors

表1 共聚物的GPC和1H NMR结果

Table 1 GPC and 1H NMR results of polymer

Sample	M_{n, GPC}	M_{n, NMR}	M_{n, TH}	M_w/M_n
PEG₁₁₂-i-BuBr	5537	5600	5200	1.36
FA-PEG₁₁₂-i-BuBr	6076	6100	5700	1.48
FA-PEG₁₁₂-PHEMA₂₀-PDEAEMA₄₀	12497	12000	14400	1.37
PCL₇₀	7680	7300	7900	1.57
PCL₇₀-i-BuBr	8241	8000	8100	1.74
PCL₇₀-PHEMA₂₀-PPEGMA₁₅	16053	15500	17700	1.39

图4 共聚物P1和P2及其前体的GPC洗脱曲线

Fig.4 GPC curves of polymer P1, P2 and their precusors

图5 I337/I331与共聚物P1、P2和P1/P2的浓度对数关系

Fig.5 I337/I331vs logarithm of P1, P2 and P1/P2 concentrations

表2 载药胶束的粒径和载药性能

Table 2 DLS and DOX-loading property results of DOX loaded micelles

Sample	(DOX/Polymer)/(mg/mg)	Size/nm	PDI	LC/%	EE/%
P1M	15/30	91.60±3.41	0.30	17.56±0.02	52.69±0.06
P2M	15/30	151.77±2.95	0.16	21.28±0.19	63.85±0.56
MM	5/30	127.20±7.00	0.09	9.78±0.07	68.47±0.51
	10/30	130.43±15.57	0.16	13.54±0.57	64.16±2.29
	15/30	133.13±1.10	0.14	20.19±0.05	60.58±0.14
	20/30	135.13±2.72	0.16	21.24±0.18	53.10±0.46
	25/30	183.77±20.75	0.13	22.05±0.01	48.51±0.03
	30/30	204.47±19.38	0.18	23.32±0.29	46.64±0.58
MM1	15/30	130.26±11.04	0.19	20.41±0.63	60.02±0.03

图6 载药胶束DLS粒径图和TEM图

Fig.6 DLS and TEM images of DOX-loaded micelles

图7 MM载药胶束的形成和药物释放示意图(a)；载药胶束的药物释放(b)和细胞毒性[(c),(d)]结果

Fig.7 The formation and DOX release of MM(a); DOX release(b) and cell viability [(c),(d)] results of drug-loaded micelles

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