两性离子共聚物负载和释放抗菌肽的计算机模拟

doi:10.11949/0438-1157.20240650

摘要/Abstract

摘要：

采用耗散粒子动力学模拟方法研究由两性离子化合物（PCBMA）或聚乙二醇化合物（PEGMA）修饰的聚赖氨酸-聚乳酸共聚物负载KLA肽和阿霉素的自组装结构与药物负载和释放行为，探讨了共聚物嵌段比、共聚物浓度、载药浓度、离子强度对载药胶束自组装的影响。结果表明，相较于PEGMA体系，当嵌段比变化时，PCBMA体系始终具有良好的胶束结构稳定性，并且能在更宽的浓度范围内形成球形胶束。此外，随着载药浓度的升高，PCBMA体系载药稳定性强于药物偏心分布的PEGMA体系；随着离子强度的升高，其球形胶束结构形成加快。酸性pH条件下，PCBMA体系的药物释放过程符合“膨胀-解胶束化-释放”的机制，PEGMA体系的释放行为过快且不均匀。本研究可在介观尺度上为探究聚合物胶束对抗菌肽与抗癌药物的双重载药/药物释放提供参考，对优化开发载药材料具有一定的指导意义。

关键词: 分子模拟, 介尺度, 聚合物, 自组装, 药物输运, 两性离子材料

Abstract:

The self-assembled structures and drug loading/release behaviors of KLA antimicrobial peptide and doxorubicin loaded by zwitterionic poly(carboxybetaine methacrylate) (PCBMA) or poly(ethylene glycol methacrylate)(PEGMA) modified poly(L-lysine-grafted-2,3-dimethylmaleic anhydride)-poly(lactic acid) copolymers PCBMA/PEGMA-PLL(-g-DMA)-PLA were investigated by dissipative particle dynamics simulations. The effects of copolymer block ratio, copolymer concentration, loading concentration and ionic strength on the micelle self-assembly were investigated. The results show that compared with the PEGMA system, when the block ratio changes, the PCBMA system always has good micelle structure stability and can form spherical micelles in a wider block ratio range. Moreover, at varying copolymer concentrations, the PCBMA system demonstrates a wider range for forming spherical micelles compared with the PEGMA system. With the increase in drug loading concentration, drugs in the PCBMA system exhibited a uniform spherical distribution, while drugs in the PEGMA system displayed an eccentric distribution when the drug concentration exceeded 3%. With the increase of ionic strength, the formation of spherical micelle structure of PCBMA system is accelerated, while PEGMA system cannot maintain the spherical micelle structure. Under the acidic pH condition, the drug release process of PCBMA system conforms to the mechanism of “dilatation-demicellation-release”, and the drug is evenly released into the aqueous solution; while the drug release behavior of PEGMA system is too fast and uneven. This study provides a reference for exploring the dual drug loading/drug release of antimicrobial peptides and anticancer drugs at the mesoscale, and has certain significance for guiding and optimizing the development of drug delivery materials.

Key words: molecular simulation, mesoscale, polymers, self-assembly, drug delivery, zwitterionic materials

中图分类号:

O 641.3

何杰锋, 苗朝虹, 周健. 两性离子共聚物负载和释放抗菌肽的计算机模拟[J]. 化工学报, 2024, 75(12): 4804-4814.

Jiefeng HE, Zhaohong MIAO, Jian ZHOU. Computer simulations on loading and release of antimicrobial peptides by zwitterionic copolymers[J]. CIESC Journal, 2024, 75(12): 4804-4814.

图/表 10

图1 模拟体系的分子结构与粗粒化珠子划分

Fig.1 Molecular structure of simulation system and partitioning of coarse-grained beads

表1 不同珠子之间的排斥力参数aij

Table 1 Repulsive parameters aij between different beads

a_ij	K	O	M	E	B	P	L	A	D1	D2	D3	W	Na⁺	Cl^-
K	104.9
O	113.2	104.9
M	110.1	113.5	104.9
E	112.5	110.5	106.0	104.9
B	115.3	112.5	114.8	—	104.9
P	106.9	111.2	112.4	108.5	110.4	104.9
L	112.4	117.8	110.2	107.0	121.2	107.5	104.9
A	108.6	113.4	113.5	107.4	109.3	106.7	105.3	104.9
D1	129.1	122.5	118.3	118.8	136.5	119.3	113.4	119.2	104.9
D2	122.4	119.3	112.5	111.7	126.9	109.8	111.4	114.1	105.0	104.9
D3	114.5	116.3	116.3	109.5	119.6	107.5	107.2	110.4	108.3	109.5	104.9
W	124.1	128.1	127.6	114.6	105.6	124.6	138.4	117.1	166.3	148.5	141.2	104.9
Na⁺	124.1	128.1	127.6	114.6	105.6	124.6	138.4	117.1	166.3	148.5	141.2	104.9	104.9
Cl^-	124.1	128.1	127.6	114.6	105.6	124.6	138.4	117.1	166.3	148.5	141.2	104.9	104.9	104.9

图2 不同嵌段比的PCBMA体系与PEGMA体系的自组装形貌图

Fig.2 Self-assembly topography of PCBMA system and PEGMA system with different block ratios

图3 不同共聚物浓度的PCBMA体系与PEGMA体系的自组装形貌图

Fig.3 Self-assembly morphologies of PCBMA systems and PEGMA systems with different copolymer concentrations

图4 PCBMA体系与PEGMA体系在不同载药含量下的自组装形貌图

Fig.4 Self-assembled morphologies of PCBMA systems and PEGMA systems at different drug contents

图5 3%载药浓度的数密度分布图

Fig.5 Density distribution profiles of 3% drug content

图6 PCBMA体系在不同离子强度下随模拟时间步长的自组装形貌变化

Fig.6 Time evolution of self-assembly morphologies of PCBMA system under different ionic strengths

图7 PEGMA体系在不同离子强度下随模拟时间步长的自组装形貌变化

Fig.7 Time evolution of self-assembly morphologies of PEGMA system under different ionic strengths

图8 酸性pH条件下载药胶束的药物释放过程: (a) PCBMA体系；(b)PEGMA体系

Fig.8 Drug release processes of drug-loading micelles of PCBMA system (a) and PEGMA system (b) under acidic pH condition

图9 不同pH条件下的RDF曲线: (a)中性PCBMA体系；(b)酸性PCBMA体系；(c)中性PEGMA体系；(d)酸性PEGMA体系

Fig.9 RDF profiles at different pH conditions: (a) PCBMA system at neutral condition; (b) PCBMA system at acidic condition; (c) PEGMA system at neutral condition; (d) PEGMA system at acidic condition

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