Computer simulations on loading and release of antimicrobial peptides by zwitterionic copolymers

doi:10.11949/0438-1157.20240650

Abstract

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

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

CLC Number:

O 641.3

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.

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.

Figures/Tables 10

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

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

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

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

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

Fig.5 Density distribution profiles of 3% drug content

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

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

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

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

References 45

1	Moretta A, Scieuzo C, Petrone A M, et al. Antimicrobial peptides: a new hope in biomedical and pharmaceutical fields[J]. Frontiers in Cellular and Infection Microbiology, 2021, 11: 668632.
2	Jenssen H, Hamill P, Hancock R E W. Peptide antimicrobial agents[J]. Clinical Microbiology Reviews, 2006, 19(3): 491-511.
3	Zhang Q Y, Yan Z B, Meng Y M, et al. Antimicrobial peptides: mechanism of action, activity and clinical potential[J]. Military Medical Research, 2021, 8(1): 48.
4	Tan P, Fu H Y, Ma X. Design, optimization, and nanotechnology of antimicrobial peptides: from exploration to applications[J]. Nano Today, 2021, 39: 101229.
5	Wang C, Hong T T, Cui P F, et al. Antimicrobial peptides towards clinical application: delivery and formulation[J]. Advanced Drug Delivery Reviews, 2021, 175: 113818.
6	Friede M, Muller S, Briand J P, et al. Induction of immune response against a short synthetic peptide antigen coupled to small neutral liposomes containing monophosphoryl lipid A[J]. Molecular Immunology, 1993, 30(6): 539-547.
7	van Gent M E, Ali M, Nibbering P H, et al. Current advances in lipid and polymeric antimicrobial peptide delivery systems and coatings for the prevention and treatment of bacterial infections[J]. Pharmaceutics, 2021, 13(11): 1840.
8	Ghasemiyeh P, Mohammadi-Samani S. Hydrogels as drug delivery systems; pros and cons[J]. Trends in Pharmaceutical Sciences, 2019, 5(1): 7-24.
9	Figueiras A, Domingues C, Jarak I, et al. New advances in biomedical application of polymeric micelles[J]. Pharmaceutics, 2022, 14(8): 1700.
10	Kumar P, Pletzer D, Haney E F, et al. Aurein-derived antimicrobial peptides formulated with pegylated phospholipid micelles to target methicillin-resistant staphylococcus aureus skin infections[J]. ACS Infectious Diseases, 2019, 5(3): 443-453.
11	Knop K, Hoogenboom R, Fischer D, et al. Poly(ethylene glycol) in drug delivery: pros and cons as well as potential alternatives[J]. Angewandte Chemie International Edition, 2010, 49(36): 6288-6308.
12	Li M Z, Zhang W, Li J X, et al. Zwitterionic polymers: addressing the barriers for drug delivery[J]. Chinese Chemical Letters, 2023, 34(11): 108177.
13	He Y, Hower J, Chen S F, et al. Molecular simulation studies of protein interactions with zwitterionic phosphorylcholine self-assembled monolayers in the presence of water[J]. Langmuir, 2008, 24(18): 10358-10364.
14	Harijan M, Singh M. Zwitterionic polymers in drug delivery: a review[J]. Journal of Molecular Recognition, 2022, 35(1): e2944.
15	Dong P, Zhou Y, He W W, et al. A strategy for enhanced antibacterial activity against Staphylococcus aureus by the assembly of alamethicin with a thermo-sensitive polymeric carrier[J]. Chemical Communications, 2016, 52(5): 896-899.
16	Ivanova A, Ivanova K, Tzanov T. Simultaneous ultrasound-assisted hybrid polyzwitterion/antimicrobial peptide nanoparticles synthesis and deposition on silicone urinary catheters for prevention of biofilm-associated infections[J]. Nanomaterials, 2021, 11(11): 3143.
17	Răileanu M, Lonetti B, Serpentini C L, et al. Encapsulation of a cationic antimicrobial peptide into self-assembled polyion complex nano-objects enhances its antitumor properties[J]. Journal of Molecular Structure, 2022, 1249: 131482.
18	Wang C H, Feng S L, Qie J K, et al. Polyion complexes of a cationic antimicrobial peptide as a potential systemically administered antibiotic[J]. International Journal of Pharmaceutics, 2019, 554: 284-291.
19	Sun J W, Jiang L, Lin Y, et al. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides[J]. International Journal of Nanomedicine, 2017, 12: 1517-1537.
20	Lim C, Won W R, Moon J, et al. Co-delivery of d-(KLAKLAK)₂ peptide and doxorubicin using a pH-sensitive nanocarrier for synergistic anticancer treatment[J]. Journal of Materials Chemistry B, 2019, 7(27): 4299-4308.
21	Wang W, Ye Z, Gao H L, et al. Computational pharmaceutics — a new paradigm of drug delivery[J]. Journal of Controlled Release, 2021, 338: 119-136.
22	苏运祥, 全学波, 闵文凤, 等. PAMAM树状大分子负载和释放阿霉素的耗散粒子动力学模拟[J]. 化工学报, 2017, 68(5): 1757-1766.
	Su Y X, Quan X B, Min W F, et al. Dissipative particle dynamics simulations on loading and release of doxorubicin by PAMAM dendrimers[J]. CIESC Journal, 2017, 68(5): 1757-1766.
23	胡建波, 刘洪超, 胡齐, 等. 有机笼跨细胞膜易位行为的分子动力学模拟研究[J]. 化工学报, 2023, 74(9): 3756-3765.
	Hu J B, Liu H C, Hu Q, et al. Molecular dynamics simulation insight into translocation behavior of organic cage across the cellular membrane[J]. CIESC Journal, 2023, 74(9): 3756-3765.
24	Feng Y H, Zhang X P, Zhao Z Q, et al. Dissipative particle dynamics aided design of drug delivery systems: a review[J]. Molecular Pharmaceutics, 2020, 17(6): 1778-1799.
25	Liao M R, Gong H N, Quan X B, et al. Intramembrane nanoaggregates of antimicrobial peptides play a vital role in bacterial killing[J]. Small, 2023, 19(3): e2204428.
26	Ulmschneider J P, Ulmschneider M B. Molecular dynamics simulations are redefining our view of peptides interacting with biological membranes[J]. Accounts of Chemical Research, 2018, 51(5): 1106-1116.
27	Asadzadeh H, Moosavi A. Investigation of the interactions between Melittin and the PLGA and PLA polymers: molecular dynamic simulation and binding free energy calculation[J]. Materials Research Express, 2019, 6(5): 055318.
28	Nejabat M, Soltani F, Alibolandi M, et al. Smac peptide and doxorubicin-encapsulated nanoparticles: design, preparation, computational molecular approach and in vitro studies on cancer cells[J]. Journal of Biomolecular Structure & Dynamics, 2022, 40(2): 807-819.
29	Guo W X, Hu L F, Feng Y H, et al. Advances in self-assembling of pH-sensitive polymers: a mini review on dissipative particle dynamics[J]. Colloids and Surfaces B: Biointerfaces, 2022, 210: 112202.
30	Chen Z, Huo J H, Hao L X, et al. Multiscale modeling and simulations of responsive polymers[J]. Current Opinion in Chemical Engineering, 2019, 23: 21-33.
31	Wang J H, Han Y F, Xu Z Y, et al. Dissipative particle dynamics simulation: a review on investigating mesoscale properties of polymer systems[J]. Macromolecular Materials and Engineering, 2021, 306(4): e2000724.
32	Su Y X, Quan X B, Li L B, et al. Computer simulation of DNA condensation by PAMAM dendrimer[J]. Macromolecular Theory and Simulations, 2018, 27(2): e1700070.
33	Zeng S J, Quan X B, Zhu H L, et al. Computer simulations on a pH-responsive anticancer drug delivery system using zwitterion-grafted polyamidoamine dendrimer unimolecular micelles[J]. Langmuir, 2021, 37(3): 1225-1234.
34	Miao Z H, Chen Z, Wang L, et al. Dual-responsive zwitterion-modified nanopores: a mesoscopic simulation study[J]. Journal of Materials Chemistry B, 2022, 10(14): 2740-2749.
35	Hoogerbrugge P J, Koelman J M V A. Simulating microscopic hydrodynamic phenomena with dissipative particle dynamics[J]. Europhysics Letters, 1992, 19: 155.
36	Groot R D, Warren P B. Dissipative particle dynamics: bridging the gap between atomistic and mesoscopic simulation[J]. The Journal of Chemical Physics, 1997, 107(11): 4423-4435.
37	Groot R D. Electrostatic interactions in dissipative particle dynamics—simulation of polyelectrolytes and anionic surfactants[J]. The Journal of Chemical Physics, 2003, 118(24): 11265-11277.
38	Wang Y L, Laaksonen A, Lu Z Y. Implementation of non-uniform FFT based Ewald summation in dissipative particle dynamics method[J]. Journal of Computational Physics, 2013, 235: 666-682.
39	Groot R D, Madden T J. Dynamic simulation of diblock copolymer microphase separation[J]. The Journal of Chemical Physics, 1998, 108(20): 8713-8724.
40	Wei J C, Liu Y W, Song F. Coarse-grained simulation of the translational and rotational diffusion of globular proteins by dissipative particle dynamics[J]. The Journal of Chemical Physics, 2020, 153(23): 234902.
41	Fan C F, Olafson B D, Blanco M, et al. Application of molecular simulation to derive phase diagrams of binary mixtures[J]. Macromolecules, 1992, 25(14): 3667-3676.
42	Zhu Y L, Liu H, Li Z W, et al. GALAMOST: GPU-accelerated large-scale molecular simulation toolkit[J]. Journal of Computational Chemistry, 2013, 34(25): 2197-2211.
43	Song X Y, Zhao S L, Fang S W, et al. Mesoscopic simulations of adsorption and association of PEO-PPO-PEO triblock copolymers on a hydrophobic surface: from mushroom hemisphere to rectangle brush[J]. Langmuir, 2016, 32(44): 11375-11385.
44	Yang S C, Zhu Y L, Qian H J, et al. Molecular dynamics simulation of antipolyelectrolyte effect and solubility of polyzwitterions[J]. Chemical Research in Chinese Universities, 2017, 33(2): 261-267.
45	Ma M K, Ahsan B, Wang J H, et al. Supramolecular crosslinks enable PIC micelles with tuneable salt stability and diverse properties[J]. Soft Matter, 2019, 15(41): 8210-8218.

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