树形大分子基药物传输系统结合强度及构型的分子动力学研究

doi:10.7503/cjcu20150050

高等学校化学学报 ›› 2015, Vol. 36 ›› Issue (6): 1156.doi: 10.7503/cjcu20150050

树形大分子基药物传输系统结合强度及构型的分子动力学研究

张法达^1,², 刘轶^2,³(), 徐京城², 李生娟², 汪秀南^1,², 孙玥², 赵新洛³

1. 上海理工大学能源与动力工程学院, 2. 材料科学与工程学院, 上海 200093
3.上海大学物理系, 上海 200444

收稿日期:2015-01-16 出版日期:2015-06-10 发布日期:2015-05-22
作者简介:联系人简介: 刘轶, 男, 博士, 教授, 主要从事计算物理化学研究. E-mail:yiliu@shu.edu.cn
基金资助:
国家自然科学基金(批准号: 51202137, 61240054, 11274222)、上海市科学技术委员会“浦江人才计划”(批准号: 12PJI406500)、上海市科委科技创新高新技术项目(批准号: 14521100602)、上海市教委科技创新重点项目(批准号: 14ZZ130)、上海市教委“先进金属基电功能材料”重点实验室和中国石油大学重质油国家重点实验室开放基金(批准号: SKLOP201402001)资助

Molecular Dynamics Study on Binding Strength and Conformation of Dendrimer-based Drug Delivery Systems^†

ZHANG Fada^1,², LIU Yi^2,^3,^*(), XU Jingcheng², LI Shengjuan², WANG Xiunan^1,², SUN Yue², ZHAO Xinluo³

1. School of Energy & Power Engineering, 2. School of Materials Science and Engineering,University of Shanghai for Science and Technology, Shanghai 200093, China
3.Department of Physics, Shanghai University, Shanghai 200444, China

Received:2015-01-16 Online:2015-06-10 Published:2015-05-22
Contact: LIU Yi E-mail:yiliu@shu.edu.cn
Supported by:
† Supported by the National Natural Science Foundation of China(Nos.51202137, 61240054, 11274222), the “Shanghai Pujiang Talent” Program, China(No.12PJ1406500), the Shanghai High-tech Area of Innovative Science and Technology, China(No.14521100602), the Key Program of Innovative Scientific Research, China(No.14ZZ130), the Key Laboratory of Advanced Metal-based Electrical Power Materials, the Education Commission of Shanghai Municipality and the State Key Laboratory of Heavy Oil Processing, China University of Petroleum, China(No;SKLOP201402001)

摘要/Abstract

摘要：

采用全原子分子动力学方法系统研究了聚酰胺(PAMAM)型树形大分子非共价搭载4种抗癌药物分子(CE6, DOX, MTX及SN38)的药物传输复合体系. 考察了药物分子种类、数量及树形大分子的代数和聚乙二醇化表面修饰对复合体系的结合强度、尺寸及溶剂中扩散行为的影响. 研究发现, PAMAM自身变形能对药物-PAMAM间的结合有重要影响. 搭载较多的药物分子可以使PAMAM自身增大, 但同样搭载条件下经过聚乙二醇化修饰过的PAMAM变化并不明显. PAMAM分子表面的聚乙二醇化可以更高的强度结合更多的药物分子, 并减缓其扩散速度, 因而提高药物分子的搭载效率和体内滞留时间. 为新型树形大分子基药物传输体系的设计提供理论依据.

关键词: 树形大分子, 聚酰胺, 聚乙二醇化, 抗癌药物, 药物传输体系, 分子动力学模拟

Abstract:

We carried out all atomistic molecular dynamics simulations on poly(amidoamine)(PAMAM) dendrimer-based drug-delivery systems where PAMAMs bind non-covalently with four types of anticancer drug molecules including CE6, DOX, MTX, and SN38, respectively. We focus on the study of binding strength, size, and drug diffusion behavior of the complex systems influenced by the number and types of drug molecules as well as the generation(G0—G2) and surface PEGlyation of PAMAM. The simulations show that the deformation of PAMAMs themselves contributes significantly to the strength of drug-PAMAM binding. Multiple drug loading expands PAMAM dendrimers significantly but affects barely the sizes of PEGlyated PAMAM. The surface PEGlyation of PAMAM allows encompassing more drug molecules with stronger binding strength, thus increasing the efficiency of drug loading and retention time. This research provides theoretical evidence for designing novel dendrimer-based drug delivery systems.

Key words: Dendrimer, Poly(amidoamine), PEGlytion, Anticancer drug, Drug delivery system, Molecular dynamics simulation

中图分类号:

O641
O631

TrendMD:

张法达, 刘轶, 徐京城, 李生娟, 汪秀南, 孙玥, 赵新洛. 树形大分子基药物传输系统结合强度及构型的分子动力学研究. 高等学校化学学报, 2015, 36(6): 1156.

ZHANG Fada, LIU Yi, XU Jingcheng, LI Shengjuan, WANG Xiunan, SUN Yue, ZHAO Xinluo. Molecular Dynamics Study on Binding Strength and Conformation of Dendrimer-based Drug Delivery Systems^†. Chem. J. Chinese Universities, 2015, 36(6): 1156.

图/表 11

参考文献 33

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Drug	D₁	D₁(D₁₆@G2)	G2	G2(D₁₆@G2)	D₁₆@G2	D₁(D₁₆@ G2-PEG)	G2-PEG	G2-PEG(D₁₆@ G2-PEG)	D₁₆@G2-PEG
None			0.896				1.965
CE6	0.465	0.469±0.05		1.294(44.4%)	1.351(50.8%)	0.467±0.05		2.411(22.7%)	2.242(14.1%)
DOX	0.479	0.484±0.07		1.314(46.7%)	1.227(67.0%)	0.484±0.07		2.475(26.0%)	2.318(18.0%)
MTX	0.525	0.541±0.42		1.228(37.1%)	1.211(35.2%)	0.542±0.45		2.315(17.8%)	2.167(10.3%)
SN38	0.434	0.434±0.01		1.14(27.2%)	1.189(32.7%)	0.435±0.01		2.36(20.1%)	2.254(14.7%)

Drug	D₁	D₁(D₁₆@G2)	G2	G2(D₁₆@G2)	D₁₆@G2	D₁(D₁₆@ G2-PEG)	G2-PEG	G2-PEG(D₁₆@ G2-PEG)	D₁₆@G2-PEG
None			0.896				1.965
CE6	0.465	0.469±0.05		1.294(44.4%)	1.351(50.8%)	0.467±0.05		2.411(22.7%)	2.242(14.1%)
DOX	0.479	0.484±0.07		1.314(46.7%)	1.227(67.0%)	0.484±0.07		2.475(26.0%)	2.318(18.0%)
MTX	0.525	0.541±0.42		1.228(37.1%)	1.211(35.2%)	0.542±0.45		2.315(17.8%)	2.167(10.3%)
SN38	0.434	0.434±0.01		1.14(27.2%)	1.189(32.7%)	0.435±0.01		2.36(20.1%)	2.254(14.7%)

D_N@Gn	E_b(H₂O)/ (kJ·mol^-1)	E_b(no H₂O)/ (kJ·mol^-1)	D_N@Gn-PEG	E_b(H₂O)/ (kJ·mol^-1)	E_b(no H₂O)/ (kJ·mol^-1)
CE6₈@G0	-218.572	-98.157	CE6₈@G0-PEG	154.808	-138.951
DOX₈@G0	-201.418	-111.587	DOX₈@G0-PEG	118.407	-146.900
MTX₈@G0	-205.476	-82.299	MTX₈@G0-PEG	166.900	-145.478
SN38₈@G0	-137.277	-84.224	SN38₈@G0-PEG	212.464	-125.813
CE6₁₀@G1	-254.136	-109.412	CE6₁₂@G1-PEG	224.555	-144.766
DOX₁₀@G1	-148.699	-125.478	DOX₁₂@G1-PEG	364.719	-129.160
MTX₁₀@G1	-210.079	-101.546	MTX₁₂@G1-PEG	301.834	-112.089
SN38₁₀@G1	-90.709	-96.650	SN38₁₂@G1-PEG	346.017	-142.047
CE6₁₆@G2	-213.761	-122.089	CE6₁₆@G2-PEG	378.610	-141.126
DOX₁₆@G2	-195.351	-137.612	DOX₁₆@G2-PEG	533.251	-119.077
MTX₁₆@G2	114.683	-115.060	MTX₁₆@G2-PEG	486.265	-136.608
SN38₁₆@G2	-109.746	-103.721	SN38₁₆@G2-PEG	-632.788	-88.408

D_N@Gn	E_b(H₂O)/ (kJ·mol^-1)	E_b(no H₂O)/ (kJ·mol^-1)	D_N@Gn-PEG	E_b(H₂O)/ (kJ·mol^-1)	E_b(no H₂O)/ (kJ·mol^-1)
CE6₈@G0	-218.572	-98.157	CE6₈@G0-PEG	154.808	-138.951
DOX₈@G0	-201.418	-111.587	DOX₈@G0-PEG	118.407	-146.900
MTX₈@G0	-205.476	-82.299	MTX₈@G0-PEG	166.900	-145.478
SN38₈@G0	-137.277	-84.224	SN38₈@G0-PEG	212.464	-125.813
CE6₁₀@G1	-254.136	-109.412	CE6₁₂@G1-PEG	224.555	-144.766
DOX₁₀@G1	-148.699	-125.478	DOX₁₂@G1-PEG	364.719	-129.160
MTX₁₀@G1	-210.079	-101.546	MTX₁₂@G1-PEG	301.834	-112.089
SN38₁₀@G1	-90.709	-96.650	SN38₁₂@G1-PEG	346.017	-142.047
CE6₁₆@G2	-213.761	-122.089	CE6₁₆@G2-PEG	378.610	-141.126
DOX₁₆@G2	-195.351	-137.612	DOX₁₆@G2-PEG	533.251	-119.077
MTX₁₆@G2	114.683	-115.060	MTX₁₆@G2-PEG	486.265	-136.608
SN38₁₆@G2	-109.746	-103.721	SN38₁₆@G2-PEG	-632.788	-88.408

D_N@Gn	E_i-PD(H₂O)/ (kJ·mol^-1)	E_i-PD(no H₂O)/ (kJ·mol^-1)	D_N@Gn-PEG	E_i-PD(H₂O)/ (kJ·mol^-1)	E_b(no H₂O)/ (kJ·mol^-1)
CE6₈@G0	-161.126	-37.447	CE6₈@G0-PEG	-204.137	-106.734
DOX₈@G0	-174.389	-20.209	DOX₈@G0-PEG	-253.969	-133.260
MTX₈@G0	-175.770	-29.079	MTX₈@G0-PEG	-195.184	-161.377
SN38₈@G0	-122.591	-21.255	SN38₈@G0-PEG	-167.862	-130.708
CE6₁₀@G1	-164.640	-54.057	CE6₁₂@G1-PEG	-193.970	-153.929
DOX₁₀@G1	-182.841	-54.099	DOX₁₂@G1-PEG	-192.087	-165.184
MTX₁₀@G1	-157.151	-42.802	MTX₁₂@G1-PEG	-177.694	-153.595
SN38₁₀@G1	-121.545	-40.417	SN38₁₂@G1-PEG	-120.792	-93.430
CE6₁₆@G2	-153.678	-60.250	CE6₁₆@G2-PEG	-230.204	-205.476
DOX₁₆@G2	-173.887	-69.036	DOX₁₆@G2-PEG	-212.589	-151.586
MTX₁₆@G2	-194.472	-59.329	MTX₁₆@G2-PEG	-192.004	-178.950
SN38₁₆@G2	-121.503	-49.162	SN38₁₆@G2-PEG	-162.088	-133.553

树形大分子基药物传输系统结合强度及构型的分子动力学研究

Molecular Dynamics Study on Binding Strength and Conformation of Dendrimer-based Drug Delivery Systems^†

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参考文献 33

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D_N@Gn	D/(nm²·ps^-1)	D_N@Gn-PEG	D/(nm²·ps^-1)
CE6₈@G0	1.1×10^-3	CE6₈@G0-PEG	6.4×10^-4
DOX₈@G0	1.0×10^-3	DOX₈@G0-PEG	8.1×10^-4
MTX₈@G0	1.0×10^-3	MTX₈@G0-PEG	8.8×10^-4
SN38₈@G0	9.6×10^-4	SN38₈@G0-PEG	7.5×10^-4
CE6₁₀@G1	7.8×10^-4	CE6₁₂@G1-PEG	7.0×10^-4
DOX₁₀@G1	8.7×10^-4	DOX₁₂@G1-PEG	7.0×10^-4
MTX₁₀@G1	1.2×10^-3	MTX₁₂@G1-PEG	7.9×10^-4
SN38₁₀@G1	1.2×10^-3	SN38₁₂@G1-PEG	5.7×10^-4
CE6₁₆@G2	8.8×10^-4	CE6₁₆@G2-PEG	5.0×10^-4
DOX₁₆@G2	7.1×10^-4	DOX₁₆@G2-PEG	5.1×10^-4
MTX₁₆@G2	6.6×10^-4	MTX₁₆@G2-PEG	5.5×10^-4
SN38₁₆@G2	7.7×10^-4	SN38₁₆@G2-PEG	3.2×10^-4

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树形大分子基药物传输系统结合强度及构型的分子动力学研究

Molecular Dynamics Study on Binding Strength and Conformation of Dendrimer-based Drug Delivery Systems†

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Molecular Dynamics Study on Binding Strength and Conformation of Dendrimer-based Drug Delivery Systems^†