分子模拟研究壳聚糖-氮化硼纳米管封装及输运阿霉素

doi:10.11949/0438-1157.20191226

摘要/Abstract

摘要：

壳聚糖-BNNTs复合载体在药物输运领域存在潜在的应用前景。通过分子动力学方法，以抗癌药物阿霉素DOX为药物模型，研究利用壳聚糖-BNNTs复合载体材料封装及跨膜输运抗癌药物的过程。结果表明，非质子化壳聚糖能吸附且调整DOX以合适的构象进入管中。细胞膜磷脂分子能自发嵌入到BNNT (14,14)管中，将管中壳聚糖挤出并使DOX在管中快速上升。该研究可以为实验提高药物封装效率，并提高癌细胞表面药物浓度提供设计思路。

关键词: 壳聚糖, 细胞膜, 纳米管, 药物

Abstract:

There is a potential application prospect of chitosan BNNTs composite carrier in the field of drug transport. It is important to understand the mechanism of the encapsulation and transport of drugs by chitosan-BNNTs from atomic level. Herein, molecular dynamics (MD) simulation was employed to investigate the process of encapsulation and transmembrane delivery of doxorubicin (DOX) by chitosan-BNNTs. The anticancer drug DOX was used as a drug model. The free energy results indicate that DOX and chitosan can spontaneously enter the tube. It is also found that DOX can be adsorbed by the non-protonated chitosan and enter the tube in a suitable conformation. The interaction energy results show that phospholipid molecules can embed into BNNT (14,14) tubes, and extrude chitosan and DOX in the tube. This study can provide ideas for experiments to improve drug encapsulation efficiency and increase drug concentration on cancer cells.

Key words: chitosan, cell membrane, nanotube, drug

中图分类号:

O 641.3

李嘉辰, 俞斌, 王琦, 张丽. 分子模拟研究壳聚糖-氮化硼纳米管封装及输运阿霉素[J]. 化工学报, 2020, 71(1): 354-360.

Jiachen LI, Bin YU, Qi WANG, Li ZHANG. Molecular simulation on doxorubicin encapsulation and transport by chitosan-boron nitride nanotubes[J]. CIESC Journal, 2020, 71(1): 354-360.

图/表 7

图1 10聚壳聚糖模型，由替换多糖—OH获得（所有原子以licorice模型显示）(a) 完全脱乙酰化的壳聚糖（—NH2 chitosan, CS_A10）；(b) 完全脱乙酰化且质子化的壳聚糖 (—NH3+ chitosan, CS_B10)；(c) 不同视角的BNNT (14,14)模型

Fig.1 Initial structure of chitosan with 10 units was generated by replacing glucose unit —OH group into —NH2 and —NH3+ groups, respectively

图2 壳聚糖-BNNTs封装(a)及跨膜输运(b)DOX的初始构型截图（CS_ B10壳聚糖为licorice模型，POPC为line模型，BNNT为licorice模型，DOX为vdW模型；截图中没有显示水分子和反离子）

Fig.2 Initial structure of encapsulation(a) and transmembrane transport(b) of DOX by chitosan-BNNT (14,14)

图3 (a) CS_A10壳聚糖/DOX与BNNT (14,14)质心距离随时间的变化；(b) 体系初始以及30 ns 瞬时构型图

Fig.3 (a) Center of mass (COM) distance between CS_A10/DOX and BNNT (14,14) versus simulation time; (b) snapshot of system at 0 and 30 ns

图4 一个单元—NH2壳聚糖与BNNT (14,14)以及DOX与BNNT (14,14)之间的PMF（坐标0为管中心位置，虚线为管口位置）

Fig.4 Potential of mean force (PMF) of —NH2 and DOX passing through BNNT (14,14) [The reaction coordinate is along the central axis of BNNTs. 0 nm is the middle location of the tube and the dotted lines represent the end location of BNNT (14,14)]

图5 (a) Ⅰ: BNNT (14,14)管中水的xy平面密度分布图；不同取向DOX的初始构型，Ⅱ: DOX共轭环相对xy面竖直（vertical）放置；Ⅲ: 水平（horizontal）放置；(b) 牵引不同取向DOX进入管中所施加外力随时间的变化（牵引速率为0.01 nm/ps，虚线表示管口位置）

Fig.5 (a) Ⅰ: Density map of water molecules in BNNT (14,14) in xy plane; DOX with different orientations in xy plane, Ⅱ: vertical; Ⅲ: horizontal; (b) external force on DOX versus simulation time [the pull rate is 0.01 nm/ps and the dotted lines represent the end location of BNNT (14,14)]

图6 壳聚糖-BNNTs复合载体跨细胞膜输运DOX的瞬时构型图

Fig.6 Snapshot of transmembrane transport of DOX by chitosan-BNNT (14,14)

图7 (a) POPC/CS_B10壳聚糖/DOX与BNNT (14,14)质心距离随时间的变化；(b) CS_B10壳聚糖/DOX/PO与BNNT (14,14)相互作用能随时间的变化（PO表示单个进入管中的POPC分子）；(c) BNNT (14,14)管中随时间的模拟细节截图（虚线为POPC的中心位置）

Fig.7 (a) COM distance between POPC/CS_B10/DOX and BNNT (14,14) versus simulation time; (b) interaction energy between CS_B10/DOX/PO and BNNT (14,14); (c) snapshot in BNNT (14,14) (the dotted line is the center of POPC)

参考文献 30

1	Bhirde A A, Patel V, Gavard J, et al. Targeted killing of cancer cells in vivo and in vitro with EGF-directed carbon nanotube-based drug delivery[J]. ACS Nano, 2009, 3(2): 307-316.
2	Huang H, Yuan Q, Shah J S, et al. A new family of folate-decorated and carbon nanotube-mediated drug delivery system: synthesis and drug delivery response[J]. Advanced Drug Delivery Reviews, 2011, 63(14/15): 1332-1339.
3	Ciofani G, Raffa V, Yu J, et al. Boron nitride nanotubes: a novel vector for targeted magnetic drug delivery[J]. Current Nanoscience, 2009, 5(1): 33-38.
4	Ciofani G. Potential applications of boron nitride nanotubes as drug delivery systems[J]. Expert Opinion on Drug Delivery, 2010, 7(8): 889-893.
5	Li L, Li L H, Ramakrishnan S, et al. Controlling wettability of boron nitride nanotube films and improved cell proliferation[J]. The Journal of Physical Chemistry C, 2012, 116(34): 18334-18339.
6	Chen X, Wu P, Rousseas M, et al. Boron nitride nanotubes are noncytotoxic and can be functionalized for interaction with proteins and cells[J]. Journal of the American Chemical Society, 2009, 131(3): 890-891.
7	Yu J, Chen Y, Cheng B M. Dispersion of boron nitride nanotubes in aqueous solution with the help of ionic surfactants[J]. Solid State Communications, 2009, 149(19/20): 763-766.
8	Tan M L, Choong P F M, Dass C R. Doxorubicin delivery systems based on chitosan for cancer therapy[J]. Journal of Pharmacy and Pharmacology, 2009, 61(2): 131-142.
9	Xu X Y, Zhou J P, Li L, et al. Preparation of doxorubicin-loaded chitosan polymeric micelle and study on its tissue biodistribution in mice[J]. Acta Pharmaceutica Sinica, 2008, 43(7): 743-748.
10	Rao W, Wang H, Han J, et al. Chitosan-decorated doxorubicin-encapsulated nanoparticle targets and eliminates tumor reinitiating cancer stem-like cells[J]. ACS Nano, 2015, 9(6): 5725-5740.
11	Ciofani G, Danti S, D’Alessandro D, et al. Assessing cytotoxicity of boron nitride nanotubes: interference with the MTT assay[J]. Biochemical and Biophysical Research Communications, 2010, 394(2): 405-411.
12	Li H J, Du J Z, Liu J, et al. Smart superstructures with ultrahigh pH-sensitivity for targeting acidic tumor microenvironment: instantaneous size switching and improved tumor penetration[J]. ACS Nano, 2016, 10(7): 6753-6761.
13	Kanamala M, Wilson W R, Yang M, et al. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: a review[J]. Biomaterials, 2016, 85: 152-167.
14	Katas H, Alpar H O. Development and characterisation of chitosan nanoparticles for siRNA delivery[J]. Journal of Controlled Release, 2006, 115(2): 216-225.
15	Risbud M V, Hardikar A A, Bhat S V, et al. pH-sensitive freeze-dried chitosan-polyvinyl pyrrolidone hydrogels as controlled release system for antibiotic delivery[J]. Journal of Controlled Release, 2000, 68(1): 23-30.
16	Jiao J, Li X, Zhang S, et al. Redox and pH dual-responsive PEG and chitosan-conjugated hollow mesoporous silica for controlled drug release[J]. Materials Science and Engineering: C, 2016, 67: 26-33.
17	Mahdavinia G R, Mosallanezhad A, Soleymani M, et al. Magnetic-and pH-responsive κ-carrageenan/chitosan complexes for controlled release of methotrexate anticancer drug[J]. International Journal of Biological Macromolecules, 2017, 97: 209-217.
18	Han Y, Elliott J. Molecular dynamics simulations of the elastic properties of polymer/carbon nanotube composites[J]. Computational Materials Science, 2007, 39(2): 315-323.
19	Liang L, Hu W, Zhang Z, et al. Theoretic study on dispersion mechanism of boron nitride nanotubes by polynucleotides[J]. Scientific Reports, 2016, 6: 39747.
20	Li J, Chen C, Zhang J, et al. Molecular dynamics study on loading mechanism of chitosan into boron nitride nanotubes [J]. Journal of Molecular Liquids， 2019, DOI: 10.1016/j.molliq.2019.111753. DOI
21	Ferreira M L, Pedroni V I, Alimenti G A, et al. The interaction between water vapor and chitosan(Ⅱ): Computational study[J]. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2008, 315(1/2/3): 241-249.
22	Frisch M J, Trucks G W, Schlegel H B, et al. Gaussian 03: revision C. 02 [CP]. Wallingford, CT: Gaussian, Inc., 2004: 26.
23	Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics[J]. Journal of Molecular Graphics, 1996, 14(1): 33-38.
24	Wu Y, Wagner L K, Aluru N R. Hexagonal boron nitride and water interaction parameters[J]. The Journal of Chemical Physics, 2016, 144(16): 164118.
25	Darden T, York D, Pedersen L. Particle mesh Ewald: an N⋅log (N) method for Ewald sums in large systems[J]. The Journal of Chemical Physics, 1993, 98(12): 10089-10092.
26	Bird R B, Hirschfelder J O, Curtiss C F. Molecular Theory of Gases and Liquids[M]. John Wiley, 1954.
27	Bussi G, Donadio D, Parrinello M. Canonical sampling through velocity rescaling[J]. The Journal of Chemical Physics, 2007, 126(1): 014101.
28	Thomas M, Enciso M, Hilder T A. Insertion mechanism and stability of boron nitride nanotubes in lipid bilayers[J]. The Journal of Physical Chemistry B, 2015, 119(15): 4929-4936.
29	Torrie G M, Valleau J P. Nonphysical sampling distributions in Monte Carlo free-energy estimation: umbrella sampling[J]. Journal of Computational Physics, 1977, 23(2): 187-199.
30	Kumar S, Rosenberg J M, Bouzida D, et al. The weighted histogram analysis method for free-energy calculations on biomolecules (Ⅰ): The method[J]. Journal of Computational Chemistry, 1992, 13(8): 1011-1021.

[1]	吴雷, 刘姣, 李长聪, 周军, 叶干, 刘田田, 朱瑞玉, 张秋利, 宋永辉. 低阶粉煤催化微波热解制备含碳纳米管的高附加值改性兰炭末[J]. 化工学报, 2023, 74(9): 3956-3967.
[2]	邓璐, 巨晓洁, 张文杰, 谢锐, 汪伟, 刘壮, 潘大伟, 褚良银. 微流控法可控制备放射性壳聚糖栓塞微球[J]. 化工学报, 2023, 74(4): 1781-1794.
[3]	裴仁花, 王永洪, 张新儒, 李晋平. 碳纳米管/环糊精金属有机骨架协同强化混合基质膜的CO₂分离[J]. 化工学报, 2022, 73(9): 3904-3914.
[4]	李承威, 骆华勇, 张铭轩, 廖鹏, 方茜, 荣宏伟, 王竞茵. 氢氧化镧交联壳聚糖微球的微流控制备及其除磷性能[J]. 化工学报, 2022, 73(9): 3929-3939.
[5]	肖皓宇, 杨海平, 张雄, 陈应泉, 王贤华, 陈汉平. 塑料催化热解制备高附加值产品的研究进展[J]. 化工学报, 2022, 73(8): 3461-3471.
[6]	刘学安, 汤丽怡, 覃健, 唐大江, 童张法, 曲慧颖. 热解Ni/Co-ZIF-8制备碳纳米管桥连多孔碳及其在超级电容器中的应用[J]. 化工学报, 2022, 73(7): 3287-3297.
[7]	蔡楚玥, 方晓明, 张正国, 凌子夜. CNTs阵列增强石蜡/硅橡胶复合相变垫片的散热性能研究[J]. 化工学报, 2022, 73(7): 2874-2884.
[8]	徐银龙, 郑文杰, 王琳, 薛中飞, 谢毅鑫. 壳聚糖联合酶诱导碳酸盐沉淀处理铜废水的劣化现象和强化机理研究[J]. 化工学报, 2022, 73(5): 2222-2232.
[9]	石兴达, 陈华艳, 戈亚南, 武春瑞, 贾红友, 吕晓龙. 低界面热阻改性氮化铝和多壁碳纳米管充填PVDF构建杂化三维网络及其导热性能强化[J]. 化工学报, 2022, 73(5): 2262-2269.
[10]	韩雪, 高生旺, 王国英, 夏训峰. 铈掺杂强化碳纳米管活化过一硫酸盐实验研究[J]. 化工学报, 2022, 73(4): 1743-1753.
[11]	徐欢, 柯律, 张生辉, 张子林, 韩广东, 崔金声, 唐道远, 黄东辉, 高杰峰, 何新建. GO表面原位生长CNTs改善聚丙烯导热复合材料分散与界面形态[J]. 化工学报, 2022, 73(11): 5150-5157.
[12]	吴诗德, 易峰, 平丹, 张逸飞, 郝健, 刘国际, 方少明. NH₄Cl辅助热解制备镍-氮-碳纳米管催化剂及其电还原CO₂性能[J]. 化工学报, 2022, 73(10): 4484-4497.
[13]	从少领, 赵捷, 杨玉飞, 吴长清, 贺凡, 袁华, 汪晓芹, 熊善新, 吴燕, 周安宁. 煤基聚苯胺制掺N碳微纳米管的实验研究[J]. 化工学报, 2021, 72(9): 4950-4960.
[14]	郑龙, 田佳鑫, 张泽鹏, 郭建, 朱晖, 谢慧翔, 何润泽, 洪文晶. 多肽药物制备工艺研究进展[J]. 化工学报, 2021, 72(7): 3538-3550.
[15]	李超凡, 温玉娟, 曹楠, 孙东, 宋晓明, 杨悦锁. 耐低温对硝基苯酚降解菌的降解动力学研究[J]. 化工学报, 2021, 72(3): 1692-1701.