1、1聚乙二醇修饰的树枝状聚合物聚乙二醇修饰的树枝状聚合物(Dendrimer)用于药物传递的分子动力用于药物传递的分子动力学研究学研究李有勇李有勇苏州大学苏州大学 功能纳米与软物质研究院功能纳米与软物质研究院中国化学会第二十七届年会中国化学会第二十七届年会 2010厦门厦门21. 生物材料用于人体组织和器官的诊断、修复或增进其功能的一类高技术材料2. 药物传递系统也是一类生物材料，主要包括口服缓控释系统、透皮给药系统和靶向给药系统。每年被数千万的人群所使用。（目前美国市场是每年200亿美元的销售额。）生物材料和药物传递系统生物材料和药物传递系统药物传递对大分子药物（如蛋白质）和基因治疗尤为重要。
2、药物传递的根本目的是获得高效低毒的药物治疗，即药物能集中在靶部位，在某时释放一定量并维持一定时间。为使药物发挥最大的效力，必须掌握药物传递的基本原必须掌握药物传递的基本原理，即药物如何在体内传递，如何获得理想理，即药物如何在体内传递，如何获得理想的药物传递系统及其研究方法。的药物传递系统及其研究方法。通过精确控制药物在体内的位置，可以减少药物的副作用，减少药物的剂量并可以发展新的疗法。3EPR 效应效应 Enhanced Permeability and Retention effect正常组织中的微血管内皮间隙致密、结构完整,大分子和脂质颗粒不易透过血管壁,而实体瘤组织中血管丰富、血管壁间隙
3、较宽、结构完整性差,淋巴回流缺失,造 成大分子类物质和脂质颗粒具有选择性高通透性和滞留性,这种现象被称作实体瘤组织的高通透性和滞留效应,简称EPR效应。 EPR效应促进了大分子类物质在肿瘤组织的选择性分布,可以增加药效并减少系统副作用。4药物的靶向传递举例药物的靶向传递举例5Non-ideal properties of drugs, their therapeutic implications, and the effects of DDS (Drug Delivery System)药物传递系统解决的问题药物传递系统解决的问题6The bullet points summarize the
4、 major develop-ability factors examined at different stages.药物传递是药物研发中的重要一环药物传递是药物研发中的重要一环7药物传递系统的分类药物传递系统的分类liposomepolymer micelledendrimerThe drug molecules are illustrated in red balls Carbon nanotubes8Dendrimers 1.highly branched, globular macromolecules with many arms emanating from a central
5、core 2.a new class of macromolecular architecture and precise construction modules 1.precise and designable architecture, 2.tunable solubility, 3.efficient membrane transport, 4.high loading capacity, 5.high uniformity and purity, 6.low toxicity and immunogenicity, and bioattachment capability 9Dend
6、rimer作为载体的协同作用作为载体的协同作用Starpharma药物小分子直接和受体进行相互作用药物小分子直接和受体进行相互作用Dendrimer可以扩展药物小分子的作用模式，可以扩展药物小分子的作用模式，如同时和受体的四个作用靶点进行作用，提高如同时和受体的四个作用靶点进行作用，提高药物的活性；同时和多个受体进行作用；可以药物的活性；同时和多个受体进行作用；可以使得不同受体之间通过使得不同受体之间通过Dendrimer进行桥梁作进行桥梁作用。用。10The advantages of dendrimer as the host for drug delivery:表面功能基团的调控表面功能
7、基团的调控11Dendrimers modified by PEG on the surface1.Hydrophilic PEG increases solubility2.Hydrophilic PEG also increases biocompatibility3.pH, ion strength, temperature, and solvent will affect the structure and functions of the dendrimer 12理论模拟需要解决的问题理论模拟需要解决的问题1.How the drug molecules interact with
8、the host and where the drug molecules locates in the host (e.g. in the core of the dendrimer or the modified shell).2.How to redesign the load to make the drug release become slower and more efficient with maximum drug loading; 3.pH effect, which varies in different cells in the body and affects the
9、 shape of the dendrimer as well as the interaction between dendrimer and drug molecules.4.Temperature, ion strength, and solvent have similar effects as pH effect.5.How the generation number and architecture of the dendrimer affect the delivery efficiency. 133D structure of PPI-5 after equibration3D
10、 structure of PPI-5 c o v e r e d b y 3 , 4 , 5 -tris(tetraethyleneoxy) benzoyl units with PEG polymers are connectedWith protonation, counter-ions, and explicit solventPPI Dendrimer 的结构预测 (CCBTX Monte Carlo 方法）14CCBTX Monte Carlo方法方法CCBTX蒙特卡洛方法是一种高效的通用的蒙特卡洛方法，可以对蛋白质loop区，聚合物，树枝状聚合物进行高效构象采样，并能对体系的系宗
11、进行热力学统计。Protein loop prediction:1.Y. Li, et al. J. Am. Chem. Soc. 2007, 129, 10720;2.Y. Li, et al. Curr. Med. Chem. 2010, 17, 1167;3.Goddard, et al. ChemMedChem, 2010, in press;4.Goddard, et al. J. Struct. Biol., 2010, in press;Polymer and Dendrimer:1.Y. Li, et al. J. Am. Chem. Soc. 2004, 126, 1872-
12、1885. 2.Y. Li, et al. J. Phys. Chem. B. 2006, 110, 18134-18137.3.Maiti, et al. J. Chem. Phys. 2009, 130, 144902.15The location of the guest molecule16Hierdock method for docking the ligands17Location of the guest molecules in the dendrimer4 guest molecules stay in the core region of the dendrimer an
13、d are stable during the dynamics12 guest molecules stay in the core region of the dendrimer and are stable during the dynamics32 guest molecules stay not only in the core region of the dendrimer but also in the PEG region on the surface. They are stable during the dynamics18Radius gyration of the gu
14、est molecules in the dendrimerRadius gyration evolution1.Radius gyration decreases as more guest molecules filled in.2.The guest molecules filled the core region first, then the surface region.3.This agrees with SAXS experiments, which measure the radius of gyration.25.52626.52727.52828.52929.502004
15、0060080010001200Time step /psRadius gyration (A)0BR4BR12BR32BR19- 0.0100.010.020.030.040.050.060.07- 551525354555Radial densityRadial Distance ()Radial density distribution of PPI5-PEG with Bengal RoseBR 0nswater 0nsBR 1nswater 1nsFavorable interaction between PEG and water20The PEG tail on the surf
16、ace is important for encapsulate guest molecules toowithPEGWithout PEG tail, guest molecule diffuses readilyThe cavity of the dendrimer core cannot host all of the guest moleculeswithoutPEGPEG修饰的平行对比修饰的平行对比2105101520253035020040060080010001200The distance of each guest molecule to the host dendrimer
17、 These guest molecules are stable during 1ns MD and are distributed in different locations of the host molecules. 有PEG修饰22PEG修饰的平行对比修饰的平行对比Without PEG tails, the dendrimer cannot hold 32 BR molecules strongly. 020040060080010000.00.10.20.30.40.50.60.70.80.9MSD (nm2)Time (ps)BR in dendrimer without P
18、EGD = 0.097 x 10-5 cm2/sBR in “Compact PEG”D = 0.039 x 10-5 cm2/sMSD for Bengal Rose molecules in “Compact PEG” (red) and PPI-5 dendrimer without PEG modification (black). We can see that Bengal Rose diffuses quickly for dendrimer without PEG and PEG plays role to encapsulate the guest molecules.23I
19、t is straightforward to use simulation to implement the new ideas to improve the efficiency of dendrimer for drug delivery (optimal loading and slow releasing)药物传递体系设计思路和实现药物传递体系设计思路和实现24Computational simulation and rational design of dendrimer for drug delivery1.We successfully sample the structure
20、 of dendrimer with Monte Carlo program (CCBTX) and use molecule dynamics to illustrate the interaction between the dendrimer and guest molecules in the solvent.2.The guest molecules fill into the core of the dendrimer first, then into the surface region. The radius gyration decreases as guest molecu
21、les filled in. This agrees with the radius gyration measured by SAXS.3.The PEG tail on the surface not only increases hydrophilic and biocompatibility of the dendrimer, but also plays role in hosting the guest molecules.4.It is necessary to use computational simulation to study pH, ion strength, temperature, and solvent effects (affecting both structure and functions of the host dendrimer molecule). 总结总结25Thank you all for the attention!
