Characterization of 1,2-Distearoyl-sn-glycero-3-phosphoethanolamine–N-[Methoxy(polyethylene glycerol)-2000] and Its Complex with Doxorubicin Using Nuclear Magnetic Resonance Spectroscopy and Molecular Dynamics

化学 核磁共振波谱 二维核磁共振波谱 胶束 光谱学 分子动力学 异核分子 异核单量子相干光谱 核过剩效应 聚乙二醇 分析化学(期刊) 水溶液 结晶学 立体化学 计算化学 有机化学 物理 量子力学
作者
Weidong Hu,Allen Mao,Patty Wong,Adrien Larsen,Paul J. Yazaki,Jeffrey Y.C. Wong,John E. Shively
出处
期刊:Bioconjugate Chemistry [American Chemical Society]
卷期号:28 (6): 1777-1790 被引量:9
标识
DOI:10.1021/acs.bioconjchem.7b00238
摘要

Polyethylene glycol (PEG) lipid nanoparticles (LNPs) spontaneously assemble in water, forming uniformly sized nanoparticles incorporating drugs with prolonged blood clearance compared to drugs alone. Previously, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine–N-[methoxy(polyethylene glycerol)-2000] (DSPE–PEG2000) and several drug adducts, including doxorubicin, were analyzed by a combination of physical and molecular dynamic (MD) studies. In this study, a complete chemical shift assignment of DSPE–PEG2000 plus or minus doxorubicin was achieved using nuclear magnetic resonance (NMR), one-dimensional selective nuclear Overhauser spectroscopy (1D-selNOESY), NOESY, correlation spectroscopy (COSY), total correlated spectroscopy (TOCSY), heteronuclear single quantum coherence (HSQC), and HSQC–TOCSY. Chemical shift perturbation, titration, relaxation enhancement, and NOESY analysis combined with MD reveal detailed structural information at the atomic level, including the location of doxorubicin in the micelle, its binding constant, the hydrophilic shell organization, and the mobility of the PEG2000 tail, demonstrating that NMR spectroscopy can characterize drug–DSPE–PEG2000 micelles with molecular weights above 180 kDa. The MD study revealed that an initial spherical organization led to a more-disorganized oblate structure in an aqueous environment and agreed with the NMR study in the details of the fine structure, in which methyl group(s) of the stearic acid in the hydrophobic core of the micelle are in contact with the phosphate headgroup of the lipid. Although the molecular size of the LNP drug complex is about 180 kDa, atomic resolution can be achieved by NMR-based methods that reveal distinct features of the drug–lipid interactions. Because many drugs have unfavorable blood clearance that may benefit from incorporation into LNPs, a thorough knowledge of their physical and chemical properties is essential to moving them into a clinical setting. This study provides an advanced basic approach that can be used to study a wide range of drug–LNP interactions.
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