核磁共振波谱法和分子动力学表征1,2-二硬脂<i>酰基-sn-</i>甘油-3-磷酸乙醇胺<i>-N-</i> [甲氧基（聚乙二醇）-2000]及其与阿霉素的配合物,Bioconjugate Chemistry

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核磁共振波谱法和分子动力学表征1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺-N- [甲氧基（聚乙二醇）-2000]及其与阿霉素的配合物
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2017-05-18 00:00:00 , DOI: 10.1021/acs.bioconjchem.7b00238
Weidong Hu , Allen Mao , Patty Wong ₁ , Adrien Larsen , Paul J. Yazaki , Jeffrey Y.C. Wong ₁ , John E. Shively

Affiliation

聚乙二醇（PEG）脂质纳米颗粒（LNP）在水中自发组装，形成均匀大小的纳米颗粒，与单独使用药物的血液清除率相比，具有更长的血液清除率。以前，通过物理和分子相结合的方法来分析1,2-二硬脂酰-sn-甘油-3-磷酸乙醇胺-N- [甲氧基（聚乙二醇）-2000]（DSPE-PEG ₂₀₀₀）和几种药物加合物，包括阿霉素动态（MD）研究。在这项研究中，DSPE–PEG ₂₀₀₀的完整化学位移分配使用核磁共振（NMR），一维选择性核Overhauser光谱（1D-selNOESY），NOESY，相关光谱（COSY），总相关光谱（TOCSY），异核单量子相干（HSQC）获得正负阿霉素和HSQC–TOCSY。化学位移扰动，滴定，弛豫增强和NOESY分析结合MD在原子水平上揭示了详细的结构信息，包括阿霉素在胶束中的位置，其结合常数，亲水性壳结构以及PEG ₂₀₀₀尾部的迁移性，表明NMR光谱可以表征药物–DSPE–PEG ₂₀₀₀分子量大于180 kDa的胶束。MD研究表明，最初的球形组织在水性环境中导致更加杂乱的扁球形结构，并且与NMR研究在精细结构的细节方面相符，在该结构中，疏水核中的硬脂酸的甲基胶束中的一部分与脂质的磷酸根基接触。尽管LNP药物复合物的分子大小约为180 kDa，但可以通过基于NMR的方法实现原子拆分，该方法揭示了药物与脂质相互作用的独特特征。由于许多药物的血液清除率很低，可能会因掺入LNP而受益，因此全面了解其物理和化学性质对于将其转移到临床环境至关重要。

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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

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.

更新日期：2017-06-10

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