用不同化学特征的PEG装饰的脂质体的体外和体内行为。,Molecular Pharmaceutics

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用不同化学特征的PEG装饰的脂质体的体外和体内行为。
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2020-01-22 , DOI: 10.1021/acs.molpharmaceut.9b00887
Francesca Mastrotto ₁ , Chiara Brazzale ₁ , Federica Bellato ₁ , Sara De Martin ₁ , Guillaume Grange ₂ , Mohamad Mahmoudzadeh ₂ , Aniket Magarkar ₃ , Alex Bunker ₂ , Stefano Salmaso ₁ , Paolo Caliceti ₁

Affiliation

比较研究了具有不同化学特征的单甲氧基聚（乙二醇）-脂质（mPEG-脂质）修饰的脂质体的胶体稳定性，体外毒性，细胞缔合和体内药代动力学行为。该研究中使用的mPEG-脂质的结构差异包括：（a）表面固定部分[1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺（DSPE），胆固醇（Chol）和胆烷（Chln）]；（b）mPEG分子量（2 kDa mPEG45和5 kDa mPEG114）；（c）mPEG形状（直链和支链PEG）。体外结果表明，相对于所有测试的聚乙二醇化剂，分支的（mPEG114）2-DSPE赋予脂质体最高的隐形性能（比裸脂质体低约31倍的细胞缔合）。然而，药代动力学研究表明，使用胆固醇作为锚定基团可产生被测制剂中具有更长的循环通透性和更高的全身生物利用度的PEG化脂质体。用mPEG114-Chol修饰的脂质体的曲线下面积（AUC）分别比裸脂质体和分支（mPEG114）2-DSPE涂层的脂质体高3.2倍和约2.1倍，这反映了这种涂层剂的高稳定性。通过比较具有相同大小的PEG化剂，即线性5 kDa PEG衍生物，线性mPEG114-DSPE产生了具有最佳体外隐身性能的包衣脂质体。然而，用线性mPEG114-DSPE修饰的脂质体的体内AUC低于用线性mPEG114-Chol修饰的脂质体获得的AUC。

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In Vitro and in Vivo Behavior of Liposomes Decorated with PEGs with Different Chemical Features.

The colloidal stability, in vitro toxicity, cell association, and in vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly(ethylene glycol)-lipids (mPEG-lipids) with different chemical features were comparatively investigated. Structural differences of the mPEG-lipids used in the study included: (a) surface-anchoring moiety [1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol), and cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG45 and 5 kDa mPEG114); and (c) mPEG shape (linear and branched PEG). In vitro results demonstrated that branched (mPEG114)2-DSPE confers the highest stealth properties to liposomes (∼31-fold lower cell association than naked liposomes) with respect to all PEGylating agents tested. However, the pharmacokinetic studies showed that the use of cholesterol as anchoring group yields PEGylated liposomes with longer permeance in the circulation and higher systemic bioavailability among the tested formulations. Liposomes decorated with mPEG114-Chol had 3.2- and ∼2.1-fold higher area under curve (AUC) than naked liposomes and branched (mPEG114)2-DSPE-coated liposomes, respectively, which reflects the high stability of this coating agent. By comparing the PEGylating agents with same size, namely, linear 5 kDa PEG derivatives, linear mPEG114-DSPE yielded coated liposomes with the best in vitro stealth performance. Nevertheless, the in vivo AUC of liposomes decorated with linear mPEG114-DSPE was lower than that obtained with liposomes decorated with linear mPEG114-Chol. Computational molecular dynamics modeling provided additional insights that complement the experimental results.

更新日期：2020-01-23

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