Obesity and inflammation influence pharmacokinetic profiles of PEG-based nanoparticles.
Obesity and inflammation influence pharmacokinetic profiles of PEG-based nanoparticles.
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肥胖和炎症影响基于 PEG 的纳米颗粒的药代动力学特征。
DOI：
10.1016/j.jconrel.2023.02.007
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Dalhaimer,Paul
中科院分区：
文献类型：
--
作者：
Raith,Mitch;Nguyen,Nicole;Kauffman,SarahJ;Kang,Namgoo;Mays,Jimmy;Dalhaimer,Paul
大多数将用软纳米颗粒（NP）治疗的患者将是肥胖的。然而，从药代动力学（PK）和毒性研究开始的NP测试几乎完全在具有健康肝脏和低炎症的瘦啮齿动物中进行。为了解决这一知识缺口，我们确定了尾静脉注射的基于PEG的圆柱形纳米颗粒（CNP）和PEG化脂质体（PL）的PK和毒性，作为瘦素缺乏的ob/ob和野生型C57 BL/6 J小鼠中肥胖、肝脏健康和炎症的函数。在注射后24小时内，CNP定位于肥胖肝脏的速度比健康肝脏快。PL定位于肥胖肝脏比健康肝脏更快，但仅在注射后30分钟。之后PL定位到瘦肝高于定位到肥胖肝。总体而言，瘦小鼠中PL肝脏信号在注射后106 h达到峰值，重小鼠中在注射后1024 h达到峰值，肥胖小鼠中在注射后1048 h达到峰值。通过组织学评估，CNP和PL对小鼠肝脏无毒;它们降低了肥胖引起的许多细胞因子和趋化因子水平。如预期，肝脏巨噬细胞消耗减少CNP和PL肝脏定位;肝脏窦状内皮细胞（LSEC）消耗减少PL肝脏定位，但令人惊讶地增加CNP肝脏定位。CNP孵育后RAW264.7巨噬细胞的强度高于PL孵育;相反，PL孵育后LSEC的强度高于CNP孵育。这显示了NP-肝脏相互作用中关键差异的可能性。通过向小鼠施用脂多糖（LPS）触发炎症增加CNP肝脏定位，但降低PL肝脏定位。结果表明，小鼠模型和体外的肥胖和炎症影响基于软PEG的NP与巨噬细胞和LSEC的相互作用，而且这些NP可以减少肥胖增加的促炎途径。
Most patients that will be treated with soft nanoparticles (NPs) will be obese. Yet, NP testing, which begins with pharmacokinetic (PK) and toxicity studies, is carried out almost exclusively in lean rodents having healthy livers and low inflammation. To address this knowledge gap, we determined the PK and toxicity of tail-vein-injected, PEG-based cylindrical nanoparticles (CNPs) and PEGylated liposomes (PLs) as a function of obesity, liver health, and inflammation in leptin-deficientob/oband wild-type C57BL/6 J mice. CNPs localized faster to obese livers than to healthy livers within 24 h of injection. PLs localized faster to obese livers than to healthy livers but only 30 min post-injection. Afterwards PL localization to lean livers was higher than localization to obese livers. Overall, PL liver signal peaked ∼6 h post-injection in lean mice, ∼24 h post-injection in heavy mice, and ∼ 48 h post-injection in obese mice. CNPs and PLs were non-toxic to mouse livers as assessed by histology; they reduced many cytokine and chemokine levels that were elevated by obesity. Liver macrophage depletion reduced CNP and PL liver localization as expected; liver sinusoidal endothelial cell (LSEC) depletion reduced PL liver localization but surprisingly increased CNP liver localization. The intensity of RAW264.7 macrophages was higher after CNP incubations than with PL incubations; conversely, the intensity of LSECs was higher after PL incubations than with CNP incubations. This shows the potential for key differences in NP-liver interactions. Triggering inflammation by administering lipopolysaccharide (LPS) to mice increased CNP liver localization but decreased PL liver localization. The results show that obesity and inflammation in a mouse model and in vitro affect soft PEG-based NP interaction with macrophages and LSECs, but also that these NPs can reduce pro-inflammatory pathways increased by obesity.
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影响因子：
17.4
作者：
Gustafson HH;Holt-Casper D;Grainger DW;Ghandehari H
通讯作者：
Ghandehari H
通用条形码预测体内不依赖于 ApoE 的脂质纳米粒子递送。
影响因子：
10.8
作者：
Alejandro Da Silva Sanchez;C. Dobrowolski;A. Cristian;Elisa Schrader Echeverri;Kun Zhao;Marine Z. C. Hatit;David Loughrey;Kalina Paunovska;J. Dahlman
通讯作者：
J. Dahlman
影响因子：
5.5
作者：
Dalhaimer, P;Bates, FS;Discher, DE
通讯作者：
Discher, DE
影响因子：
38.3
作者：
Geng, Yan;Dalhaimer, Paul;Discher, Dennis E.
通讯作者：
Discher, Dennis E.
影响因子：
17.1
作者：
Dalhaimer, Paul;Florey, Brice;Isaac, Sami
通讯作者：
Isaac, Sami