Effect of Cationic Charge Density on Transcytosis of Polyethylenimine,Biomacromolecules

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Effect of Cationic Charge Density on Transcytosis of Polyethylenimine
Biomacromolecules ( IF 5.5 ) Pub Date : 2021-11-13 , DOI: 10.1021/acs.biomac.1c01109
Siqin Chen _{1,

2} , Quan Zhou _{1,

3} , Guowei Wang _{1,

2} , Zhuxian Zhou _{1,

2} , Jianbin Tang _{1,

2} , Tao Xie _{1,

2} , Youqing Shen _{1,

2}

Affiliation

The adsorption-mediated transcytosis (AMT) induced by the electrostatic interaction between the positively charged surface of carriers and negatively charged cell membrane is a new paradigm enabling nanomedicine’s tumor extravasation and infiltration. However, little is known about the correlation between the carrier’s charge density and its AMT-induced tumor infiltration efficiency. Herein, we investigate the effect of the cationic polymer’s charge on the AMT-induced tumor penetration ability using in vitro multilayer tumor spheroids (MTSs). A cationic polymer, polyethylenimine (PEI), is amidized with acetic anhydride to obtain acetylated PEIs (AcPEIs) with different cationic charge densities. As the amidization ratio increases, the AcPEIs’ cytotoxicity, zeta potential, and cell-binding affinity significantly decrease. Notably, not only does the weak cell binding (AcPEIs with high acetylation degrees) lead to slow endocytosis and inefficient transcytosis, so does the strong cell-binding PEI. The PEI with 24% acetylation (AcPEI_24%) is found to have the highest transcytosis efficiency because its balanced cell-binding affinity triggers fast adsorption-mediated endocytosis. The subsequent Golgi apparatus/endoplasmic reticulum-mediated exocytosis via extracellular vesicles leads to highly effective transcellular delivery and tumor penetration in MTSs. Therefore, the drug carrier’s surface cationic charge density critically influences its AMT-induced tumor penetration efficiency. This study provides mechanistic insights into the design of drug-delivery systems with active transcytosis for improved tumor penetration and enhanced therapeutic efficiency.

中文翻译：

阳离子电荷密度对聚乙烯亚胺转胞吞作用的影响

由带正电荷的载体表面和带负电荷的细胞膜之间的静电相互作用诱导的吸附介导的胞吞作用（AMT）是一种新的范式，使纳米药物的肿瘤外渗和浸润成为可能。然而，关于载体的电荷密度与其AMT诱导的肿瘤浸润效率之间的相关性知之甚少。在此，我们在体外研究了阳离子聚合物的电荷对 AMT 诱导的肿瘤穿透能力的影响。多层肿瘤球体（MTS）。阳离子聚合物聚乙烯亚胺 (PEI) 与乙酸酐一起酰胺化，得到具有不同阳离子电荷密度的乙酰化 PEI (AcPEI)。随着酰胺化比率的增加，AcPEI 的细胞毒性、zeta 电位和细胞结合亲和力显着降低。值得注意的是，不仅弱细胞结合（乙酰化程度高的 AcPEI）导致内吞作用缓慢和转胞吞作用低效，细胞结合能力强的 PEI 也是如此。发现具有 24% 乙酰化的 PEI (AcPEI _24% ) 具有最高的转胞吞效率，因为其平衡的细胞结合亲和力触发快速吸附介导的内吞作用。随后的高尔基体/内质网介导的胞吐作用通过细胞外囊泡在 MTS 中导致高效的跨细胞递送和肿瘤穿透。因此，药物载体的表面阳离子电荷密度严重影响其 AMT 诱导的肿瘤穿透效率。这项研究为设计具有主动转胞吞作用的药物递送系统提供了机制见解，以改善肿瘤穿透和提高治疗效率。

更新日期：2021-12-13

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