Enhancing Cationic Drug Delivery with Polymeric Carriers: The Coulomb‐pH Switch Approach,Advanced Theory and Simulations

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Enhancing Cationic Drug Delivery with Polymeric Carriers: The Coulomb‐pH Switch Approach
Advanced Theory and Simulations ( IF 2.9 ) Pub Date : 2020-12-21 , DOI: 10.1002/adts.202000247
Sergio De Luca ₁ , Jennifer Treny ₂ , Fan Chen ₂ , Prasenjit Seal ₃ , Martina H. Stenzel ₂ , Sean C. Smith ₁

Affiliation

A new coulomb‐pH switch method is proposed to enhance the efficient release of cationic drugs under acidic conditions occurring near tumor cells or during uptake into cells via endocytosis. The strategy is based on incorporation into the polymeric carrier of both weak acid and weak base functionalities. The consequence of this new design is that the polymeric vector adopts negative charge at physiological pH—facilitating complexation—while at late endosomal pH of 4.5, the polymeric vector adopts a positive charge—promoting highly efficient release of the drug. To illustrate the strategy, molecular dynamics simulations are carried out for a representative system comprising of a peptide dendrimer Gly‐Lys(Arg)2 as a model cationic drug and a short poly(4‐vinyl imidazole)‐b poly(acrylic acid) (PVI‐b‐PAA) block co‐polymer vector. Simulations suggest that these coulomb‐pH switch vectors bind the cationic drug effectively at pH = 7.0 and release it decisively once the charge state is changed to reflect pH = 4.5, as indicated by hydrogen bonding, close contact, and distance correlation analyses. Complementary experiments with bespoke synthesized peptide dendrimers indicate that the complexation involves much larger aggregrates than the one‐to‐one simulation; however unambiguous evidence is provided for the dissolution of the aggregates at pH = 4.5.

中文翻译：

使用聚合物载体增强阳离子药物的递送：库仑-pH转换方法

提出了一种新的库仑-pH转换方法，以增强在肿瘤细胞附近或通过胞吞作用吸收进入细胞的酸性条件下阳离子药物的有效释放。该策略是基于将弱酸和弱碱官能团两者结合到聚合物载体中。这种新设计的结果是，聚合载体在生理pH值下带负电荷，从而促进了络合；而在内体pH值为4.5时，聚合载体则带正电荷，从而促进了药物的高效释放。为了说明该策略，对一个代表性的系统进行了分子动力学模拟，该系统包含作为模型阳离子药物的肽树状大分子Gly-Lys（Arg）2和短聚（4-乙烯基咪唑）-b聚丙烯酸（ PVI-b-PAA）嵌段共聚物载体。模拟表明，这些库仑-pH转换载体在pH = 7.0时能有效结合阳离子药物，并在电荷状态改变以反映pH = 4.5时果断释放，如氢键，紧密接触和距离相关性分析所示。定制合成肽树状聚合物的补充实验表明，与一对一模拟相比，该络合涉及更大的聚集物。然而，提供了明确的证据表明聚集体在pH = 4.5时溶解。定制合成肽树状聚合物的补充实验表明，与一对一模拟相比，该络合涉及更大的聚集物。然而，提供了明确的证据表明聚集体在pH = 4.5时溶解。定制合成肽树状聚合物的补充实验表明，与一对一模拟相比，该络合涉及更大的聚集物。然而，提供了明确的证据表明聚集体在pH = 4.5时溶解。

更新日期：2021-02-04

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