The controlled pH-reversible conjugation of amine-functionalized molecules to nano-sized carrier systems is a promising achievement to enhance the efficacy of small molecular drugs at the target site. Various pH-responsive structures, such as ketals or hydrazones are accessible for drug delivery but suffer from high pH-gradients and elaborative modifications. The latter often further affects the specific activity of the released drugs. In this study, we establish the synthesis of a highly pH-sensitive bifunctional linker based on 2-propionic-3-methylmaleic anhydride. The underlying chemical structure enables the pH-reversible conjugation of different amines, although the attachment of primary amines competes with the formation of a pH-resistant imide structure. Remarkably, by analysis of the pH-reversible amidation profile in different solvents, the ring-opened amide structures are generated with primary aliphatic amines in diethyl ether. The formed conjugates rapidly phase separate from the reaction mixture and preserve the pH sensitivity of the linker system. Based on these findings, this manufacturing process is highly relevant in providing amine-conjugated 2-propionic-3-methylmaleic anhydride linkers and restoring their pH-responsiveness, particularly for primary amine-bearing drugs. This can pave their way for future applications, for instance, in nanomedicine.

中文翻译：

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恢复胺缀合 2-丙酸-3-甲基马来酸酐连接体的 pH 响应性


胺功能化分子与纳米载体系统的受控 pH 可逆缀合是增强小分子药物在靶位点功效的一项有希望的成就。各种 pH 响应结构，例如缩酮或腙，可用于药物递送，但会受到高 pH 梯度和精细修饰的影响。后者往往进一步影响所释放药物的比活性。在本研究中，我们建立了基于 2-丙酸-3-甲基马来酸酐的高度 pH 敏感双功能连接体的合成。尽管伯胺的附着会与耐pH的酰亚胺结构的形成竞争，但其基本化学结构使得不同胺能够进行pH可逆的缀合。值得注意的是，通过分析不同溶剂中的 pH 可逆酰胺化曲线，开环酰胺结构是由脂肪伯胺在乙醚中生成的。形成的缀合物迅速从反应混合物中相分离，并保持连接系统的 pH 敏感性。基于这些发现，该制造工艺对于提供胺缀合的 2-丙酸-3-甲基马来酸酐连接体并恢复其 pH 响应性高度相关，特别是对于含伯胺的药物。这可以为未来的应用铺平道路，例如在纳米医学中。