Restoring the pH-responsiveness for amine-conjugated 2-propionic-3-methylmaleic anhydride linkers†‡

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.