AEEA-AEEA PH

Principle of pH-dependent release: The pH values of the tumor microenvironment (pH 6.5-7.0) and lysosomes (pH 4.5-5.0) are significantly lower than that of normal tissues (pH 7.4). Leveraging the instability of certain chemical bonds under acidic conditions (such as hydrazone bonds, acetal bonds, and vinyl ether bonds), site-specific release can be achieved. The carboxylate group in the molecule can serve as part of a "pH-sensitive switch": for instance, by connecting the carboxyl group to an amino-containing molecule via a pH-sensitive bond (such as a cis-aconitoyl group), this bond hydrolyzes under acidic conditions, releasing the drug. Alternatively, the carboxyl group can form a coordination complex with metal ions, which dissociates under acidic conditions.
Specific design strategies: ① Hydrazone-carboxyl cooperative system: After activating the carboxyl group of the molecule, it reacts with drugs containing ketone groups (such as doxorubicin) to form a hydrazone bond. The hydrazone bond has a hydrolysis half-life of approximately 1 hour at pH 5.0 and is stable at pH 7.4. The ether bond in the linker enhances hydrophilicity, allowing the hydrazone bond to be fully exposed to acidic environments. ② Metal chelation-acidolysis strategy: Utilizing the coordination ability of carboxyl groups with Fe³⁺ or Zn²⁺, a metal-polyphenol coordination network is constructed. Under acidic conditions, the coordination bond breaks, releasing the encapsulated drug. ③ pH-responsive self-elimination: The amino group of the molecule is linked to a PABC-drug, but the carbamate bond of PABC is stable under acidic conditions. Therefore, this strategy requires the introduction of additional pH-sensitive groups (such as dimethylmaleic anhydride). In vitro release experiments show that the release rate can reach 85% at pH 5.0 for 24 hours, while it is less than 10% at pH 7.4. This pH-dependent release is particularly suitable for lysosome-targeted ADCs and tumor interstitial drug delivery, further enhancing tumor selectivity.