Preparation of Multifunctional Drug Carrier for Tumor-Specific Uptake and Enhanced Intracellular Delivery through the Conjugation of Weak Acid Labile Linker

We demonstrate that multifuctional drug carriers, e.g., polymeric micelles, for tumor-specific uptake and intracellular delivery can be generated from the pH-dependent progressive hydrolysis of a novel benzoic-imine linker in the micelle-forming amphiphilic polymer. The linker, hence the micelle, is stable at physiological pH, partially hydrolyzes at the extracellular pH of the solid tumor, and completely hydrolyzes at the endosomal pH. Meanwhile, the surface property of the micelle converts from neutral to positively charged due to the generation of amino groups from the cleavage of the imine bond at tumor pH. The ionization on the surface facilitates the cellular uptake of the micelles through the electrostatic interaction between the micelle and the cell membrane. Subsequently, at the endosomal pH, with more complete cleavage of the polymer the micellar structure dissociates, and the system becomes very membrane-disruptive, inferring an enhanced intracellular delivery capability via the endosomal pathway.