Polyprodrug with ultra-high drug content for tumor intracellular acid-triggered degradation and drug delivery

Abstract

• Degradable polyprodrug was designed with drug as repeating units. • An ultrahigh drug content of 1.67 mmol/g was obtained. • Excellent pH-triggered degradation and drug release were achieved. • The pH-triggered degradation and drug release mechanism was proposed. Polyprodrugs are expected to possess better drug release performance than the conventional polymer prodrugs, because the drug molecules are conjugated in the main chain as structural units, different from the side groups or end groups in the later one. Here, acid-triggered degradable polyprodrug P(DOX-NH) was designed as drug self-delivery system (DSDS) for the tumor intracellular acid-triggered drug delivery, via a facile condensation polymerization of N-hydazinated doxorubicin (DOX-NH). Owing to the unique structure by direct connecting the DOX-NH repeating units via hydrazone bond with each other without any linker, an ultrahigh drug content of 1.67 mmol/g was achieved. Therefore, the chemotherapeutic drug DOX-NH could be released in the acidic tumor intracellular microenvironment, without any by-product. With the emulsification of PEGylated doxorubicin (DOX-PEG), prodrug nanoparticles (P(DOX-NH)@PEG-NP) were obtained with a mean hydrodynamic diameter of 167.4 ± 8.4 nm, possessing an excellent drug release property. Furthermore, the enhanced antitumor efficacy was obtained than free DOX in the in vitro cellular experiments, demonstrating the promising potential of the proposed polyprodrug for future tumor chemotherapy.