Polymer microspheres with high drug-loading capacity via dual-modal drug-loading for modulating controlled release property in pH/reduction dual-responsive tumor-specific intracellular triggered doxorubicin release

pH/Reduction dual-responsive poly(4-formylphenyl acrylate-co-acryloyl-β-cyclodextrin) (P(FPA-co-ACD)) microspheres were synthesized as multi-functional vehicle for tumor-specific intracellular triggered doxorubicin (DOX) release, via emulsion copolymerization of acryloyl-β-cyclodextrin (ACD) and 4-formylphenyl acrylate (FPA), with N,N-bis(acryloyl)cystamine (BACy) as crosslinker. In comparison with the drug delivery system (DDS) via mono-modal drug-loading, the DOX/P(FPA-co-ACD)C via only covalent conjugation, or the DOX/P(FPA-co-ACD)N via only host-guest inclusion, the dual-modal drug-loaded DDS, DOX/P(FPA-co-ACD)C+N, were fabricated with a higher drug-loading capacity (DLC) of >53% via both acid-labile Schiff-base conjugation and host-guest inclusion complexation. Furthermore, the DOX release rate from the DOX/P(FPA-co-ACD)C+N was faster than the DOX/P(FPA-co-ACD)C but slower than the DOX/P(FPA-co-ACD)N in the simulated tumor intracellular microenvironment, demonstrating the controlled release behavior of such DDS could be modulated with dual-modal drug-loading.