Charge reversible and biodegradable nanocarriers showing dual pH-/reduction-sensitive disintegration for rapid site-specific drug delivery

Dual pH-/reduction-sensitive biodegradable poly(methacrylic acid-co-N,N-bis(acryloyl)cystamine)/chitosan/dimethylmaleic anhydride-modified chitosan (PMAABACy/CS/CS-DMMA) nanoparticles with PMAABACy cores as carriers and dimethylmaleic anhydride-modified chitosan as charge reversible shells were rationally designed. PMAABACy cores using N,N-Bis(acryloyl)cystamine (BACy) as a crosslinker and methacrylic acid (MAA) as a monomer were fabricated via a mild and facile one-pot distillation-precipitation polymerization. After that, CS and CS-DMMA were alternately adsorbed on the surface of PMAABACy cores through a mild self-assembly. The results from TEM and DLS reveal that the PMAABACy/CS/CS-DMMA nanoparticles with desired size and hydrodynamic diameter. And then the nanoparticles exhibit the excellent drug-loading capacity and encapsulation efficiency toward anti-cancer agent doxorubicin (DOX), whereas be rapidly triggered to realize the GSH-sensitive site-specific release via the destruction of sulfide cross-linked structure in response to the intracellular environment of tumor cells. Furthermore, their surface charges could transfer from negative in neutral or basic medium to positive in acidic medium to enhance cellular uptake. Most importantly, the excellent anticancer activity has been also revealed using confocal laser scanning microscope (CLSM) analysis, namely successfully delivering DOX molecules to the cell nucleus. These experimental results indicate that such the novel dual pH-/reduction-sensitive biodegradable PMAABACy/CS/CS-DMMA with surface charge reversal have great potential as a desired anticancer drug carrier for cancer therapy.