Carrier-free single-molecule hypoxia-activated nanoprodrug of SN38 with ultrahigh drug loading for pancreatic cancer treatment

Pancreatic cancer remains one of the most lethal malignancies for human health. The anticancer drug SN38 has been proven effective against pancreatic cancer cells; however, its clinical application is limited by its poor aqueous solubility and restricted bioavailability <i>in vivo</i>. In this work, we developed a novel carrier-free single-molecule hypoxia-responsive nanoprodrug of SN38 for the treatment of pancreatic tumors. The nanoprodrug has an ultrahigh drug-loading content of ∼80 wt% and a nanoscale size of ∼50 nm. The drug molecules are masked by a hypoxia-sensitive aromatic azo group in the nanoprodrug, thereby shielding the therapeutic effects and toxicities of SN38 under normoxic conditions. Thus, the toxicity of the new regimen toward healthy cells and tissues is alleviated. In response to the upregulated level of azoreductase enzymes in the hypoxic tumor microenvironment, SN38 molecules are released <i>in situ</i> with their intact structures, exerting a powerful suppressive effect on tumor cells.