Fabrication of water-soluble polymer-encapsulated As(4)S(4) to increase oral bioavailability and chemotherapeutic efficacy in AML mice

Realgar (As(4)S(4)) has been demonstrated to be effective for the treatment of acute myeloid leukemia (AML); it has the advantages of no drug resistance and oral administration. Nevertheless, its poor solubility has been an obstacle to its bioavailability, requiring high-dose administration over a long period. We investigated whether crushing realgar crystals to the nanoscale and encapsulating the particles in a water-soluble polymer in one step using hot-melt extrusion would increase the bioavailability of As(4)S(4). Raw As(4)S(4) (r-As(4)S(4)) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As(4)S(4)) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As(4)S(4) were evaluated in vivo and in vitro. The results show that e-As(4)S(4) dissolved rapidly in water, forming a stable colloid solution. The average size of e-As(4)S(4) particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As(4)S(4). The bioavailability of e-As(4)S(4) was up to 12.6-fold higher than that of r-As(4)S(4), and it inhibited the proliferation of HL-60 cells much more effectively than did r-As(4)S(4), inducing apoptosis and significantly reducing the infiltration of HL-60 cells into the bone marrow, spleen, and liver. This in turn prolonged the survival of AML mice.