Fabrication of water-soluble polymer-encapsulated As4S4 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.