Fabrication of water-soluble polymer-encapsulated As4 S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice

Abstract

Realgar (As4 S4) 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 As4 S4. Raw As4 S4 (r-As4 S4) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As4 S4) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As4 S4 were evaluated in vivo and in vitro. The results show that e-As4 S4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As4 S4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As4 S4. The bioavailability of e-As4 S4 was up to 12.6-fold higher than that of r-As4 S4, and it inhibited the proliferation of HL-60 cells much more effectively than did r-As4 S4, 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.