Fabrication of water-soluble polymer-encapsulated As4S4 to increase oral bioavailability and chemotherapeutic efficacy in AML mice

Abstract

Realgar (As4S4) 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 As4S4. Raw As4S4 (r-As4S4) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As4S4) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As4S4 were evaluated in vivo and in vitro. The results show that e-As4S4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As4S4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As4S4. The bioavailability of e-As4S4 was up to 12.6-fold higher than that of r-As4S4, and it inhibited the proliferation of HL-60 cells much more effectively than did r-As4S4, 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.

Inhibition of Murine Breast Cancer Metastases by Hydrophilic As4S4 Nanoparticles Is Associated With Decreased ROS and HIF-1α Downregulation

“…The e-As 4 S 4 was prepared according to the procedure previously reported (11). The commercial compound As 4 S 4 (powder of 28 μm in average diameter) and soluplus were mixed in a ratio of 1:15 (w/w) and fed into a co-rotating twin-screw extruder (HAAKE MiniLab II, ThermoFisher Scientific, Rockford, IL).…”

“…In recent years we and other research groups have made efforts to increase its poor water solubility by reducing the original crystal size into nanoscale in different ways (10–12). We have demonstrated that the bioavailability and the therapeutic effect of As 4 S 4 were increased significantly on acute myeloid leukemia (AML) in vitro and in vivo when the crystal particles were reduced into nanoscale and encapsulated with hydrophilic polymers (11). Moreover, nanoscaled As 4 S 4 also inhibited the proliferation of multiple myeloma cells (10) and melanoma cancer cells (12) effectively.…”

Involvement of autophagy in realgar quantum dots (RQDs) inhibition of human endometrial cancer JEC cells

“…The water-soluble-As 4 S 4 showed much higher cytotoxicity towards HL-60 leukemia cells in vivo and in vitro studies than raw-As 4 S 4 ( Ma et al, 2016 ). Milling realgar into nanoparticles has more potent anti-multiple myeloma (MM) activities than arsenic trioxide (ATO), with enhanced depletion of MM stem-like SP cells and synergistic anti-MM activity with lenalidomide and melphalan ( Cholujova et al, 2017 ).…”

Effect of micronization on Panax notoginseng: In vitro dissolution & in vivo bioavailability evaluations

“…The effects of particle size and hydrothermal treatment (Powder 4 were treated at 30, 40, 50, and 100°C) on the dissolution behavior of the PNP were investigated. Dissolution studies were carried out on a dissolution apparatus (ZRS-8L, Tianda Tianfa, China) with a rotation speed of 75 rpm according to the China Pharmacopoeia apparatus paddle method [24,25] The content of notoginsenoside R 1 and ginsenosides Rg 1 and Rb 1 in the medium were determined by HPLC as described above. Because the dissolution of ingredients was affected by the particle size, the dissolution rate calculated using the revised equation is as follow:…”