A combined arsenic trioxide/tetrandrine nanoparticle formulation with improved inhibitory effect against promyelocytic leukemia

Abstract

Co-loading nanoparticles encapsulated in a copolymer carrier is a very effective strategy for anti-tumor treatment. A combination of arsenic trioxide (ATO) and tetrandrine (TET) synergistically inhibits tumor angiogenesis and lung metastasis. Moreover, TET reduces the cardiotoxicity of ATO. However, the bioavailability of this combination is limited due to poor solubility. In this study, co-loading nanoparticle formulations were developed by co-loading poly(lactic-co-glycolic acid) (PLGA) nanoparticles with ATO and TET (ATO/TET@PLGA) and by co-loading methoxypoly(ethylene glycol)-poly(lactide) (mPEG-PLGA) nanoparticles with ATO and TET (ATO/TET@mPEG-PLGA). The sonication emulsion-solvent volatilization method was employed. The combination ratio of ATO and TET was determined by results of the MTT assay, which showed that when the TET: ATO ratio was 3/4, the best synergistic anti-tumor effect was achieved. Transmission electron microscopy and particle size analysis of the nanoparticles showed that the particle size was below 100 nm mPEG-PLGA was an excellent carrier for constructing ATO/TET co-loading nanoparticles based on characterization, release study, and pharmacokinetics results. The average encapsulation efficiencies of ATO and TET were 89.78% and 82.80%, respectively. In vivo distribution experiments showed that the drugs had an improved targeting effect in the liver and bone when formulated as nanoparticles. In vitro anti-tumor studies showed that ATO/TET@mPEG-PLGA had stronger cytotoxicity than ATO alone or ATO/TET intravenous emulsion and could induce apoptosis in HL-60 cells to a greater extent. Additionally, ATO/TET@mPEG-PLGA could induce G2/M cell cycle arrest. In conclusion, ATO/TET@mPEG-PLGA has excellent anti-tumor activity as a co-delivery system of ATO and TET.