Enhanced pharmacokinetic and therapeutic of GSH-responsive mPEG-b-P(HPMA)-SGI1776 conjugate for osteosarcoma

SGI-1776 represents the first serine/threonine kinase inhibitor to be utilized in the treatment of osteosarcoma. It is severely restricted by poor aqueous solubility, short degradation half-life and severe side effect.

A polymeric prodrug is prepared by covalently embedding SGI-1776 into mPEG-b-P(N-(2-hydroxypropyl) methylacrylamide) carrier via GSH-responsive disulfide bond. The chemical composition and assembly properties of the conjugate are characterized.

The loading capacity of SGI1776 in the conjugate is 22%. The conjugate displays a typical spherical nanoparticle with diameters around 150-260 nm. Cumulative release amounts of SGI1776 can be detected to be 52.9% at the concentration dithiothreitol of 20 mM at 24 h. The hemolysis rate is about 2.35% even when the concentration increases up to 1,000 mg/L. The value of IC50 is about 18.8 μg SGI1776 equiv. per mL for 143b cells.

The conjugate is more likely to induce apoptosis and can be blocked 143b cells in the S cycle phase. The maximum plasma concentration of the conjugate is attained 0.52 ± 0.092 μg/mL at 4 ± 0 h after the oral administration. The conjugate exhibits better lysosomal escape ability, biocompatibility.