Release Of Arseniouc Acid From A Self-delivery Nanodrug And Cancer Therapy

On-demand drug delivery is becoming feasible via the design of either exogenous or endogenous stimulus-responsive drug delivery systems.Herein we report the development of dextran-coated gadolinium arsenite nanoparticles as a self-delivery platform to store,deliver and release arsenic trioxide(ATO,Trisenox),a clinical anti-cancer drug.Specifically,unloading of ATO is triggered by an endogenous stimulus: inorganic phosphate(Pi)in the blood,fluid,and tissues.In vitro kinetics demonstrated that ATO is released with high ON/OFF ratio and no leakage was observed in the silent state.The nanoparticles induced tumor cell apoptosis,and reduced cancer cell migration and invasion.Plasma pharmacokinetics verified extended retention time,but no obvious disturbance of phosphate balance.Therapeutic efficacy on a liver cancer xenograft mouse model was dramatically potentiated with reduced toxicity compared to the free drug.These results suggest a new drug delivery strategy which might be applied for ATO therapy on solid tumors.On the basis of these results,we have conducted the related gadolinium arsenite nanoparticles to overcome multidrug resistance(MDR).Herein,we propose a strategy of combined therapy to overcome MDR of paclitaxel(PTX)by introducing a hybrid paclitaxel-loaded gadolinium arsenite nanoparticle(HPAN),where PTX was conjugated with gadolinium arsenite(GdAsOx)nanoparticle(NP)by forming rod-shape hybrid clusters.Triggered by endogenous inorganic phosphate(Pi),the hybrid nanoparticles readily collapse,thereby releasing PTX and arsenic trioxide(ATO)from this self-delivery nanoparticle system.An MTT assay indicated IC50 values for HPAN one order of magnitude lower than for a simple equivalent mixture of PTX and ATO against PTX-resistant human colon cancer cells(HCT 166),indicating remarkable synergistic effect.Species-type dependent cellular uptake,induced apoptosis,and cell cycle modulation were also evaluated.Cellular uptake tests indicate that the HPAN presents higher PTX intracellular loading for the PTX-resistant cells and longer intracellular retention time,displaying resistance to drug efflux from the cancer cell than pristine PTX or the equivalent mixture of PTX and ATO.Cell cycle and apoptosis tests consistently proved that addition of HPAN resulted in higher G2/M and apoptosis in PTX-resistant cells.In vivo anticancer experiments evidenced that HPAN had better therapeutic effect on the resistant tumor in the murine xenograft model than pristine PTX or a mixture of PTX and ATO,when the dosage of PTX and ATO was equivalent.Our results suggest that HPAN might enhance the therapeutic index and overcome PTX resistance,and also demonstrate that the combined therapeutic effect is not only related to the species of combined agents,but also their physiochemical states.