Chemical Synthesis And Release Of Arsenic Trioxide Nanoprodrugs

Arsenic trioxide has benefited thousands of patients suffered from acute promyelocytic leukemia(APL)yearly,and is expected to benefit other types of leukemia,even solid tumors.However,this expectation was hampered by its immoderate pharmokinetics and toxicity.Colloidal gadolinium arsenite has been proposed as the prodrug of anticancer ATO by our group,and it has illustrated highly promising for liver cancer therapy.We have designed a “Pi-activated” arsenic trioxide(ATO)pro-drug(ATONP)based on colloidal gadolinium arsenite nanoparticles.In this paper,we first tried to use rare earth gadolinium and hydrothermal synthesis method to examine the influence of reaction time and reaction temperature on the product,characterize the morphology and structure of the product,and study the physical and chemical properties of colloidal zeta potential and hydration radius.According to the reaction,the chemical reaction equation is inferred from the valence state and the reaction product.In vitro release experiments showed that Pi triggered ATONP to effectively release ATO,resulting in the consumption of Pi in the serum,and the pH increased.After the tail vein administration of healthy rats,the interstitial inorganic phosphorus decreased and the pH increased accordingly.As a new type of ATO nano-prodrug,arsenite gadolinium colloid may be suitable for the treatment of solid tumors.Due to the similarity of the properties of rare earths,we examined the reaction law of rare earths including gadolinium.On the basis of these results,Here we systemically investigate rare earth arsenite's physico-chemical property,and mapping their element-dependant chemistry rules,ATO releasing property as well as cytotoxicity.Firstly all rare earth elements except Ce,can transform into colloid with arsenite under hydrothermal condiction;Secondly,some of the rare earth colloid are composed of crystallized nanorod(Y,Nd,Sm,Eu,Gd,Tb,Dy,Ho,Er,Tm,Yb,Lu),and others are amorphous(La,Pr).Thirdly,although we haven't revealed the nanorod structure based from collected data,the electron-diffraction pattern displayed anatomic number-dependant “d” value,and even displayed “quasi-tetrad effect”.Moreover,the chemical position of individual rare earth is clearly different,Nd,Sm,Eu,Gd arsenite has close stoichemistry ratio between rare earth and arsenic(1:1).Finally,all the nanorod or amorphous colloid showed similar ATO releasing kinetic against plasma,and close cytotoxicity.We have mapped all rare earth arsenite from chemical synthesis,physicochemical characterization,drug release and cytotoxicity,and those results remarkably disclosed inorganic synthesis of rare earth arsenite,potentially used as anticancer prodrug of ATO.