Size control of copper nanodrugs through emulsion atom transfer radical polymerization

Abstract

Copper (Cu) nanodrugs can be efficiently prepared via miniemulsion atom transfer radical polymerization (ATRP) using a Cu complex with anticancer activity as the catalyst, but the size of Cu nanodrugs is difficult to control in a wide range through that process. In this study, emulsion activator generated by electron transfer (AGET) ATRP was used to copolymerize poly(ethylene glycol) methyl ether acrylate (mPEG-acrylate) and methyl methacrylate (MMA) in the presence of dichloro-{bis[2-(4-methoxy-3,5-dimethyl)pyridylmethyl]octadecylamine} cuprate(II) [Cu(BMMODA)Cl₂] as a catalyst, ethyl 2-chloropropionate (ECIP) as an initiator, and ascorbic acid (AA) as a reducing agent, to give Cu nanodrugs with diverse sizes in an aqueous phase within one step. MMA, Cu(BMMODA)Cl₂ and ECIP dispersed in water would form monomer droplets, whereas AA was dissolved in the aqueous phase. The reduction of Cu(II) within the monomer droplet was impeded, preventing the polymerization in that region. During the mass transport process of the chemicals in monomer droplets towards micelles formed by the aggregation of mPEG-acrylate, Cu(II) would be reduced to Cu(I) by AA in the aqueous phase, and the polymerization would start inside the micelles, presenting the micellar nucleation feature. The particle size of Cu nanodrugs can be precisely adjusted from about 70 nm to 440 nm by increasing the feed ratio of MMA to mPEG-acrylate. Cu nanodrugs with small particle size are more easily taken up by cancer cells than those with a large diameter, showing the highest anticancer activity. This work provides an idea about the scalable and precise preparation of Cu nanodrugs, and shows a method to optimize antitumor activity through size control.