Thermoresponsive Micelles from Double LCST-Poly(3-methyl-N-vinylcaprolactam) Block Copolymers for Cancer Therapy.

We present synthesis and assembly of novel thermoresponsive block copolymers with double LCST precisely controlled within the physiological temperature range. Two separate phase transition temperatures were achieved by RAFT polymerization of structurally similar monomers with varied hydrophobicity. The LCST1 was varied from 19 to 27 °C by copolymerization of N-vinylcaprolactam with a novel hydrophobic monomer, 3-methyl-N-vinylcaprolactam, while the LCST2 at 41-42 °C was attained by copolymerization of N-vinylcaprolactam with hydrophilic N-vinylpyrrolidone. The LCST1 facilitates micelle formation and entrapment of anticancer drug doxorubicin or hydrophobic dye Nile Red into the micelle core surrounded with hydrophilic yet temperature-sensitive corona. The LCST2 induces collapse of the micelle corona and the consequent drug release. The second elevated temperature is typical for tumors and can trigger the drug-loaded micelle aggregation/accumulation within the tumor resulting in the enhanced passive targeting.