Sci. Transl. Med. 4, 128ra39 (2012)

Credit: © 2012 AAAS

Although nanoparticles encapsulating anticancer drugs and targeting membrane antigens have long been investigated, their clinical application has been hampered by difficulties in finding the physicochemical parameters that lead to optimal targeting efficacy, controlled drug release and the evasion of immune responses. Now, Jeffrey Hrkach and colleagues present an approach for the screening and optimization of block-copolymer nanoparticles entrapping docetaxel — a chemotherapeutic drug — and functionalized with poly(ethylene glycol) decorated with a small molecule that targets the extracellular domain of PSMA, a receptor expressed in the neovasculature of various solid tumours. The researchers evaluated both in vitro and in vivo a combinatorial library of nanoparticles of the same constituents but with systematically varied particle size, surface hydrophilicity, drug loading, targeting ligand density and drug-release properties, and found that the optimal nanoparticles showed similar pharmacokinetic profiles and minimal liver accumulation in tumour-bearing mice, rats and monkeys. The study also reports initial clinical data in humans that is consistent with these results. The combinatorial screening and optimization approach should be applicable to the clinical translation of other drugs and targeting molecules.