In-Batch and In-Flow Synthesis of Thermo-responsive Polymeric Inorganic Nanoparticle Platforms for Cancer Therapy

Inorganic nanoparticles (INPs) possess unique optical, magnetic, and electronic features accounting for their wide applicability in fields ranging from opto-electronics to medicine to catalysis. When their hydrophobic surfaces are coated with polymers engineered to become responsive to stimuli like heat, pH, light etc., the resulting polymeric-INPs could be used as platforms to simultaneously mediate the diagnosis and treatment of tumors. To this end, using an in-batch Photo-induced Copper mediated atom transfer radical polymerization technique, the synthesis of a PEG-based thermo-responsive polymer (TR-polymer) grafted onto the surface of chalcopyrite NPs was pursued. On the resulting polymeric-inorganic nanoparticle platform (TR-CuFeS2) Doxorubicin, a chemotherapeutic drug, was loaded in the TR-polymer shell for a heat-mediated drug release while the CuFeS2 NP displayed high heating and tunable reactive oxygen species (ROS) generation upon irradiation with 808nm-NIR laser. Using this platform the multi-therapeutic effect was proven. Similarly, a multi-catechol polymer having PEG stabilizing side chains and furfuryl moieties was synthesized and grafted to the surface of Iron Oxide NPs. To the furfuryl groups, thermal labile fluorescein dyes were tagged as a model drug by Diels-Alder chemistry. The obtained platform under alternating magnetic field (AMF) of clinical use and at very low nanocube dose ([Fe] of 0.5 g/L) were leading to local hot spots which drives the release of the dye without macroscopic temperature change of the solution. Lastly, a novel protocol was developed to produce TR-polymer coated iron oxide nanocubes (TR-Cube) using in-flow processing technique. In comparison with the previous in-batch TR-Cube synthesis, the optimize in-flow synthesis conditions features a much shorter reaction time, easy post polymerization cleanup, and higher % yield of TR-cubes. Thus, the in-flow method is more feasible for large scale clinical production of TR-Cubes than the batch process.