The effect of Z-group modification on the RAFT polymerization of N-vinylpyrrolidone controlled by "switchable" N-pyridyl-functional dithiocarbamates

This is an accepted manuscript of an article published by Royal Society of Chemistry in the Polymer Chemistry on 24/08/2015, available online: https://doi.org/10.1039/C5PY01021G The accepted version of the publication may differ from the final published version.The ability of a RAFT agent to control the polymerization of a monomer is dictated by the structures of both the monomer and the RAFT agent. In this paper, the polymerization of N-vinylpyrrolidone was examined with a series of cyanomethyl N-aryl-N-pyridyldithiocarbamates [(4-R′Ph)N(py)C(S)SCH2CN] varying in the substituent (R′) at the 4-position on the phenyl ring. The polymerization of N-vinylpyrrolidone was best controlled when R′ was methoxy; one of the least active RAFT agents in the series. The preservation of RAFT agent functionality was demonstrated by chain extension experiments with further N-vinylpyrrolidone. Again best control again was found for the RAFT agent with R′ = MeOPh. The utility of this RAFT agent was also proved with the preparation of poly(N-isopropylacrylamide)-block-poly(N-vinylpyrrolidone).The authors gratefully acknowledge the Australian Government for award of an Australian Postgraduate Award to S.J.S., the CSIRO Manufacturing Flagship and the School of Science and Technology at the University of New England for project funding.Published versio

The roadmap to micro: Generation of micron‐sized polymeric particles using a commercial microfluidic system

Microfluidic-assisted particle fabrication provides a route to circumvent the disadvantages associated with traditional methods of polymeric particle generation, such as low drug loading efficiency, challenges in controlling encapsulated drug release rates, batch-to-batch variability in particle physical properties and formulation instability. However, this approach primarily produces particles with nanometer size dimensions, which limits drug delivery modalities. Herein, we systematically studied parameters for the generation of micron-sized poly(lactic-co-glycolic) acid (PLGA) particles using a microfluidic system, the NanoAssemblr benchtop. Initially, we used two organic solvents that have been reported suitable for the fabrication of PLGA nanoparticles - acetone and acetonitrile. Subsequently, we methodically manipulated polymer concentration, organic: aqueous flow rate ratios, total flow rate, organic phase composition, and surfactant concentration to develop a route for the fabrication of micron-sized PLGA particles. Further, we incorporated hydroxychloroquine (HCQ), a clinically approved drug for malaria and lymphoma, and measured how its incorporation impacted particle physicochemical properties. Briefly, altering the organic phase composition by including ethyl acetate (less polar solvent), resulted in micron-scale particles, as well as increased polydispersity indexes (PDIs). Adjusting the surfactant concentration of poly vinyl alcohol (PVA) after the addition of these solvent mixtures rendered large particles with lower PDI variability. Moreover, encapsulation of HCQ influenced particle hydrodynamic diameter and PDI in a PVA concentration dependent manner. Finally, we demonstrated that unloaded and HCQ-loaded microparticles did not affect the viability of RAW 264.7 macrophages. This study provides an itinerary for fabricating biocompatible, drug-loaded, micron-sized polymeric particles, particularly when the drug of interest is not readily soluble in conventional organic solvents

Functionalization of strongly interacting magnetic nanocubes with (thermo)responsive coating and their application in hyperthermia and heat-triggered drug delivery

Herein, we prepare nanohybrids by incorporating iron oxide nanocubes (cubic-IONPs) within a thermoresponsive polymer shell that can act as drug carriers for doxorubicin(doxo). The cubic-shaped nanoparticles employed are at the interface between superparamagnetic and ferromagnetic behavior and have an exceptionally high specific absorption rate (SAR), but their functionalization is extremely challenging compared to bare superparamagnetic iron oxide nanoparticles as they strongly interact with each other. By conducting the polymer grafting reaction using reversible addition-fragmentation chain transfer (RAFT) polymerization in a viscous solvent medium, we have here developed a facile approach to decorate the nanocubes with stimuli-responsive polymers. When the thermoresponsive shell is composed of poly(N-isopropylacrylamide-co-polyethylene glycolmethyl ether acrylate), nanohybrids have a phase transition temperature, the lower critical solution temperature (LCST), above 37 °C in physiological conditions. Doxo loaded nanohybrids exhibited a negligible drug release below 37 °C but showed a consistent release of their cargo on demand by exploiting the capability of the nanocubes to generate heat under an alternating magnetic field (AMF). Moreover, the drug free nanocarrier does not exhibit cytotoxicity even when administered at high concentration of nanocubes (1g/L of iron) and internalized at high extent (260 pg of iron per cell). We have also implemented the synthesis protocol to decorate the surface of nanocubes with poly(vinylpyridine) polymer and thus prepare pH-responsive shell coated nanocubes