Tuning polymer architecture and chemistry to produce stimuli-responsive nanocarriers

The growing necessity to maximize the activity of therapeutics while minimizing their side effects is the major driving force behind the continuous development of novel drug delivery systems. Polymeric nanoparticles formed by the self-assembly of amphiphilic block copolymers in aqueous solution have emerged as an excellent platform for the delivery of poorly water-soluble drugs or imaging agents, greatly improving their solubility, bioavailability and prolonging circulation times. Recent advances in polymerization techniques have enabled the engineering of nanocarriers with carefully tuned physicochemical properties, such as shape, size, core and surface chemistry. Stimuli responsiveness is an appealing trait of emerging polymeric materials. One of the advantages of environmentally sensitive delivery vehicles is their ability to undergo physiochemical changes upon exposure to external signals, subsequently releasing their payload at target sites. Due to the elevated amounts of reactive oxygen species (ROS) often detected in cancerous and inflamed tissue, it is highly desirable to develop ROS-sensitive drug delivery systems. We will discuss the use of phenylboronic acid-installed polycarbonate block copolymers (PEG-PPBCs) to formulate oxidation responsive nanocarriers for targeted drug delivery. Following a systematic study of nanoparticle oxidation in the presence of various amounts of hydrogen peroxide, it was found that PEG-PPBC based nanoparticles, prepared under conditions of rapid mixing, exhibited excellent sensitivity to concentrations as low as 250 μM H2O2. It was further concluded that particle stability post oxidation greatly depends on the CCMC of the fully oxidized polymer, and that future experiments should be specifically designed in such a way so that the concentration of the final polymer product falls below its CCMC value. Although polymeric micelles have shown significant advantages in their ability to improve the bioavailability of therapeutics, they have also been reported to suffer from disruption or dissociation, largely attributed to dilution in the bloodstream. One strategy to address instability issues of polymeric nanoparticles includes the use of unimolecular micelles. We have previously demonstrated the ability of heterografted amphiphilic double-brushes with poly(glycidyl methacrylate) backbone bearing poly(ethylene glycol) and poly(D,L-lactide) side chains to form unimolecular micelles when transferred into a selective solvent. In the presence of a solute, such brushes underwent a conformational worm-to-sphere transition. We discuss that modifying the double-brush by grafting longer hydrophilic side chains restricts the solute-induced conformational changes observed earlier. The effect of physicochemical properties of the solute on nanoparticle morphology is also discussed and contrasted to a linear diblock copolymer system. Inspired by the abundance of phospholipids with zwitterionic headgroups in the external membrane of mammalian cells, zwitterionic-based materials are gaining importance as protein-resistant surface coatings. We discuss the synthesis of novel zwitterionic triblock copolymers, with poly(propylene oxide) (PPO) as the hydrophobic center block, that were prepared to serve as analogues of conventional Pluronics for stabilization of colloids. Different polymerization techniques were evaluated and it was concluded that ARGET ATRP is the most efficient method to produce zwitterionic triblocks with high molecular weights and low polydispersity