Biocompatible, Antifouling, and Thermosensitive Core Shell Nanogels Synthesized by RAFT Aqueous Dispersion Polymerization

Hydrogels, networks of cross-linked hydrophilic polymers, are an important class of soft materials with many of their properties similar to those of biological tissues. While these macroscopic materials have been intensively studied and exploited in various technological areas, their nanosized counterparts, the so-called nanogels, are currently attracting significant attention for their potential use in advanced technologies such as targeted drug delivery and imaging. 8 Nanogels suitable for drug delivery or imaging should be biocompatible and nontoxic, antifouling, biodegradable (if the size is above the renal threshold), and highly specific for target cells, to name but a few. However, meeting all these critical requirements still represents a grand challenge for clinical application of nanogels in particular and polymer nanoparticles in general. Therefore, optimizing the design and synthesis of novel nanogels suitable for drug delivery is an important ongoing theme across several interdisciplinary areas. In designing nanogels with desirable characteristics for drug delivery, linear poly(ethylene glycol)s (l-PEGs) and their nonlinear analogues such as polymers derived from oligo(ethylene glycol) (meth)acrylates (g-PEGs), are particularly attractive compositional polymers. Indeed, l-PEGs are frequently used to coat nanoparticles to prolong the blood circulation time by blocking adhesion of opsonins to the nanoparticles. g-PEGs, synthesized by polymerization of oligo(ethylene glycol) (meth)acrylates, have been increasingly studied during the past several years. 16 g-PEGs share many important features of l-PEGs such as being highly hydrophilic and antifouling. For example, they have been used to decorate flat or nanoparticle surfaces to confer antifouling properties. 19 Also g-PEGs were proposed as alternatives for PEGylation of proteins and RNAs. A recent study demonstrated that significantly improved pharmacokinetics (41-fold increase) was achieved for myoglobin conjugated with g-PEGs compared with the bare protein. Importantly, g-PEGs have intriguing unique assets that l-PEGs do not possess. g-PEGs are synthesized from (meth)acrylates via versatile radical polymerization processes, thus their molecular weights, architectures and functionalities can be easily tailored, especially via the controlled/living radical polymerization processes. 31 Furthermore, by varying the length of the side oligo(ethylene glycol) chains or by copolymerizing two monomers of different side chain lengths, g-PEGs can be made thermosensitive. Lutz showed that thermosensitive g-PEGs have properties rivalling those of poly(Nisopropylacrylamide), one of the mostly studied thermosensitive polymers. These thermosensitive polymers were used to thermally switch wetting properties when coated onto surfaces. Recently, hyperbranched thermosensitive copolymers based on g-PEGs were reported by Davis and co-worker using reversible addition fragmentation chain transfer (RAFT) polymerization, and by Tai and Wang using in situ deactivation enhanced atom transfer radical polymerization (ATRP). In addition, Alexander and co-workers reported that such g-PEGs can have dual thermoand ion-responsiveness. Microgels based on g-PEGs have also been reported. Hu and co-workers