Improving therapeutic delivery to the body will have significant benefits for the treatment of a variety of diseases. Incorporating drugs inside engineered colloidal carriers is a promising approach that can lead to improved drug delivery. Such carriers offer a number of advantages, as they can protect therapeutic cargo from degradation by the body, limit potentially harmful side effects of the drug, and also allow targeted drug delivery to the desired site of action. Colloidal carriers have the potential to enable clinical use of a number of therapeutics, such as siRNA and peptides, which if administered in their naked form degrade before demonstrating a viable therapeutic effect. A number of challenges, such as efficient therapeutic loading into the carrier, targeted and specific delivery in the body whilst evading biological defence mechanisms, and controlled release of therapeutically active cargo, must be met for these systems to be clinically relevant. In this review, we focus on recent advances and some of the pertinent challenges faced in developing clinically relevant colloidal drug carriers. We primarily focus on self-assembled carriers such as liposomes, polymer micelles and polymersomes, and carriers prepared through templated assembly, for example, layer-by-layer assembled capsules and PRINT (particle replication in non-wetting templates) particles.

The assembly of low-fouling polymer capsules with redox-responsive behavior and intracellular degradability is reported. Thiol-containing poly(2ethyl-2-oxazoline) (PEtOxMA SH ) brushes are synthesized by atom transfer radical polymerization (ATRP) of oligo(2-ethyl-2-oxazoline)methacrylate and glycidyl methacrylate (GMA) and subsequent ring-opening reaction of the GMA. Sequential deposition of PEtOxMA SH /poly(methacrylic acid) (PMA) multilayers onto silica (SiO 2 ) particle templates and crosslinking through disulfi de formation yield stable capsules after the removal of the SiO 2 templates by buffered hydrofl uoric acid (HF). The redox-responsive nature of the disulfi de crosslinking groups enables the degradation of these capsules under simulated intracellular conditions at pH 5.9 and 5 m M glutathione (GSH). Furthermore, capsule degradation is observed after incubation with dendritic (JAWS II) cells. Even at high capsule-to-cell ratios, PEtOxMA SH capsules show only negligible cytotoxicity. Quartz crystal microgravimetry (QCM) studies, using 100% human serum, reveal that fi lms prepared from PEtOxMA SH exhibit low-fouling properties. The degradation and low-fouling properties are promising for application of PEtOxMA SH fi lms/capsules for the delivery and triggered release of therapeutics.

Hollow polymer capsules were prepared from linear as well as brush-like poly(2-oxazoline)s (POxs). Linear POxs containing alkene functionalities were obtained by cationic ring-opening polymerization (CROP), whereas the brush POxs bearing alkyne moieties were synthesized by a combination of CROP and reversible addition fragmentation chain transfer (RAFT) polymerization. Multilayers consisting of POx/poly(methacrylic acid) (PMA) were sequentially deposited onto silica particle templates and the films were stabilized either by thiol-ene (TE) chemistry or copper-catalyzed azidealkyne cycloaddition (CuAAc). Stable, monodisperse capsules were formed after removal of the silica particles with hydrofluoric acid, and were observed using fluorescence and atomic force microscopy (AFM). Both architectures exhibited lowfouling behavior, an essential criteria for therapeutic carriers to be utilized in bioapplications. In particular, the brush-like POx capsules show potential as a viable alternative material for the fabrication of low-fouling capsules.

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a b s t r a c tThe preparation of layer-by-layer (LbL) polymer capsules stabilized by a combination of copper-catalyzed azide-alkyne cycloaddition (CuAAC, "click chemistry") and disulfide cross-linking is reported. The capsules obtained possess gated permeability due to the reversible nature of the disulfide cross-linking. Poly(methacrylic acid) (PMA) was modified with different ratios of alkyne and protected thiol functionalities (PMA Alk,SH ). Exploiting hydrogen bonding interactions, multilayered films were prepared by the alternate deposition of PMA Alk,SH (hydrogen bonding donor) and poly(N-vinylpyrrolidone) (PVPON; hydrogen bonding acceptor), yielding stable PMA Alk,SH capsules. Capsule pH responsive behavior and permeability, using a series of different size and labeled dextrans, were investigated in both the "closed" state (disulfide cross-linking intact) and "open" state (free thiol groups). To demonstrate the potential of these gateable systems, post-loading studies with fluorescent 45-base pair (bp) linear double-stranded (ds) DNA were performed. Fluorescence studies revealed the potential of these capsules to reversibly encapsulate cargo: cleavage and reformation of the disulfide groups resulted in reversible permeability to the DNA.