Polymeric vesicles, or polymersomes, are nano-to micrometre sized polymeric capsules with a bilayered membrane. Applications of these vesicles are foreseen in nanomedicine, in vivo imaging and drug delivery. These applications put many restrictions on the choice of polymer, the size and the surface of the vesicle. In this respect much can be learned and translated to polymersome science from lines of research with a longer history of practical knowledge such as liposomal formulation and polymer drug conjugation. The dimensions of a vesicle, such as size and shape can be controlled for polymersomes and will influence the in vivo circulation time. The surface can be adjusted to induce stealth character, or chemically modified to introduce targeting moieties. And last but not least the choice of block copolymers-the building blocks of a polymersome-can introduce features like biocompatibility, inherent or induced permeability and triggered release. In this review we will discuss the recent advances in polymersome science with regard to biomedical applications and will specifically address the abovementioned features which affect their biological behaviour.

Polymersomes, composed of amphiphilic polystyrene-block-poly(acrylic acid) (PS-b-PAA), with the periphery being covered with azide groups, were used for further functionalization using "click" chemistry.

Polymersomes, self-assembled from the block copolymer polybutadiene-block-poly(ethylene glycol), were prepared with well-defined diameters between 90 and 250 nm. The presence of ∼1% of diethylene triamine penta acetic acid on the polymersome periphery allowed to chelate radioactive 111 In onto the surface and determine the biodistribution in mice as a function of both the polymersome size and poly(ethylene glycol) corona thickness (i.e., PEG molecular weight). Doubling the PEG molecular weight from 1 kg/mol to 2 kg/mol did not change the blood circulation half-life significantly. However, the size of the different polymersome samples did have a drastic effect on the blood circulation times. It was found that polymersomes of 120 nm and larger become mostly cleared from the blood within 4 h, presumably due to recognition by the reticuloendothelial system. In contrast, smaller polymersomes of around 90 nm circulated much longer. After 24 h more than 30% of the injected dose was still present in the blood pool. This sharp transition in blood circulation kinetics due to size is much more abrupt than observed for liposomes and was additionally visualized by SPECT/CT imaging. These findings should be considered in the formulation and design of polymersomes for biomedical applications. Size, much more than for liposomes, will influence the pharmacokinetics, and therefore, long circulating preparations should be well below 100 nm.

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