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Polymeric micelles (PM) are extensively used to improve the delivery of hydrophobic drugs. Many different PM have been designed and evaluated over the years, and some of them have steadily progressed through clinical trials. Increasing evidence suggests, however, that for prolonged circulation times and for efficient EPR-mediated drug targeting to tumors and to sites of inflammation, PM need to be stabilized, to prevent premature disintegration. Core-crosslinking is among the most popular methods to improve the in vivo stability of PM, and a number of corecrosslinked polymeric micelles (CCPM) have demonstrated promising efficacy in animal models. The latter is particularly true for CCPM in which (pro−) drugs are covalently entrapped. This ensures proper drug retention in the micelles during systemic circulation, efficient drug delivery to pathological sites via EPR, and tailorable drug release kinetics at the target site. We here summarize recent advances in the CCPM field, addressing the chemistry involved in preparing them, their in vitro and in vivo performance, potential biomedical applications, and guidelines for efficient clinical translation.

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with cells, [10] can shield recognition units, [15] but its role for biodistribution and circulation is still far from well understood. [8,16] Except for liposomes, other types of nano-sized drug delivery systems, such as polymeric micelles or more complex polymer constructs like cylindrical polymer brushes [17] have been so far hardly investigated with respect to protein corona formation (for comparison between the structures of these nanoparticles and the colloidal nanoparticles discussed above, see Figures S1 and S2 in the Supporting Information). [8,[18][19][20] However, the former are interesting, since polymeric micelles are in advanced stages of clinical testing (e.g., CPC634 (phase II) [21] and NC-6004 Nanoplatin (phase III) [22] ).To evaluate the formation of a protein corona, separation of the nanoparticle-protein-complex from unbound proteins used for incubation or upon in vivo exposure becomes a necessity. The isolation of incubated nanoparticles (colloids and inorganic nanoparticles) from unbound proteins was mainly performed by centrifugation, which is a separation method based on differences in density. [23] Thus, this method allows only the purification of nanoparticles with a higher density but can hardly be used for low density particles, such as polymeric micelles and polymer brushes. [24] Only recently, size exclusion techniques such as size exclusion chromatography and asymmetrical flow field-flow fractionation (AF4) have been employed for this purpose. [19,25,26] AF4 is a separation technique, which can be applied for the separation of particle and protein mixtures in the size range between 1 nm and 1 µm. [27,28] It consists of a separation channel with a flow gradient in which the particles are separated by an additional vertical force field depending on their diffusion coefficient. [29,30] During an AF4 measurement, the injected particles are pushed by the vertical cross flow toward the membrane at the bottom of the channel. Due to Brownian motion, the particles are diffusing back into the middle of the channel. Since smaller particles are faster than larger ones (because of their higher diffusion coefficient), they are concentrating faster in the middle, thus eluting first through the channel outlet. In contrast to conventional size exclusion chromatography, in AF4 the contact to the interface and the shear forces are substantially reduced, which leads to very mild separation conditions, minimizing perturbations of a potential protein corona. [26,31] Based on this method, Landfester and coworkers recently fully characterized the protein corona of Lutensol AT50-coated polystyrene nanoparticles and PEG functionalized liposomes, identifying all adsorbed proteins. [19,26] Here, we present a purification procedure based on AF4 for the separation of smaller polymeric architectures (R h : 20-30 nm) that are hardly separable by centrifugation. We isolated polymeric nanoparticles from unbound blood plasma components and characterized them by dynamic light scattering, gel electrophoresis and mass s...