Kinetically frozen copolymer micelles are commonly prepared by confining amphiphilic block copolymers in the evaporating dispersed phase of oil-in-water emulsions. We revisit the mechanisms of this process by examining its successive steps separately: the formation of the solvent/water interface, the emulsification, the solvent evaporation and the formation of aggregates. We bring into evidence that: (i) spontaneous water-in-solvent emulsification, i.e., the formation of a double emulsion, is a necessary step for the subsequent assembly of the copolymers into kinetically frozen aggregates with certain morphologies far from equilibrium. (ii) Equilibration of the copolymer conformation at the solvent–water interfaces is a relatively slow process that can be outpaced, or even quenched before completion, by fast solvent evaporation rates. (iii) Rather than being dictated by the packing parameter at equilibrium, the morphology of the aggregates is determined by the effective copolymer conformation at the solvent–water interface when they form. (iv) Ultra-long worm-like micelles do not form by a direct digitation of the dispersed oil phase into the water continuous phase but through the inversion of the double emulsion. From these findings, we design a simple setup that allows us to control the morphology of the frozen aggregates obtained from a given copolymer composition by simply tuning the solvent evaporation rate.@en

Pluronics P94 are block-copolymer showing prolonged circulation time and tumor-cell internalization in vitro, suggesting a potential for tumor accumulation and as a drug carrier. Here we report the results of the radiolabeled-P94 unimers (P94-¹¹¹In-DTPA) on tumor uptake/retention and biodistribution after intravenous and intratumoral injection to tumor-bearing mice. Intravenous administration results in a high radioactive signal in the liver; while in tumor and other healthy tissues only low levels of radioactivity could be measured. In contrast, the intratumoral injection of P94 resulted in elevated levels of radioactivity in the tumor and low levels in other organs, including the liver. Independently from the injection route, the tumor tissue presented long retention of radioactivity. The minimal involvement of off-target tissues of P94, together with the excellent tracer retention over-time in the tumor designates Pluronic P94 copolymer as a highly promising carrier for anti-tumor drugs.

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Understanding how nanoparticle properties such as size, morphology and rigidity influence their circulation time and biodistribution is essential for the development of nanomedicine therapies. Herein we assess the influence of morphology on cellular internalization, in vivo biodistribution and circulation time of nanocarriers using polystyrene-b-poly(ethylene oxide) micelles of spherical or elongated morphology. The glassy nature of polystyrene guarantees the morphological stability of the carriers in vivo and by encapsulating Indium-111 in their core, an assessment of the longitudinal in vivo biodistribution of the particles in healthy mice is performed with single photon emission computed tomography imaging. Our results show prolonged blood circulation, longer than 24 hours, for all micelle morphologies studied. Dynamics of micelle accumulation in the liver and other organs of the reticuloendothelial system show a size-dependent nature and late stage liver clearance is observed for the elongated morphology. Apparent contradictions between recent similar studies can be resolved by considering the effects of flexibility and degradation of the elongated micelles on their circulation time and biodistribution.

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Optimal biodistribution and prolonged circulation of nanocarriers improve diagnostic and therapeutic effects of enhanced permeability and retention-based nanomedicines. Despite extensive use of Pluronics in polymer-based pharmaceuticals, the influence of different poly(ethylene oxide) (PEO) block length and aggregation state on the biodistribution of the carriers is rather unexplored. In this work, we studied these effects by evaluating the biodistribution of Pluronic unimers and cross-linked micelles with different PEO block size. In vivo biodistribution of ¹¹¹In-radiolabeled Pluronic nanocarriers was investigated in healthy mice using single photon emission computed tomography. All carriers show fast uptake in the organs from the reticuloendothelial system followed by a steady elimination through the hepatobiliary tract and renal filtration. The PEO block length affects the initial renal clearance of the compounds and the overall liver uptake. The aggregation state influences the long-term accumulation of the nanocarriers in the liver. We showed that the circulation time and elimination pathways can be tuned by varying the physicochemical properties of Pluronic copolymers. Our results can be beneficial for the design of future Pluronic-based nanomedicines.

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We present an approach which makes it possible to directly determine the bending modulus of single elongated block copolymer micelles. This is done by forming arrays of suspended micelles onto microfabricated substrates and by performing three-point bending flexural tests, using an atomic force microscope, on their suspended portions. By coupling the direct atomic force microscopy measurements with differential scanning calorimetry data, we show that the presence of a crystalline corona strongly increases the modulus of the copolymer elongated micelles. This large increase suggests that crystallites in the corona are larger and more uniformly oriented due to confinement effects. Our findings together with this hypothesis open new interesting avenues for the preparation of core-templated polymer fibres with enhanced mechanical properties.

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A novel and facile approach to fabricating well-organized macroscopic 2D networks of cylindrical micelles is reported, based on transfer printing and thermal welding of aligned supramolecular micelles of block copolymers. This versatile approach provides a new strategy for fabricating functional 2D superstructures with a higher level of order.

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We report kinetic experiments on dilute brine solutions of P84, P94 and P104 Pluronic copolymer micelles. The growth and the decay of micelles after temperature steps are measured by non-standard time resolved multi-angle photon correlation spectroscopy. Several concurrent mechanisms are at work during the very slow equilibration of solutions, namely insertion/expulsion of unimers, aggregation/dissociation of micellar aggregates, and fusion/budding of micellar aggregates. Their relative rates determine both the kinetic pathways and the morphologies of the micellar assemblies, which depend markedly on modest changes in the copolymer molecular weight. For the typical Pluronic copolymers investigated here, none of these elementary processes can be neglected if the resulting morphology is to be explained. This feature imposes multiple kinetic behaviours where growth and decay of Pluronic micelles become strongly dependent on the thermal history. We point out to some possible shortcomings in the studies of micellar growth kinetics by light scattering techniques. Extensive time-resolved multiangle measurements are a prerequisite for avoiding these pitfalls.@en