In this study, we report detailed information on the internal structure of PNIPAM-b-PEG-b-PNIPAM nanoparticles formed from self-assembly in aqueous solutions upon increase in temperature. NMR spectroscopy, light scattering, and small-angle neutron scattering (SANS) were used to monitor different stages of nanoparticle formation as a function of temperature, providing insight into the fundamental processes involved. The presence of PEG in a copolymer structure significantly affects the formation of nanoparticles, making their transition to occur over a broader temperature range. The crucial parameter that controls the transition is the ratio of PEG/PNIPAM. For pure PNIPAM, the transition is sharp; the higher the PEG/PNIPAM ratio results in a broader transition. This behavior is explained by different mechanisms of PNIPAM block incorporation during nanoparticle formation at different PEG/PNIPAM ratios. Contrast variation experiments using SANS show that the structure of nanoparticles above cloud point temperatures for PNIPAM-b-PEG-b-PNIPAM copolymers is drastically different from the structure of PNIPAM mesoglobules. In contrast with pure PNIPAM mesoglobules, where solidlike particles and chain network with a mesh size of 1-3 nm are present, nanoparticles formed from PNIPAM-b-PEG-b-PNIPAM copolymers have nonuniform structure with "frozen" areas interconnected by single chains in Gaussian conformation. SANS data with deuterated "invisible" PEG blocks imply that PEG is uniformly distributed inside of a nanoparticle. It is kinetically flexible PEG blocks which affect the nanoparticle formation by prevention of PNIPAM microphase separation.

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The synthesis of defined triphilic terpolymers with hydrophilic, lyophilic and fluorophilic blocks is an important challenge as basis for the development of multicompartment self-assembled structures with potential for, e.g., cascade catalysis and multi-drug loading. The synthesis of fluorophilic poly(2oxazoline)s generally suffers from a very low reactivity of fluorinated 2-oxazoline monomers in cationic ring-opening polymerization (CROP). We report a systematic study on overcoming the extremely low reactivity of 2-perfluoroalkyl-2-oxazolines in CROP by the insertion of methyl and ethyl hydrocarbon spacers between the 2-oxazoline ring and the trifluoromethyl group. The kinetic studies showed the gradual increase of the rate of polymerization with increasing of the hydrocarbon spacer length. The monomer with an ethyl spacer was found to have similar reactivity as 2-alkyl-2-oxazolines and allowed the synthesis of defined triphilic triblock copolymers.Poly(2-oxazoline)s are widely used in many medical and biological applications 1,2 . The cationic ringopening polymerization (CROP) of 2-substituted-2-oxazolines can proceed at certain conditions in a living mode, which allows to synthesize defined polymers with very low dispersity. In combination with a variety of commercially and synthetically available monomers, it makes 2-oxazolines very attractive candidates for the design of amphiphilic polymer systems with controlled properties 3,4,5 . The majority of these systems is amphiphilic AB block and ABA triblock copolymers. However, in recent years, the behavior of hydrophilic-hydrophobic-fluorophilic ABC triblock copolymers has attracted significant attention as they form more complex self-assembled structures than traditional AB copolymers due to mutual incompatibility of all three blocks 6,7,8,9 . Such multicompartment self-assembled structures are highly interesting as for developing cascade catalysis or multidrug drug delivery by encapsulation incompatible catalysts or drugs into the separate compartments.

This work focused on the synthesis and self-assembly of triphilic poly(2-oxazoline) triblock copolymers with high fluorine content towards our future aim of developing poly(2-oxazoline) MRI contrast agents. A highly fluorinated 2-substituted-2-oxazoline monomer, namely 2-(1H,1H,2H,2H-perfluorooctyl)-2-oxazoline was synthesized using the Grignard reaction. The polymerization kinetics of the synthesized monomer was studied and it was used for the preparation of triblock copolymers with hydrophilic 2-methyl-2-oxazoline, hydrophobic 2octyl-2-oxazoline and fluorophilic blocks by Cationic Ring-Opening Polymerization yielding polymer with low relatively dispersity (1.2-1.4). The presence of the blocks with the different nature in one copolymer structure facilitated self-assembly of the copolymers in water and dimethylsulfoxide as observed by dynamic light scattering, cryo-transmition electron microscopy, and small-angle neutron scattering. The nanoparticle morphology is strongly influenced by the order and length of each block and the nature of solvent, leading to nanoparticles with core-shell structure as confirmed by small angle neutron scattering. The reported poly(2-oxazoline) block copolymers with high fluorine content have high potential for future development of MRI contrast agents.

International audienceWe report on the self-assembly behavior of poly(2-methyl-2-oxazoline)–block–poly(2-octyl-2-oxazoline) comprising different terminal perfluoroalkyl fragments in aqueous solutions. As reported previously [Eur. Polym. J., 2017, 88, 645-655] such polyphiles can form a plethora of nanostructures depending of the composition and on the way of preparation. Here we report, for the first time, detailed information on the internal structure of the nanoparticles resulting from the self-assembly of these copolymers. Small-angle neutron and x-ray scattering (SANS/SAXS) experiments unambiguously prove the existence of polymersomes, wormlike micelles and their aggregates in aqueous solution. It is shown that increasing content of fluorine in the poly(2-oxazoline) copolymers results in a morphological transition from bilayered or multi-layered vesicles to wormlike micelles for solutions prepared by direct dissolution.In contrast, nanoparticles prepared by dialysis of a polymer solution in a non-selective organic solvent against water are characterized by SAXS method. The internal structure of the nanoparticles could be assessed by fitting of the scattering data, revealing complex core-double shell architecture of spherical symmetry. Additionally, long range ordering is identified for all studied nanoparticles due to the crystallization of the poly(2-octyl-2-oxazoline) segments inside the nanoparticles