Fluorination of polyesters favors the encapsulation efficiency of perfluorooctyl bromide into nanocapsules.

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Imaging the enhanced permeation and retention effect by ultrasound is hindered by the large size of commercial ultrasound contrast agents (UCAs). To obtain nanosized UCAs, triblock copolymers of poly(ethylene glycol)-polylactide-poly(1 H,1 H,2 H,2 H-heptadecafluorodecyl methacrylate) (PEG-PLA-PFMA) with distinct numbers of perfluorinated pendant chains (5, 10, or 20) are synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. Nanocapsules (NCs) containing perfluorooctyl bromide (PFOB) intended as UCAs are obtained with a 2-fold increase in PFOB encapsulation efficiency in fluorinated NCs as compared with plain PEG-PLA NCs thanks to fluorous interactions. NC morphology is strongly influenced by the number of perfluorinated chains and the amount of polymer used for formulation, leading to peculiar capsules with several PFOB cores at high PEG-PLA-PFMA amount and single-cored NCs with a thinner shell at low fluorinated polymer amount, as confirmed by small-angle neutron scattering. Finally, fluorinated NCs yield higher in vitro ultrasound signal compared with PEG-PLA NCs, and no in vitro cytotoxicity is induced by fluorinated polymers and their degradation products. Our results highlight the benefit of adding comb-like fluorinated blocks in PEG-PLA polymers to modify the nanostructure and enhance the echogenicity of nanocapsules intended as UCAs.

We have synthesized novel fluorinated polyesters and formulated them into nanocapsules of perfluorohexane as ultrasound contrast agents. This nanosystem has been thoroughly characterized by several techniques and we show that fluorination of the biodegradable polymer favors the encapsulation of perfluorohexane without producing further reduction of cell viability. Contrary to nanocapsules of perfluoroctyl bromide formulated with the fluorinated polymers [32], the presence of the fluorinated moieties leads to an increase of echogenicity that is dependent of the length of the fluorinated moiety. Morevover, the ability of nanocapsules to explode when submitted to focused ultrasound also depends on the length of the fluorinated chain. These results pave the way to theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound.

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We have synthesized polylactide (PLA) polymers containing five distinct lengths of fluorinated end-groups (from C 3 F 7 to C 13 F 27). The influence of fluorinated end-groups length and their dynamics in chlorinated solvents (chloroform and dichloromethane) was investigated as a function of the presence of perfluohexane (PFH) and related to the morphology of capsules of PFH obtained using these fluorinated polylactides. 19 F spin-spin relaxation time (T 2) measurements revealed a reduced mobility of the fluorinated units with dependency on fluorinated chain length in the order C 3 F 7 >C 8 F 17 >C 13 F 27. The presence of perfluorohexane (PFH) led to a further decrease on the segmental mobility, indicating the existence of fluorous interactions. The T 2 relaxation time of the CF 3 resonance of PLA-C 3 F 7 decreased from 540±50 ms in CDCl 3 to 81±15 ms after the addition of PFH. Due to these fluorous interactions, PLA polymers containing short fluorinated groups (C 3 F 7 and C 6 F 13) led to microcapsules with core-shell morphologies, whereas those formulated with long F-units (C 8 F 17 , C 11 F 23 and C 13 F 27) favored the formation of multinucleated capsules as observed by confocal microscopy.