Echogenicity enhancement by end-fluorinated polylactide perfluorohexane nanocapsules: towards ultrasound-activable nanosystems

Publication date: Available online 3 October 2017
Source:Acta Biomaterialia
Author(s): Guilherme Picheth, Sophie Houvenagel, Camille Dejean, Olivier Couture, Rilton Alves de Freitas, Laurence Moine, Nicolas Tsapis
Polylactide (PLA) polymers containing five distinct lengths of fluorinated (from C3F7 to C13F27) and non-fluorinated (C6H13) end-groups were successfully synthesized by ring-opening polymerization of D,L-lactide. Fluorination was expected to increase the encapsulation efficiency of perfluorohexane (PFH). 150 nm nanocapsules were obtained and ¹⁹F nuclear magnetic resonance revealed that nanocapsules formulated with fluorinated polymers increased by 2-fold the encapsulation efficiency of PFH compared with non-fluorinated derivatives, without any effect of fluorine chain length. Fluorination of the polymers did not induce any specific in vitro cytotoxicity of nanocapsules towards HUVEC and J774.A1 cell lines. The echogenicity of fluorinated-shelled nanocapsules was increased by 3-fold to 40-fold compared to non-fluorinated nanocapsules or nanoparticles devoid of a perfluorohexane core for both fundamental and harmonic ultrasound imaging modalities. In particular, an enhanced echogenicity and harmonic response was observed as the fluorinated chain-length increased, probably due to an increase of density and promotion of bubble nucleation. When submitted to focused ultrasound, both intact and exploded nanocapsules could be observed, also with end-group dependency, indicating that PFH was partly vaporized. These results pave the way to the design of theranostic perfluorohexane nanocapsules co-encapsulating a drug for precision delivery using focused ultrasound.Statement of significanceWe believe that Acta Biomaterialia is an appropriate journal for our article since we present new and original experimental research in the field of nanomaterials for biomedical applications. In particular, 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 (Houvenagel et al, Polymer Chemistry 2017), 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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