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Synthesis and characterization of acoustic-sensitive perfluorinated microvesicles and nanocapsules for theranostic application

Abstract : Fluorinated materials are intensively used as ultrasound contrast agents (UCA) to facilitate the diagnosis of many diseases by real-time imaging. All the commercially available UCAs are microbubbles constituted by a perfluorinated gaseous-core stabilized by a monolayer of phospholipids, proteins or surfactants. Unfortunately, the theranostic application (i.e. therapeutic and diagnostic ability) of such materials are severely limited by the (i) poor stability of the fluorinated component, (ii) inherent micrometer size range and (iii) lack of effective compartments for drug accumulation. To overcome these limitations, we proposed two different strategies to improve the persistence of the fluorinated core and simultaneously provide functional interfaces for drug encapsulation.The first approach involves intercalating chitosan with phospholipids (DSPC) to increase the stability of microvesicles containing the fluorinated gas decafluorobutane (C4F10). The affinity of DSPC and chitosan was disclosed by surface sensitive techniques and fluorescence microscopy. 19F nuclear magnetic resonance (19F-NMR) and in vitro ultrasound of chitosan-coated microvesicles exhibited intense signals of the gaseous-component after 48 h, twice as long compared to plain samples. Altogether, chitosan increased the stability of microvesicles and is a suitable platform for drug accumulation. As a result, the chitosan-phospholipid shell may enhance the theranostic potential of related microvesicles. However, the use of a fluorinated gas-core imposed an important restriction to stabilize sub-micrometric vesicles. Therefore, the second strategy was focused in developing a theranostic agent at the nanoscale by entrapping a liquid fluorinated core of perfluorohexane (PFH; C6F14) into a rigid polymeric shell of polylactide (PLA). To enhance the interaction of biodegradable polymers with perfluorocarbons, we synthesized PLA polymers containing five distinct lengths of fluorinated end-groups (from C3F7 until C13F27) by ring-opening polymerization of D,L-lactide. A greater extent of fluorous interactions was indicated by 19F spin-spin relaxation time and, subsequently, all the block copolymers were formulated into spherical nanocapsules (NC) with average diameter of 150 nm as verified by transmission electron microscopy. 19F-NMR showed that NC produced with fluorinated polymers increased two-fold the encapsulation efficiency of PFH compared with non-fluorinated derivatives. As a result, the NC echogenicity increased 10-fold for both fundamental and harmonic ultrasound imaging modalities. In addition, acoustic drop vaporization of PFH was successfully attained by focused ultrasound as observed by fragmented or disrupted morphologies in many samples. Effects of the fluorinated end-groups were further explored by a morphological evaluation of microcapsules (MC) produced with the polymers. Finally, both NC and MC present an interesting theranostic potential, being able to perform ultrasound-assisted diagnosis and potentially release drug contents when irradiated by high acoustic pressures.
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Guilherme Picheth. Synthesis and characterization of acoustic-sensitive perfluorinated microvesicles and nanocapsules for theranostic application. Galenic pharmacology. Université Paris Saclay (COmUE); Universidade federal do Paraná (Brésil), 2017. English. ⟨NNT : 2017SACLS105⟩. ⟨tel-02085930⟩

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