Microfluidic preparation of fluorocarbon nanodroplets
AssigneesBracco Suisse SA, Avignon Université
InventorsRomain MELICH, Philippe BUSSAT, Samir CHERKAOUI, Christiane CONTINO-PEPIN, Stéphane DESGRANGES
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Abstract
The present invention relates to calibrated (per)fluorocarbon nanodroplets comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant and said inner core comprising a (per)fluorocarbon. The invention further relates to a method of preparation of said calibrated (per)fluorocarbon nanodroplets through microfluidic technique, and to their use for in vivo or in vitro diagnostic and/or for therapy.
Claims21
1) A nanodroplet comprising an outer layer and an inner core, said outer layer comprising a biocompatible fluorinated surfactant and said inner core comprising a fluorocarbon, characterized in that the molar ratio between said biocompatible surfactant and said fluorocarbon is higher than 0.06, wherein said biocompatible fluorinated surfactant is selected from
- (A) an amphiphilic dendrimer (Dendri-TAC) of generation n comprising:
- a hydrophobic central core of valence 2 or 3;
- generation chains attached to each respective open end of the central core and branching around the core;
- and
- a hydrophilic terminal group at the end of each generation chain;
- wherein
- n is an integer from 0 to 12 and identifies the hydrophilic terminal group comprising:
- a mono-, oligo- or polysaccharide residue,
- a cyclodextrin residue,
- a peptide residue,
- a tris(hydroxymethyl)aminomethane (Tris), or
- a 2-amino-2-methylpropane-1,3-diol;
- the hydrophobic central core is a group of formula (Ia) or (Ib)
- wherein:
- W is RF or a group selected from W0, W1, W2 or W3:
- RF is a C4-C10 perfluoroalkyl or a C1-C24 alkyl group,
- RH is a C1-C24 alkyl group,
- p is 0, 1, 2, 3 or 4;
- q is 0, 1, 2, 3 or 4;
- L is a linear or branched C1-C12 alkylene group, optionally interrupted by one or more —O—, —S—,
- Z is C(═O)NH or NHC(═O),
- R is a C1-C6 alkyl group, and
- e is at each occurrence independently selected from 0, 1, 2, 3 or 4,
- (B) an amphiphilic linear oligomer (F-TAC) of formula II
- wherein:
- n is the number of repeating Tris units (n=DPn is the average degree of polymerization), wherein the term Tris indicates the tris(hydroxymethyl)aminomethane unit, and
- i is the number of carbon atoms in the fluoroalkyl chain or a mixture thereof.
9) A method for the preparation of an aqueous suspension of calibrated fluorocarbon nanodroplets, said method comprising the steps of:
- a) Preparing an aqueous phase;
- b) Preparing an organic phase,
- wherein
- i) said aqueous phase comprises a biocompatible fluorinated surfactant selected from a Dendri-TAC, a F-TAC or a mixture thereof and the organic phase comprises a fluorocarbon or
- ii) said organic phase comprises a biocompatible fluorinated surfactant selected from a Dendri-TAC, a F-TAC or a mixture thereof and a fluorocarbon.
- c) Injecting said aqueous phase into a first inlet and said organic phase into a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing device of the microfluidic cartridge to obtain an aqueous suspension of calibrated fluorocarbon nanodroplets, and
- d) Collecting the aqueous suspension of calibrated fluorocarbon nanodroplets from the exit channel of the microfluidic cartridge.
16) (canceled)
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18) (canceled)
19) An aqueous suspension comprising a plurality of calibrated fluorocarbon nanodroplets obtainable by a method of preparation comprising the steps of:
- a) Preparing an aqueous phase;
- b) Preparing an organic phase,
- wherein i) said aqueous phase comprises a biocompatible fluorinated surfactant, selected from Dendri-TAC, F-TAC or a mixture thereof, and the organic phase comprises a fluorocarbon or
- ii) said organic phase comprises a biocompatible fluorinated surfactant, selected from selected from Dendri-TAC, F-TAC or a mixture thereof and a fluorocarbon.
- c) Injecting said aqueous phase into a first inlet and said organic phase into a second inlet of a microfluidic cartridge, thereby mixing said aqueous phase and said organic phase in a mixing device of the microfluidic cartridge to obtain an aqueous suspension of calibrated fluorocarbon nanodroplets, and
- d) Collecting the aqueous suspension of calibrated fluorocarbon nanodroplets from the exit channel of the microfluidic cartridge,
- wherein said nanodroplets have a z-average diameter comprised between 100 nm and 1000 nm and a polydispersity lower than 0.25.
20) (canceled)
Dependencies are inferred from the claim text.