WO2016055493A1 - Bola-amphiphilic compounds and their uses for biomedical applications - Google Patents
Bola-amphiphilic compounds and their uses for biomedical applications Download PDFInfo
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
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Definitions
- the invention relates to bola-amphiphilic compounds and their uses for biomedical applications.
- the invention particularly relates to the use of bola-amphiphilic compounds for providing low molecular weight gels (LMWG), useful, in particular, as culture media for cells, in particular isolated stem cells.
- LMWG low molecular weight gels
- Hydrogels which are non-toxic, easy to use, cytocompatible, injectable and degradable are valuable biomaterials as cell-culture media.
- biocompatible artificial matrixes that can be used for stem cell culture remains a great challenge in cell culture engineering and/or regenerative medicine.
- polymers often suffer from several limitations, including poor biocompatibility, toxicity, biodegradability, pro-inflammatory activity etc.
- small-molecule based hydrogels are currently emerging as a new powerful tool for regenerative medicine strategy capable of restoring biological and mechanical properties and/or function.
- the invention thus relates to new bola-amphiphilic compounds derived from nucleolipids and to a new generation of low molecular weight gels (LMWG) which are suitable for cell culture, in particular for stem cell culture.
- LMWG low molecular weight gels
- Bola-amphiphile based hydrogel matrixes exhibit the following requested properties: non-toxicity, easy to handle, injectability, and biocompatible rheology (thixotropic behavior).
- Bola-amphiphiles are composed of one or two hydrophobic chains covalently linked at both ends to hydrophilic head groups. This type of molecular architecture, which can be found in archaebacteria membranes, have been used in numerous applications which range from nanomaterial synthesis to drug or gene delivery.
- glycosyl-nucleosides-lipids (GNL) and glycosyl- nucleosides-fluorolipids (GNF) for forming LMWG has been reported.
- GNL have been reported as being useful for promoting internalization of GNL based liposomes into stem cells (L. Latxague et al., Chem. Commun., 2011 , 47, 12598-12600).
- GNF-based gels were reported as being only compatible with stem cell cultures where the stem cells formed aggregates, and clearly not compatible with the survival and growth of isolated stem cells (S. Ziane et al., Eur. Cells and Math., 2012, 23, 147-160).
- GNBA glycosylated nucleoside based bola- amphiphile
- the invention thus relates to a compound of formula (I)
- - X is oxygen, -NH-C(0)-NH- or -C(0)-NH-
- - A is a C4-C30 hydrocarbon chain, linear or branched, saturated or unsaturated, which is unsubstituted or substituted by one or more C1-C12 linear or branched alkyl groups, or A represents a C4-C30 hydrocarbon chain, linear or branched, saturated or unsaturated, which is partially or completely halogenated;
- n, m and p, identical or different, are 0 to 10;
- R3 represents a heteroaryl group comprising 1 to 4 oxygen or nitrogen atom(s);
- R4 represents a nucleosidyl group or does not exist ;
- R 5 represents a heteroaryl group comprising 1 to 4 heteroatom(s);
- Re represents a residue of a cyclic carbohydrate or a derivative of the said carbohydrate
- A is a C4-C18 hydrocarbon chain, more preferably a C12 or Ci4 hydrocarbon chain, linear or branched, saturated or unsaturated, which is unsubstituted or substituted by one or more C1-C 12 linear or branched a Iky I groups;
- A is a C 4 -Ci 8 hydrocarbon chain, more preferably a C-i 0 or C12 hydrocarbon chain linear or branched, saturated or unsaturated, which is partially or completely halogenated.
- the invention relates to compound of formula (I) in which R 4 represents a nucleosidyl group.
- Ri and R 2 identical or different, represent
- the invention relates to a compound of formula (I)
- - X is oxygen, -NH-C(0)-NH- or -C(0)-NH-
- - A is a C4-C30 hydrocarbon chain, linear or branched, saturated or unsaturated, which is unsubstituted or substituted by one or more C1-C12 linear or branched a Iky I groups, or A represents a C 4 -C 30 hydrocarbon chain, linear or branched, saturated or unsaturated, which is partially or completely halogenated;
- n, m and p identical or different, are 0 to 10;
- R3 represents a heteroaryl group comprising 1 to 4 oxygen or nitrogen atom(s);
- R 4 represents a nucleosidyl group
- R 5 represents a heteroaryl group comprising 1 to 4 heteroatom(s);
- R 6 represents a residue of a cyclic carbohydrate or a derivative of the said carbohydrate.
- R 5 can be covalently linked to R4 via -(CH 2 ) P - to the carbon atom at position 5' of the ribose or deoxyribose ring of the nucleoside, or, alternatively, to the oxygen atom at position 3' of the ribose or deoxyribose ring of the nucleoside.
- Heteroaryl group containing 1 to 4 oxygen or nitrogen atoms » refers to a monocyclic or bicyclic, aromatic or partially unsaturated, carbocyclic group containing 5 to 12 atoms, interrupted by 1 to 4 oxygen or nitrogen atoms, which can be, for example, selected from furane, pyrrole, oxazole, oxadiazole, isoxazole, pyrazole, triazole, tetrazole, imidazole, pyridine, pyrimidine, pyridazine, pyrazine, benzofurane, indole, quinoleine, isoquinoleine, chromane, naphtyridine or benzodiazine groups, triazole being preferred.
- Hydrocarbon chain which is partially or completely halogenated » refers to a saturated or unsaturated alkyl chain in which some or all hydrogen atoms are replaced by halogen atoms, such as fluorine, iodine, chlorine or bromine, fluorine being preferred.
- Nucleosidyl group refers to a group consisting of a ribose or deoxyribose moiety which is linked to a purine or pyrimidine base, or to derivatives of said purine or pyrimidine base, or to a non-natural mono- or bicyclic heterocyclic base, all said bases being optionally substituted.
- the purine base can be, for example, selected from the group consisting of adenine, guanine and hypoxanthine.
- the pyrimidine base can be, for example, selected from the group consisting of thymine, uracile and cytosine, thymine being preferred.
- non-natural mono-or bicycle heterocyclic base is meant a universal base, such as, for example, 3-nitropyrrole, 4-nitroimidazole or 5- nitroindole.
- the purine or pyrimidine base, or the non-natural heterocyclic base can be substituted by at least one substituent chosen, for example, from a halogen, an amino group, a carboxy group, a carbonyl group, a carbonylamino group, a hydroxy, azido, cyano, alkyl, cycloalkyl, perfluoroalkyl, alkyloxy (for example, methoxy), oxycarbonyl, vinyl, ethynyl, propynyl, acyl group etc.
- substituent chosen, for example, from a halogen, an amino group, a carboxy group, a carbonyl group, a carbonylamino group, a hydroxy, azido, cyano, alkyl, cycloalkyl, perfluoroalkyl, alkyloxy (for example, methoxy), oxycarbonyl, vinyl, ethynyl, propynyl, acyl group etc.
- Residue of a cyclic carbohydrate or a derivative of the said carbohydrate » refers to a residue of a 5- or 6- membered osidic cycle, which can be, for instance, selected from D-glucopyranose, D-galactopyranose, D- mannopyranose, D-fructopyranose or D-ribofuranose, or oligosaccharide-type glycans deriving therefrom, as well as their N-acyl derivatives, in particular their N-acetyl derivatives, such as, for instance, N-acetylglucosamine, N- acetylgalactosamine, N-acetylmannosamine or sialic acid, or a protected derivative thereof, such as an O-acyl derivative, in particular an O-acetyl derivative, D-glucopyranose being preferred.
- a 5- or 6- membered osidic cycle which can be, for instance, selected from D-glucopyra
- the invention relates to compounds of formula (I), in which at least one of the following conditions is fulfilled:
- R3 and R 5 identical or different, represent a heteroaryl group containing 1 to 4 nitrogen atoms selected from the group consisting of pyrazole, triazole, tetrazole and imidazole;
- R4 represents a nucleosidyl group selected from adenosine, deoxyadenosine, guanosine, deoxyguanosine, thymidine, deoxythymidine, uridine, deoxyuridine, cytidine and deoxycytidine.
- - Re represents a residue of a cyclic carbohydrate selected from D- glucopyranose, D-galactopyranose, D-mannopyranose, D-fructopyranose, D- ribofuranose, N-acetylglucosamine, N-acetylgalactosamine, N- acetylmannosamine and sialic acid or a protected derivative thereof.
- Preferred compounds of formula (I) are those in which X is oxygen.
- compounds of formula (I) of interest are those in which X is -NH-C(0)-NH- or -C(O)-NH-.
- Preferred compounds of formula (I) are those in which:
- - A represents a Ci 2 or Cu saturated hydrocarbon chain
- - Ri is hydrogen, or-(CH 2 )n- 3-(CH2) m -R4-(CH2)p-R 5 -R6;
- R 2 is -(CH 2 )n-R3-(CH2)n-R4-(CH 2 )p-R 5 -R6;
- R3 is a triazole group
- R5 is a triazole group
- R 6 is ⁇ -D-glucopyranosyl or 2,3,4,6 tetra-O-protected -glucopyranosyl, preferably 2,3,4,6 tetra-O-acetyl-glucopyranosyl.
- - A represents a C-i 0 hydrocarbon chain which is partially fluorinated
- Ri and R 2 are -(CH 2 )n-R3-(CH 2 ) m -R 4- (CH 2 )p-R 5 -R6;
- R3 is a triazole group
- R5 is a triazole group
- - Re is ⁇ -D-glucopyranosyl or 2,3,4,6 tetra-O-protected-glucopyranosyl, preferably 2,3,4,6 tetra-O-acetyl-glucopyranosyl.
- R 5 is covalently linked to R4 via -(CH 2 )p- to the carbon atom at position 5' of the ribose or deoxyribose ring of the nucleosidyl group.
- R5 is covalently linked to R4 via -(CH 2 )p- to the oxygen atom at position 3' of the ribose or deoxyribose ring of the nucleosidyl group.
- the click reaction is carried out with a 1 :1 (v/v) mixture of water and dichloromethane with vigorous stirring at 40°C or a 1 :1 (v/v) mixture of water and THF at 60-65°C with 10% CuS0 4 and 20% ascorbic acid;
- reaction conditions are preferred : - the alkylating reaction of the purine or pyrimidine base or universal base with R-CH 2 -C ⁇ CH is carried out under basic conditions;
- the first click-reaction is Cu(l) catalyzed and is carried out in a 1 :1 (v/v) mixture of water and terf-butanol, preferably at 60°C, and preferably with 10% CuS0 4 and 20% ascorbic acid;
- an organophosphorous compound such as, for example, triphenylphosphine (PPh 3 ), a carbon halide such as, for example, tetrabromide (CBr 4 ) and sodium azide (NaN 3 ).
- organophosphorous compound such as, for example, triphenylphosphine (PPh 3 ), a carbon halide such as, for example, tetrabromide (CBr 4 ) and sodium azide (NaN 3 ).
- the invention further relates to compounds of formula (IV)
- - X is -NH-C(O)-NH-
- - A is a C4-C30 hydrocarbon chain, linear or branched, saturated or unsaturated, which is unsubstituted or substituted by one or more Ci-C-
- R 3 represents a heteroaryl group comprising 1 to 4 oxygen or nitrogen atom(s);
- - R 4 represents a nucleosidyl group
- - R 7 is the residue of an alkylating agent of formula R-(CH 2 ) q -C ⁇ CH where q is 1 or 2 and R is an halide, which is linked by a covalent bond with a nitrogen atom of the purine, pyrimidine or universal base moiety of R4 ;
- R is preferably chloride or bromide, and q is preferably 1.
- the compounds of formula (IV) are useful as synthesis intermediates for obtaining the compounds of formula (I) in which X is oxygen.
- Preferred compounds of formula (IV) are those in which
- R3 is a triazole group
- the invention further relates to compounds of formula (V)
- R4 represents a nucleosidyl group
- - R5 represents a heteroaryl group comprising 1 to 4 heteroatom(s), which is linked to R by a covalent bond to a nitrogen atom of the pyrimidine base or of the purine base of the nucleosidyl group ;
- - Re represents a residue of a cyclic carbohydrate or a derivative of the said carbohydrate, which is optionally substituted;
- f3 ⁇ 4 is a triazole group.
- f3 ⁇ 4 is thymidinyl, and f3 ⁇ 4 is linked to the nitrogen in position 3 of R 5 .
- cyclic carbohydrate or derivative thereof can be substituted by at least one substituent chosen, for example, from a halogen, an amino group, a carboxy group, a carbonyl group, a carbonylamino group, a hydroxy, azido, cyano, alkyl, cycloalkyl, perfluoroalkyl, alkyloxy (for example, methoxy), oxycarbonyl, vinyl, ethynyl, propynyl, acyl group etc.
- substituent chosen, for example, from a halogen, an amino group, a carboxy group, a carbonyl group, a carbonylamino group, a hydroxy, azido, cyano, alkyl, cycloalkyl, perfluoroalkyl, alkyloxy (for example, methoxy), oxycarbonyl, vinyl, ethynyl, propynyl, acyl group etc.
- the compounds of formula (V) are useful as synthesis intermediates for obtaining the compounds of formula (I) in which X is -NH-C(0)-NH-or -C(0)-NH-.
- Preferred compounds of formula (V) are those in which
- R3 is a triazole group
- R 5 is thymidine
- R 6 is a residue of 2,3,4,6 tetra-O-protected-glucopyranosyl.
- the invention also relates to biocompatible hydrogels formed from at least one compound of formula (I).
- these hydrogels are formed from an aqueous solution of compounds of formula (I) which can contain, for example, 0.1 to 10 wt% of compound of formula (I), in particular 1 to 5 wt%.
- the biocompatible hydrogels according to the invention can comprise one or more compound(s) of formula (I), or a mixture of one or more compound(s) of formula (I) and one or more glycosyl-nucleoside(s)-lipid(s) (also called GNL) and/or glycosyl-nucleoside(s)-fluorolipid(s) (also called GNF).
- the biocompatible hydrogels according to the invention can also contain a mixture of one or more compound(s) of formula (I) with one or more protein(s) or glycoprotein(s), such as for example collagen or hyaluronic acid, and optionally, one or more GNL or GNF.
- Biocompatible is understood as a material which is well tolerated by the host organism and which does not cause any rejection, toxic reaction, injury or harmful effect on the biological functions of the host organism.
- biocompatible hydrogels according to the invention can be prepared, for example, by hating the compounds of formula (I) until dissolution, for example at a temperature of 40° C to 50°C, and allowing the solution to cool gradually to room temperature.
- the invention also relates to the use of hydrogels formed from compounds of formula (I) as cell culture media, in particular as culture media for animal or human cells.
- the hydrogels according to the invention are particularly suitable as culture media for eukaryotic cells, in particular for stem cell culture. Indeed, it has been surprisingly found that these hydrogels allow the culture of stem cells under isolated form, while when using existing LMWG, such as those formed from GNF, formation of clusters of stem cells was observed.
- the culture of isolated eukaryotic cells, in particular stem cells is highly valuable and promising in view of the extensive research which is currently carried out on stem cells.
- the hydrogels formed from compounds of formula (I) possess particular viscoelastic properties. Indeed, rheological studies on the variation of the storage modulus G' (also called elastic modulus) and the loss modulus G" (also called viscous modulus) as a function of the applied frequency were performed.
- G' describes the amount of energy which is stored and released in each oscillation, and G" corresponds to the energy which is dissipated at heat.
- the hydrogel formed from compounds of formula (I) possess a thixotropic behaviour, and thus can be delivered by a syringe, thus allowing surgical use. Actually, said hydrogel is able to regain its gel behaviour and strength after a high strain is applied thereto.
- hydrogel according to the invention can be used as biocompatible materials in the following biomedical applications:
- gel-cell complexes which can be used, for example, for bone regeneration;
- biocompatible hydrogel according to the invention can be used as biocompatible material for drug delivery, for instance :
- High resolution electronspray ionization mass spectra were performed by the CESAMO (Bordeaux, France) on a QSsat Elite mass spectrometer (Applied Biosystems). The instrument is equipped with an ESI source and spectra were recorded in negative mode. The electrospray needle was maintained at 4500 V and operated at room temperature. Samples were introduced by injection through a 10 pL sample loop into a 200 pLJmin flow of methanol from the LC pump.
- Figure 1 shows the synthetic scheme used in the Preparations and Examples for compounds of formula (I) in which X is oxygen.
- Figure 2 shows the synthetic scheme used in the Preparations and Examples for compounds of formula (I) in which X is -NH-C(0)-NH-.
- Figure 3 shows the synthetic scheme used in the Preparations and Examples for compounds of formula (I) in which X is-NH-C(O)- ..
- Figure 4 shows the frequency sweep results for hydrogels obtained from compounds 5 and 6.
- Figure 5 shows the step-strain measurement of the hydrogel obtained from compound 6.
- Figure 6 shows the determination of the cytotoxicity of compound 6 by MTT test on human mesenchymal stem cells.
- Figure 7 shows the cytocompatibility of compound 6 by monitoring alamar blue metabolism in rat osteoblastic cells (A) or human stem cells ASCs (B) grown in compound 6-based gels.
- Figure 8 shows the cytotoxycity of compound GNL of G. Godeau et al., Chem. Comm., 2009, 34, 5127-5130_by MTT test in human hepatic carcinoma cells HuH-7 (comparative example).
- aqueous dispersions (Milli-Q water, 18 ⁇ -cnrf 1 ) containing 1.5 wt% of compounds 5 and 6 obtained in examples 1 and 2 were heated until dissolution (at 45°C) and gradually allowed to cool to room temperature unless otherwise stated.
- the resulting solid aggregate mass was stable to inversion of the container when the test tube was tumed upside down, which shows that the compounds 5 and 6 form gels.
- Figure 4 shows the frequency sweep results for hydrogels obtained from compound 5 and 6 (at 23.1 OmM) at a constant strain of 0.03%.
- Figure 5 shows the step-strain measurement of the hydrogel obtained from compound 6 at 1 % (w/v) at a fixed angular frequency of 6.283rad.s "1 . This experiment was repeated at least three times to verify its reproducibility.
- the determination of gel-sol transition temperature can also be determinated by rheology.
- the hydrogel (3% product 6 of example 2, w/v) was heated progressively from 25 to 60 °C (3 °C/min).
- the oscillatory stress applied was set to 5 Pa at a constant frequency (1 Hz).
- the sol-gel transition point was taken as the temperature at which the gel became liquid. This melting temperature is reached at the intersection of the viscoelastic moduli (G' and G"). This value is of 46°C which is compatible with the cell culture at the gel state (37°C).
- Mesenchymal stem cells were isolated from human adipose tissue.
- Human subcutaneous fat was obtained from healthy patients aged 20 to 80 years old who underwent hip surgery in Bordeaux Pellegrin CHU (Bordeaux, France). Fat mass was separated from other tissues, washed with sterilized PBS, finely cut and incubated with 0.1 % (w/v) collagenase type I (Worthington, Lakewood, NJ, USA) at 37°C with gentle agitation for 1 h30. After filtration and centrifugation, the top liquid layer was removed and the remaining Stromal Vascular Fraction (SVF) was treated for 10 min with ELB (Erythocyte Lysis Buffer; 155mM NH 4 CI (Sigma-Aldrich, St.
- ELB Erythocyte Lysis Buffer
- 155mM NH 4 CI Sigma-Aldrich, St.
- D1-ORL-UVA (ATCC® CRL-12424) were cultured in DMEM (Invitrogen/Life Technologies) containing 10% FBS, and 1 % Penicillin- Streptomycin (Invitrogen/Life Technologies). Culture medium was replaced every two days. c) Preparation of 3D scaffold with hASCs or D1 seeding
- the hydrogel obtained from compound 6 was prepared at a concentration of 3 % (w/v).
- the compound 6 powder was solubilized in PBS 1X under agitation (900rpm) at 25°C during 45 minutes. Then, when the gel was formed, it was left at room temperature, without agitation, during 3 to 4 hours. To allow cell seeding, the gel was heated during 30 minutes at 55°C. Once the liquid solution was obtained, it was rapidly cooled down to 37°C and thoroughly mixed with 10 pL cell suspension at a concentration of 1 million cells per mL of gel. Finally, the cellularized hydrogel was maintained under agitation (600rpm), at 25°C during 45 minutes. After this period, medium was been added (250pL / tube) and tubes were incubated at controlled atmosphere (5 % C0 2 , 37°C) d) Evaluation of compound 6 cytotoxicity and of BOLA gel cytocompatibility
- the cytotoxicity of compound 6 was evaluated by the measurement of the cell metabolic activity (MTT assay).
- MTT tetrazolium bromide
- MTT tetrazolium bromide
- This reduction results in a change of colour from yellow to violet- blue.
- the colour intensity is proportional to the amount of living cells.
- hASCs or D1 were seeded in a 96 wells plate (Nunc) at a density of 10 000 cells/cm 2 .
- Product 6 was solubilized at concentrations from 5 ⁇ to 5mM in culture media.
- MTT assay was performed after 72h of incubation.
- As a positive control the culture medium without GNBA was used.
- As a negative control Triton X100 was added in the culture medium. Results were expressed as a percentage of the metabolic activity of the positive control. Absorbance was measured at a wavelength of 570 nm with background subtraction at 630 nm.
- cytotoxicity of compound 6 was determined by MTT test to measure the metabolic activity of human mesenchymal stem cells (ASCs) 48 hours after incubation with increasing concentrations of compound 6. Results are shown as percentage of positive control consisting in BOLA-free cell culture medium. **: p ⁇ 0.01 (Mann-Whitney U-Test).
- Cytocompatibility was determined by monitoring alamar blue metabolism in rat osteoblastic cells (A) or human ASCs (B) grown in compound 6-based gels. Results are shown as percentage of the value obtained at day 1 . *: p ⁇ 0.05 ; **: p ⁇ 0.01 (Mann-Whitney U-Test).
- Viability was assessed after 1 , 4 and 7 days by using Live/Dead staining with calcein-AM and ethidium homodimer (Molecular Probes, Invitrogen, USA). Cells seeded within gels were incubated for 1 h at 37°C in Hank's medium supplemented with 1.25 ⁇ . calcein-AM and 5 ⁇ _ EthD-1. Samples were observed with a Confocal microscope (Leica TCS SPE).
- Live/dead staining at 2 weeks showed a vast majority of green (living) cells.
- Huh-7 cells were grown in DMEM medium supplemented with 10% foetal calf serum, 2 mM L-glutamine and 1 % non-essential amino acids, at 37 °C in a 5% C02 atmosphere. All culture reagents were purchased from Invitrogen. 2000 Huh-7 cells per well were seeded into a 96-well plate and incubated the following day with increasing concentrations of compound GNLin complete growth medium. After 5 days in the presence of the compounds, the living cells were quantified by the colorimetric CellTiter Aqueous One Solution Cell Proliferation Assay (Promega), as recommended. The viability results are shown on Figure 8.
- the GNL compound does not have a significant toxicity for concentrations which are equal to or lower thanl OO ⁇ . For higher concentration, toxicity quickly becomes important and 100 % of the cells die at a concentration of 200 ⁇ .
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Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2017518337A JP2017531654A (en) | 2014-10-06 | 2015-10-06 | Bora amphiphiles and their use for biomedical applications |
US15/517,313 US10227372B2 (en) | 2014-10-06 | 2015-10-06 | Bola-amphiphilic compounds and their uses for biomedical applications |
CA2962742A CA2962742A1 (en) | 2014-10-06 | 2015-10-06 | Bola-amphiphilic compounds and their uses for biomedical applications |
US16/251,287 US10633409B2 (en) | 2014-10-06 | 2019-01-18 | Bola-amphiphilic compounds and their uses for biomedical applications |
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US16/251,287 Division US10633409B2 (en) | 2014-10-06 | 2019-01-18 | Bola-amphiphilic compounds and their uses for biomedical applications |
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EP (1) | EP3006452B1 (en) |
JP (1) | JP2017531654A (en) |
CA (1) | CA2962742A1 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106674212A (en) * | 2017-01-04 | 2017-05-17 | 云南大学 | Thiophene triazole bola (Bola) compound |
EP3871678A1 (en) | 2020-02-26 | 2021-09-01 | Universite De Bordeaux | Pro-angiogenic compounds |
Citations (1)
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WO2008103618A1 (en) * | 2007-02-22 | 2008-08-28 | University Of Utah Research Foundation | Synthesis of novel xylosides and potential uses thereof |
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2014
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2015
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- 2015-10-06 US US15/517,313 patent/US10227372B2/en not_active Expired - Fee Related
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- 2015-10-06 JP JP2017518337A patent/JP2017531654A/en active Pending
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WO2008103618A1 (en) * | 2007-02-22 | 2008-08-28 | University Of Utah Research Foundation | Synthesis of novel xylosides and potential uses thereof |
Non-Patent Citations (5)
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GUILHEM GODEAU ET AL: "Glycosyl-nucleoside-lipid based supramolecular assembly as a nanostructured material with nucleic acid delivery capabilities", CHEMICAL COMMUNICATIONS, no. 34, 1 January 2009 (2009-01-01), pages 5127, XP055044911, ISSN: 1359-7345, DOI: 10.1039/b906212b * |
LAURENT LATXAGUE ET AL: "Glycosylated nucleoside lipid promotes the liposome internalization in stem cells", CHEMICAL COMMUNICATIONS, vol. 47, no. 47, 1 January 2011 (2011-01-01), pages 12598, XP055161588, ISSN: 1359-7345, DOI: 10.1039/c1cc13948g * |
LAURENT LATXAGUE ET AL: "Glycosyl-Nucleolipids as New Bioinspired Amphiphiles", MOLECULES, vol. 18, no. 10, 1 January 2013 (2013-01-01), pages 12241 - 12263, XP055161834, DOI: 10.3390/molecules181012241 * |
NURAJE NURXAT ET AL: "Bolaamphiphilic molecules: Assembly and applications", PROGRESS IN POLYMER SCIENCE, PERGAMON PRESS, OXFORD, GB, vol. 38, no. 2, 15 September 2012 (2012-09-15), pages 302 - 343, XP028980022, ISSN: 0079-6700, DOI: 10.1016/J.PROGPOLYMSCI.2012.09.003 * |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106674212A (en) * | 2017-01-04 | 2017-05-17 | 云南大学 | Thiophene triazole bola (Bola) compound |
CN106674212B (en) * | 2017-01-04 | 2019-08-09 | 云南大学 | Thiophene triazole wave draws (Bola) compound |
EP3871678A1 (en) | 2020-02-26 | 2021-09-01 | Universite De Bordeaux | Pro-angiogenic compounds |
Also Published As
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EP3006452A1 (en) | 2016-04-13 |
CA2962742A1 (en) | 2016-04-14 |
JP2017531654A (en) | 2017-10-26 |
EP3006452B1 (en) | 2017-12-13 |
US20170240583A1 (en) | 2017-08-24 |
US10633409B2 (en) | 2020-04-28 |
ES2660752T3 (en) | 2018-03-26 |
US20190233460A1 (en) | 2019-08-01 |
US10227372B2 (en) | 2019-03-12 |
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