WO2009098404A2 - Procédé de préparation de nanoparticules à base de molécules ou macromolécules amphiphiles fonctionnelles et leur utilisation - Google Patents
Procédé de préparation de nanoparticules à base de molécules ou macromolécules amphiphiles fonctionnelles et leur utilisation Download PDFInfo
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- WO2009098404A2 WO2009098404A2 PCT/FR2008/001661 FR2008001661W WO2009098404A2 WO 2009098404 A2 WO2009098404 A2 WO 2009098404A2 FR 2008001661 W FR2008001661 W FR 2008001661W WO 2009098404 A2 WO2009098404 A2 WO 2009098404A2
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- SHMVYPORADJPTM-UHFFFAOYSA-N CCCCCCCCCCCCCCCCCCOCC1N=NN(CC(C(C2)O)OC2N(C=C(C)C(N2)=O)C2=O)C1 Chemical compound CCCCCCCCCCCCCCCCCCOCC1N=NN(CC(C(C2)O)OC2N(C=C(C)C(N2)=O)C2=O)C1 SHMVYPORADJPTM-UHFFFAOYSA-N 0.000 description 1
- YASYGMZRKOQIAK-QQFBHYJXSA-N CCCCCCc1c[n](CC([C@@H](C2)O)OC2N(C=C(C)C(N2)=O)C2=O)nn1 Chemical compound CCCCCCc1c[n](CC([C@@H](C2)O)OC2N(C=C(C)C(N2)=O)C2=O)nn1 YASYGMZRKOQIAK-QQFBHYJXSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
- A61K31/282—Platinum compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
- A61K31/708—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/242—Gold; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- 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
- C07H19/06—Pyrimidine radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- 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
- C07H19/06—Pyrimidine radicals
- C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- 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
- C07H19/16—Purine radicals
Definitions
- the invention relates to a process for preparing nanoparticles based on functional amphiphilic molecules or macromolecules and their use for the transport or vectorization of therapeutic agents, in particular antitumor agents.
- cis-platinum is a widely used antitumor agent, especially for the treatment of solid tumors.
- its use is limited by its toxicity and the appearance of acquired resistance.
- compositions containing cisplatin and a vector comprising at least one nucleoside or deoxynucleoside are described.
- US Pat. No. 7,908,160 relates to ligand-bound cis-platinum derivatives whose activity is reversible as a function of ligand binding.
- WO01 / 32139 describes cis-platinum compositions encapsulated in lipophilic nanoparticles obtained by repeated cycles of heating and freezing, based on negatively charged natural lipids, in particular dioleylphosphatidylserine. It is stated in this application that cis-platinum forms positively charged aggregates in water with a higher solubility than uncharged species, allowing their interaction with negatively charged lipid membranes and reorganization of membranes. lipids around cis-platinum aggregates.
- nanoparticles formed from functional amphiphilic molecules or macromolecules allows efficient and rapid intracellular delivery of therapeutic agents and has improved stability properties, particularly at 37 ° C, allowing prolonged vectorization in the time of said therapeutic agents.
- therapeutic agents is meant, for example, a natural or synthetic molecule used for the prevention or treatment of a pathology or the restoration of a biological function, in vitro or in vivo, in particular in animals, including humans, or isolated cells, with the exception of nucleic acids or their fragments.
- Such a molecule may be chosen, for example, from the active ingredients of medicaments, in particular from anti-tumor agents such as, for example:
- platinum complexes among which we may especially mention cis-platinum, carboplatin, oxaliplatin, nedaplatin, lobaplatin, etc., or ruthenium capable of binding to platinum complexes, or platinum-free inorganic complexes based on ruthenium II and / or III, titanium, for example titanocene or gallium dichloride, for example gallium salts such as gallium nitrate, gallium chloride, KP46 or iron derivatives, such as, for example, ferrocenium salts, iron-containing nucleoside analogues, iron (II) complexes containing pyridyl pentadenate ligands, or
- cobalt derivatives such as, for example, hexacarbonyl-dicobalt complexes, alkyne-cobalt complexes, the Co (III) complex containing a bicyclic nitrogen ligand, or
- gold derivatives such as, for example, Auranofin, gold complexes (I), (III) and (III), aurothioglucose, etc.
- nanoparticles formed from functional amphiphilic molecules or macromolecules of formula (I) for encapsulating these compounds and ensuring their intracellular delivery makes it possible to limit the phenomena of resistance to these compounds.
- Platinum complexes in particular cis-platinum, are preferred therapeutic agents for the purpose of the invention.
- Inorganic complexes based on ruthenium II and / or III may be, for example, the complexes called NAMI-A, RAPTA-C, KP1019.
- Such non-platinum complexes are described in Ott I. and Gust R., Arch. Pharm. Chem. Life ScL 2007, 340, 117-126; Reedijk J., Curr Opin Chem Biol., 1999, 3, 236-40; Haimei Chen et al., J. Am. Chem. Soc., 2003, 125, 173-186.
- Iron-containing nucleoside analogues are described in US Pat.
- the invention thus relates, in a first aspect, to a method of encapsulating a therapeutic agent, preferably an antitumor agent, comprising the steps of: a) preparing a mixture of at least one functional amphiphilic compound of formula (I) in which
- X represents an oxygen atom, sulfur atom or a methylene group
- - B represents a purine or pyrimidine base such as uracil, adenine, guanine, cytosine, thymine, hypoxanthine, or their derivatives, or a mono- or bi heterocyclic base; non-natural cyclic of which each cycle has 4 to 7 members, optionally substituted
- I 1 and L 2 which may be identical or different, represent hydrogen, an oxycarbonyl group -O-C (O) -, a thiocarbamate group -O-C (S) -NH-, a carbonate group -O-C (O) -O-, a carbamate group -O-C (O) -NH-, an oxygen atom, a phosphate group, a phosphonate group or a heteroaryl group comprising 1 to 4 nitrogen atoms, substituted or unsubstituted by a hydrocarbon chain, saturated or unsatur
- Li or L 2 represents hydrogen, and the other represents a hydroxy group or a heteroaryl group comprising 1 to 4 nitrogen atoms, unsubstituted or substituted by a linear or branched C 2 -C 3 0 alkyl chain;
- Ri and R 2 identical or different, represent
- - a linear or branched hydrocarbon chain C 2 -C 30, preferably Ce-C 25, particularly C 8 -C 25 saturated or partially unsaturated, optionally partially or completely fluorinated, unsubstituted or substituted on the atoms of chain end with a fluorine atom or with a benzyl or naphthyl ester or ether, or a diacyl chain in which each C 2 -C 3 0 acyl chain, or
- Li or L 2 represents hydrogen and the other represents a hydroxyl group or a heteroaryl group comprising 1 to 4 nitrogen atoms, R 1 and R 2 do not exist;
- R 3 represents
- R 4 , R 5 and R 6 which are identical, or different, represent a hydrogen atom or a linear or branched alkyl chain-C 5 linear or branched hydroxyalkyl, or Cr C5, or
- V is -O -, - S-, or -NH-
- R 7 is H or
- R 3 is covalently linked to another substituent R 3 , identical or different, of another compound of formula (I), identical or different, to form a compound of formula (I) in the form of a dimer, and a therapeutic agent, preferably an anti-tumor agent,
- the therapeutic agent nucleobase, nucleoside, modified nucleoside, nucleotides, oligonucleotide, heterocycle, etc.
- the substituent B and having an amphiphilic character because of the presence of at least one hydrophilic part (phosphate, carboxylate, etc.), and at least one hydrophobic part
- n is advantageously between 1 and 500, preferably between 1 and 100, in particular between 1 and 50, most particularly between 1 and 10.
- linear or branched C 1 -C 5 alkyl is meant for example a methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl or tert-butyl radical, preferably methyl or ethyl.
- the purine or pyrimidine base, or the non-natural heterocyclic base may be substituted with at least one substituent selected from, for example, a halogen, an amino group, a carboxy group, a carbonyl group, carbonylamino group, hydroxy, azido, cyano, alkyl, cycloalkyl, perfluoroalkyl, alkyloxy (for example, methoxy), oxycarbonyl, vinyl, ethynyl, propynyl, acyl and so on.
- substituent selected from, for example, a halogen, an amino group, a carboxy group, a carbonyl group, carbonylamino group, hydroxy, azido, cyano, alkyl, cycloalkyl, perfluoroalkyl, alkyloxy (for example, methoxy), oxycarbonyl, vinyl, ethynyl, propynyl, acyl and so on.
- non-natural heterocyclic base means a base other than uracil, adenine, guanine, cytosine, thymine or hypoxanthine, which does not exist in nature.
- heteroaryl group containing 1 to 4 nitrogen atoms is meant a monocyclic or bycyclic carbocyclic group, aromatic or partially unsaturated, containing 5 to 12 atoms, interrupted by 1 to 4 nitrogen atoms, in particular the pyrazole groups, triazole, tetrazole or imidazole.
- the method according to the invention may comprise the steps implemented in the following general conditions:
- the compound of formula (I) is dissolved in an organic solvent to form a lipidic mixture and then, after removal, evaporated to form a film;
- the desired quantity of therapeutic agent preferably an anti-tumor agent
- the lipid film is rehydrated in the therapeutic agent solution, preferably an anti-tumor agent.
- a clear solution is obtained by sonification and heating;
- the solution is rapidly cooled, for example by immersion in liquid nitrogen.
- This heating / cooling cycle is preferably carried out from 1 to 10 times, in particular from 5 to 10 times, in particular 10 times.
- the solution obtained is centrifuged.
- the supernatant is discarded. After several centrifugations, the pellet is dried.
- the organic solvent may be chosen, for example, from organic solvents customary in the field, such as, for example, chloroform, an alcohol such as methanol or ethanol, etc.
- the heating is preferably carried out at a temperature of the order of 20 ° C. to 80 ° C. and the cooling at a temperature of the order of
- a suitable heating / cooling cycle may, for example, be 45 ° C for heating and -78 ° C for cooling.
- the therapeutic agent is chosen from platinum complexes (cis-platinum, carboplatin, etc.), cis-platinum being particularly preferred, or ruthenium capable of binding to platinum complexes, or else platinum-free inorganic complexes based on ruthenium II or III, titanium, gallium, cobalt, iron or gold mentioned above.
- platinum complexes cis-platinum, carboplatin, etc.
- cis-platinum being particularly preferred
- ruthenium capable of binding to platinum complexes
- platinum-free inorganic complexes based on ruthenium II or III, titanium, gallium, cobalt, iron or gold mentioned above.
- the nanoparticles obtained may optionally be extruded on a polycarbonate filter having, for example, a pore diameter of the order of 100 or 200 nm.
- Solid nanoparticles consist of a core rich in therapeutic agent (active principle) surrounded by one or more lipid layers consisting of functional amphiphilic compound of formula (I) as defined above, with or without co-lipid .
- Said nanoparticles, solid, consisting of a core rich in therapeutic agent, preferably an antitumor agent, in particular a platinum complex, surrounded by one or more lipid layers consisting of functional amphiphilic compound of formula (I) as defined above , with or without co-lipid represent a further object of the invention.
- all the lipid layers consist of the same lipids (compound of formula (I) with or without co-lipid).
- the lipid mixture in addition to the compound of formula (I), at least one colipid.
- colipid is meant a compound used in combination with the compound of formula (I), which participates in the development of the structure of the lipid layer (s) of the nanoparticle.
- a zwitterionic colipid will preferably be used.
- Said colipid may be, for example, chosen from dioleylphosphatidylcholine (DOPC) or dioleylphosphatidyluridine phosphatidylcholine (DOUPC), in combination with the compound of formula (I) to form the lipid layer (s) of the nanoparticle.
- DOPC dioleylphosphatidylcholine
- DOUPC dioleylphosphatidyluridine phosphatidylcholine
- These compounds can act as colipids when used in admixture with a compound of formula (I).
- they can be included in formula (I), such as, for example, dioleylphosphatidyluridinephosphatidylcholine (SOHC).
- SOHC dioleylphosphatidyluridinephosphatidylcholine
- they will play either the role of compound of formula (I) or, in combination with another compound of formula (I), the role of colipid.
- said lipid mixture contains only at least one compound of formula (I) and does not contain a colipid.
- the therapeutic agent will preferably be used at a concentration of the order of 0.1 ng / ml to 10 mg / ml in the aqueous phase, so that the intracellular delivery of the active principle is important.
- Preferred compounds of formula (I) are those wherein X is oxygen.
- the compounds of formula (I) in which B represents thymine or adenine are also preferred compounds.
- L 1 represents a phosphate group
- L 2 represents hydrogen
- R 1 represents a C 2 -C 30 alkyl group or a diacyl group in which each acyl chain is C 2 -C 3 O
- R 3 is a hydroxyl group
- Li and L 2 represent an oxygen atom
- R 1 and R 2 represent hydrogen and R 3 represents a triazole group, tetrazole, pyrazole or imidazole substituted with a C 2 -C 30 alkyl group, or
- Li represents a triazole, tetrazole, pyrazole or imidazole group
- L 2 represents hydrogen
- R 1 represents a C 2 -C 30 alkyl group and R 3 represents a hydroxy group
- - Li represents a hydroxyl group
- the above compounds are novel compounds which represent an object of the invention, as well as the nanoparticles comprising these compounds and a therapeutic agent, in particular an anti-tumor agent, in particular platinum complexes (such as, for example cis-platinum, carboplatin, oxaliplatin, nedaplatin, lobaplatin,), or ruthenium capable of binding to platinum complexes, or inorganic complexes without platinum based on ruthenium, titanium, gallium , cobalt, iron or gold mentioned above.
- platinum complexes such as, for example cis-platinum, carboplatin, oxaliplatin, nedaplatin, lobaplatin,
- ruthenium capable of binding to platinum complexes, or inorganic complexes without platinum based on ruthenium, titanium, gallium , cobalt, iron or gold mentioned above.
- Cisplatin is a preferred anti-tumor agent for the purpose of the invention.
- the compounds of formula (I) may comprise purine or pyrimidine base derivatives having antineoplastic activity, such as, for example, aracytosine (AraC), 5-fluorouracil (5-FU), lododeoxyuridine (IdU) 2'-deoxy-2'-methylidenecytidine (DMDC) or 5-chloro-6-azido-5,6-dihydro-2'-deoxyuridine.
- antineoplastic activity such as, for example, aracytosine (AraC), 5-fluorouracil (5-FU), lododeoxyuridine (IdU) 2'-deoxy-2'-methylidenecytidine (DMDC) or 5-chloro-6-azido-5,6-dihydro-2'-deoxyuridine.
- the invention also relates to the use of nanoparticles that can be obtained by the method described above, for the transport or vectorization of therapeutic agents, in particular antitumor agents.
- the invention relates to the use of the nanoparticles that can be obtained by the method described above, for the intracellular delivery of therapeutic agents, in particular antitumor agents.
- the invention also relates to the use of the nanoparticles that can be obtained by the above process, for the preparation of anti-tumor drugs.
- the invention also relates to the nanoparticles that can be obtained by the above process, for the treatment of diseases tumors, particularly cancers, such as, for example, ovarian, testicular, colon, cervical, lung, or adenosarcoma etc.
- diseases tumors particularly cancers, such as, for example, ovarian, testicular, colon, cervical, lung, or adenosarcoma etc.
- Thymidine 3 (1,2-dimyristoyl-sn-glycero-3-phosphate) (diC14dT)
- the mixture is then oxidized by adding 43 ml of a solution of 0.02M diiod in THF / Pyr / H 2 O. After 12 h at room temperature, the solvent is evaporated in vacuo. The residue is dissolved in 8 mL of dichloromethane. Then 0.2 mL of 1, 5- diazabicyclo [5.4.0] undec-7-ene (DBU) (1.3 eq, 0.87 mmol) are added to the reaction medium for 5 h. The reaction medium is washed with a 0.1N solution of HCl and then with a saturated solution of Na 2 S 2 O 7 . The organic phase is concentrated under vacuum. The compound is obtained after purification by flash chromatography (381 mg) using an elution gradient (MeOH / DCM 9: 1 to 1: 1).
- Thymidine 3 (1, 2-dipalmitoyl-sn-glycero-3-phosphate) (di C16dT)
- the reaction medium is stirred magnetically for 24 hours at room temperature and under nitrogen.
- the mixture is then oxidized by adding 43 ml of a solution of 0.02M diiodode in THF / Pyr / H 2 O. After 12 h at room temperature, the solvent is evaporated under vacuum and dried at the pump under P 2 O 5 overnight. The residue is dissolved in 8 mL of dichloromethane. Then, 0.2 ml of 1,5-diazabicyclo [5.4.0] undec-7-ene (DBU) (1.3 eq, 0.87 mmol) are added to the reaction medium for 5 h. The reaction medium is washed with a solution of 0.1N HCl and then with a saturated solution of Na 2 S 2 O 3 .
- DBU 1,5-diazabicyclo [5.4.0] undec-7-ene
- Solution A 20 mg of diC16dT are solubilized in 2 mL of chloroform (10 mg / mL). This sample is stored at -20 ° C.
- Solution B DOPC: 20 mg / mL solution in chloroform, stored at -20 ° C. 2) Preparation of lipid formulations
- 1.2 ml of the cis-platinum solution pre-incubated at 37 ° C are used to rehydrate the previously prepared lipid film.
- the mixture is incubated at 37 ° C for 30 min.
- a series of 10 cycles of heating (water bath at 45 ° C) and freezing (dry ice / methanol -78 ° C) is carried out.
- the concentration (ICP / Optical) of the resuspended pellet in 1 mL of milliQ water is 2.844 mM equivalent in cisplatin (852.2 mg / L). This concentration corresponds to 47.4% of the cisplatin initially used.
- Solution A 20 mg of diC16dT are solubilized in 2 ml of dichloromethane (10 mg / ml). The solution is stored at -2O 0 C.
- Solution B DOPC: 20 mg / mL solution in dichloromethane, stored at -20 ° C.
- the dichloromethane is evaporated with compressed nitrogen so as to obtain a homogeneous lipid film.
- the suspension is stirred and placed in a glass hemolysis tube and sonicated for 5 minutes. After sonication, the suspension is centrifuged at
- the nanoparticles are found in the pellet.
- the latter is resuspended in 1 ml of milliQ water and a second centrifugation is carried out.
- the pellet is suspended in 1 mL and dosed in
- ICP Inductively Coupled Plasma
- the nanoparticles prepared according to the protocol of Example 16 are assayed in optical ICP (the measured value corresponds to the total concentration).
- the suspension of the nanoparticles is aliquoted in 5 eppendorf® tubes (150 ⁇ L). These are incubated at 37 ° C with shaking
- the tube is centrifuged at 14,000 rpm / 10min / 20 ° C and 50 ⁇ l of supernatant (recovered gently so as not to resuspend the pellet) are assayed.
- DOPS 1,2-dioleoyl-sn-glyero-3-phosphocholine
- Cx concentration found at a given time (x).
- CO concentration found in the supernatant before incubation.
- Ct total concentration found without incubation and without centrifugation.
- the nanoparticles of Example 16 are represented by the symbol -O- and the nanoparticles based on
- the nanoparticles prepared according to the protocol of Example 16 were analyzed with a MALVERN zeta-stabilizer.
- the nanoparticles are suspended in 2 ml of milliQ water (volume necessary for size measurement). The concentration is about 0.5 mM (the suspension must be turbid to diffuse the light). Single-use vats (1 cm / 1 cm) are used for the measurement.
- the results show that more than 95% of the nanoparticles have a size between 100 and 250 nm with a polydispersity of 0.228.
- Example 19 Intracellular cisplatin dosage
- IGROV1 cells (ovarian adenocarcinoma line) at 80% confluency (10 cm diameter dish) are treated with 100 ⁇ M of free cisplatin or encapsulated in the nanoparticles of Example 16 for 2, 4 or 6 hours. .
- two washes with PBS are carried out.
- the cells are treated with trypsin and resuspended in PBS.
- Two PBS washes of cell suspensions were performed (centrifugation 1000 rpm / 1 min). The cells are suspended in 1 mL of PBS and counted.
- 10 6 cells are lysed with 500 ⁇ l of the cell lysis solution (lysis buffer from SIGMA). The volume is supplemented with milliQ water at 1% HNO 3 acid to reach 5 mL.
- FIG. 2 shows the concentration of cis-platinum released after cell lysis as a function of time, corresponding to the concentration of internalized cis-platinum in the treated cells.
- the hatched column (left) corresponds to free cis-platinum and the dotted column (right) to nanoparticles containing cis-platinum.
- the results show that the internalisation of cis-platinum is significantly more efficient in the presence of nanoparticles. For example, under identical conditions (10 6 cells, 100 ⁇ M, 2 h) 0.5 nanomole of cis-platinum is internalized in the case of free cis-platinum whereas internalisation is 4.5 times greater in the case of free cisplatin. case of nanoparticles (2.3 nanomoles).
- the test used uses the human cancer cell line HCT8 (colorectal adenocarcinoma), known for its intrinsic resistance to platinum derivatives.
- HCT8 colonal adenocarcinoma
- the protocol is as follows:
- the cells are implanted in 96-well plates at the density of 50,000 cells per well.
- the cells are treated with the test formulation, either for a short exposure time (30 min) in physiological saline or for a long exposure time (72 h) in culture medium.
- the range of concentrations achieved includes the points 0 - 0,4 - 0,8 - 1, 5 - 3 - 6,25 -
- Negative controls untreated cells
- positive controls cisplatin
- the survival of the cells was determined, and the percentage of overall death (or cytotoxicity) obtained at the different concentrations of the test formulation was compared with that obtained with the negative controls (untreated cells).
- the cytotoxicity results were presented in the form of dose-effect curves characterized by their inhibitory concentration (IC 50 ), that is to say the concentration at which 50% of dead cells are observed.
- diC16dT Thimidine 3 '- (1, 2-dipalmitoyl-s /? - glycero-3-phosphate) of Example 2 and a colipid (DOPC), or
- the nanoparticles were prepared according to the method described in Example 15, but with a single heating / cooling cycle for the compound of Example 12.
- IGROV1 cells 1000 to 5000 IGROV1 cells are incubated in 100 ⁇ l of medium with serum per well (96-well plate). After 24 hours the medium is removed and the cells are treated for 1 to 3 days with the formulations according to the invention and / or the free cis-Pt (at the desired concentrations). The cells are incubated at 37 ° C. in 200 ⁇ l of medium with serum. The cell viability is revealed in colorimetry by an MTS test at the end of the treatment.
- the survival of the cells was determined, and the percentage of overall death (or cytotoxicity) obtained at the different concentrations of tested formulations was compared with that obtained with the negative controls (untreated cells).
- the cytotoxicity results were presented in the form of dose-effect curves characterized by their inhibitory concentration (IC 50), that is, the concentration at which 50% of dead cells are observed.
- IC 50 inhibitory concentration
- 2500 cells (IGROV1, SKOV3, ovarian adenocarcinoma lines) per well are incubated in 100 ⁇ l of the medium with serum. After 24 hours, the medium is aspirated and the cells are treated with free cis-platinum or encapsulated in the nanoparticles of Example 16 in 100 ⁇ L of medium without serum at different concentrations (500, 100, 10, 1, 0.1, 0.01 0.001 ⁇ M). After 24 hours of treatment, the medium is removed and the cells are washed twice with 100 ⁇ l of PBS and then incubated with 100 ⁇ l of medium with serum.
- cell viability is revealed by adding 20 ⁇ L of MTS.
- the absorbance at 490 nm is measured after 2 to 4 incubation hours at 37 ° C. Absorbance is proportional to cell viability.
- Figure 3A relates to the IGROV1 cell line and Figure 3B relates to the SKOV3 cell line.
- Example 16 containing cis-platinum are more effective than free cisplatin in both cell lines, IGROV1 (sensitive to cisplatin) and SKOV3 (cisplatin-resistant).
- IGROV1 sensitive to cisplatin
- SKOV3 cisplatin-resistant
- nanoparticles containing cis-platinum 0.27 ⁇ M of nanoparticles containing cis-platinum whereas 2.41 ⁇ M of free cisplatin must be used to obtain this result.
- 50% of cell death is obtained with 0.54 ⁇ M of nanoparticles containing cis-platinum against 4.3 ⁇ M of free cis-platinum.
- the nanoparticles containing cis-platinum are respectively 9 and 8 times more effective than free cisplatin on IGROV1 and SKOV3 lines.
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CN2008801260085A CN101932310B (zh) | 2007-11-30 | 2008-11-28 | 制备基于官能两亲分子或者大分子的纳米颗粒的方法和其用途 |
US12/745,670 US20110059180A1 (en) | 2007-11-30 | 2008-11-28 | Method for Preparing Nanoparticles Based on Functional Amphiphilic Molecules or Macromolecules, and the Use Thereof |
JP2010535425A JP5719594B2 (ja) | 2007-11-30 | 2008-11-28 | 機能性両親媒性の分子又は巨大分子を基とするナノ粒子の調製方法及びその使用 |
EP08872219A EP2231132A2 (fr) | 2007-11-30 | 2008-11-28 | Procédé de préparation de nanoparticules à base de molécules ou macromolécules amphiphiles fonctionnelles et leur utilisation |
CA2706812A CA2706812A1 (fr) | 2007-11-30 | 2008-11-28 | Procede de preparation de nanoparticules a base de molecules ou macromolecules amphiphiles fonctionnelles et leur utilisation |
US14/208,978 US9533049B2 (en) | 2007-11-30 | 2014-03-13 | Method for preparing nanoparticles based on functional amphiphilic molecules or macromolecules, and the use thereof |
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EP2435031B1 (fr) * | 2009-05-29 | 2015-09-16 | Université de Bordeaux | Formulations à compartiments multiples à base de molécules ou macromolécules amphiphiles fonctionnelles |
EP3085360A1 (fr) | 2015-04-20 | 2016-10-26 | Universite De Bordeaux | Compositions de nanovecteurs à base de lipide chargées avec des nanoparticules métalliques et agent thérapeutique |
EP3502684A1 (fr) | 2017-12-22 | 2019-06-26 | Universite De Bordeaux | Procédé de détection d'ions métalliques dans des solutions aqueuses au moyen de composés nucléolipides |
EP3505178A1 (fr) | 2017-12-29 | 2019-07-03 | Universite De Bordeaux | Formulations de gel de bio-encres comprenant un composé à base de nucléolipides |
WO2019162633A1 (fr) | 2018-02-22 | 2019-08-29 | Universite de Bordeaux | Procédé de décontamination d'un milieu liquide aqueux contenant des micropolluants ou d'une surface contaminée par des micropolluants |
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US11981703B2 (en) | 2016-08-17 | 2024-05-14 | Sirius Therapeutics, Inc. | Polynucleotide constructs |
US11597744B2 (en) | 2017-06-30 | 2023-03-07 | Sirius Therapeutics, Inc. | Chiral phosphoramidite auxiliaries and methods of their use |
US20220304929A1 (en) * | 2019-08-12 | 2022-09-29 | Integrated Nanotherapeutics Inc. | Lipids for delivery of charged material, formulations thereof and method for making same |
TW202428288A (zh) * | 2022-12-13 | 2024-07-16 | 大陸商上海拓界生物醫藥科技有限公司 | 包含親脂性單體的寡核苷酸以及其在非肝遞送中的應用 |
WO2024140624A1 (fr) * | 2022-12-27 | 2024-07-04 | Suzhou Abogen Biosciences Co., Ltd. | Composés lipidiques et compositions de nanoparticules lipidiques |
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- 2008-11-28 WO PCT/FR2008/001661 patent/WO2009098404A2/fr active Application Filing
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Cited By (8)
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EP2435031B1 (fr) * | 2009-05-29 | 2015-09-16 | Université de Bordeaux | Formulations à compartiments multiples à base de molécules ou macromolécules amphiphiles fonctionnelles |
EP3085360A1 (fr) | 2015-04-20 | 2016-10-26 | Universite De Bordeaux | Compositions de nanovecteurs à base de lipide chargées avec des nanoparticules métalliques et agent thérapeutique |
WO2016170010A1 (fr) | 2015-04-20 | 2016-10-27 | Universite de Bordeaux | Compositions de nanovecteurs à base de lipides chargées de nanoparticules métalliques et d'un agent thérapeutique |
EP3502684A1 (fr) | 2017-12-22 | 2019-06-26 | Universite De Bordeaux | Procédé de détection d'ions métalliques dans des solutions aqueuses au moyen de composés nucléolipides |
WO2019122420A1 (fr) | 2017-12-22 | 2019-06-27 | Universite de Bordeaux | Procédé de détection d'ions métalliques dans des solutions aqueuses à l'aide de composés nucléolipidiques |
EP3505178A1 (fr) | 2017-12-29 | 2019-07-03 | Universite De Bordeaux | Formulations de gel de bio-encres comprenant un composé à base de nucléolipides |
WO2019130236A1 (fr) | 2017-12-29 | 2019-07-04 | Université De Bordeaux | Formulations de gel d'encre biologique comprenant un composé à base de nucléolipides |
WO2019162633A1 (fr) | 2018-02-22 | 2019-08-29 | Universite de Bordeaux | Procédé de décontamination d'un milieu liquide aqueux contenant des micropolluants ou d'une surface contaminée par des micropolluants |
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CN101932310A (zh) | 2010-12-29 |
JP6280167B2 (ja) | 2018-02-14 |
WO2009098404A3 (fr) | 2009-11-12 |
US20110059180A1 (en) | 2011-03-10 |
EP2231132A2 (fr) | 2010-09-29 |
US9533049B2 (en) | 2017-01-03 |
JP2015044815A (ja) | 2015-03-12 |
WO2009098404A8 (fr) | 2010-01-28 |
FR2924430B1 (fr) | 2010-03-19 |
FR2924430A1 (fr) | 2009-06-05 |
JP2011504920A (ja) | 2011-02-17 |
JP5719594B2 (ja) | 2015-05-20 |
US20140308343A1 (en) | 2014-10-16 |
CA2706812A1 (fr) | 2009-08-13 |
JP2017014243A (ja) | 2017-01-19 |
CN101932310B (zh) | 2013-11-13 |
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