WO1996018635A1 - Conjugues fullerene-oligonucleotide, ou fullerene-nucleotide, leurs complexes avec des nanoparticules et leurs utilisations theraputiques - Google Patents

Conjugues fullerene-oligonucleotide, ou fullerene-nucleotide, leurs complexes avec des nanoparticules et leurs utilisations theraputiques Download PDF

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Publication number
WO1996018635A1
WO1996018635A1 PCT/FR1995/001649 FR9501649W WO9618635A1 WO 1996018635 A1 WO1996018635 A1 WO 1996018635A1 FR 9501649 W FR9501649 W FR 9501649W WO 9618635 A1 WO9618635 A1 WO 9618635A1
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WO
WIPO (PCT)
Prior art keywords
conjugate
fullerene
oligonucleotide
nucleotide
complex according
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PCT/FR1995/001649
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English (en)
French (fr)
Inventor
Claude Helene
Alexandre Boutorine
Eichi Nakamura
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Institut National De La Sante Et De La Recherche Medicale (Inserm)
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Publication of WO1996018635A1 publication Critical patent/WO1996018635A1/fr

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Classifications

    • 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
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/52—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6907—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a microemulsion, nanoemulsion or micelle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A61K47/6937—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol the polymer being PLGA, PLA or polyglycolic acid
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Definitions

  • the present invention relates to fullerene-oligonucleotide conjugates and fullerene-nucleotide conjugates as well as complexes comprising such conjugates associated with nanoparticles.
  • the oligonucleotides can be used against both single-stranded nucleic acids and messenger RNA or double-stranded DNA (Hélène and Toulmé, Biochim, Biophys. Acta, 1990, 1049, 99-1258); Thuong and Hélène, Angew, Chem. 1993, 105, 697-726; Angew. Chem. Int. Ed. Engl. 1993, 32, 666-690) to block the translation of the target messenger RNA (antisense strategy) or the transcription of the target gene by the formation of a triple helix (anti-gene strategy).
  • the present invention therefore relates to a fullerene-oligonucleotide or fullerene-nucleotide conjugate, in which said fullerene is advantageously a fullerene at Cg Q to Cg4 •
  • fullerenes can be in particular those described by Diederich and Rubin (1992 previously cited) and in particular a fullerene in Cg 0 , or a higher fullerene in C 7Q or in Cg 4 .
  • the oligonucleotide covalently linked to the fullerene in order to form the above-mentioned conjugate is advantageously a simple oligonucleotide strand and may comprise from 2 to 100 nucleotides.
  • Such oligonucleotides have a sequence complementary to that of the site in the DNA or RNA molecule into which the cleavage or cleavage is to be introduced, also called the target molecule.
  • target DNA or RNA can be, for example, sequences of viruses or sequences of genes involved in cancer and / or viral pathologies.
  • the above-mentioned conjugate can also be associated with a nanoparticle in the form of a complex, and in particular with a hydrophobic nanoparticle.
  • a nanoparticle is formed from a polylactic acid or from a polylactic acid-glycolic copolymer, optionally associated with polyethylene glycol, or from a polyalkylcyanoacrylate such as polyisohexylcyanoacrylate.
  • the conjugates not associated with a nanoparticle form structures observable by electron microscopy which can be filaments of the order of several tens of nanometers in length, and having a diameter of less than 10 nm, or nacelles of the order of 40 at 50 nm in diameter.
  • the filaments disappear and the conjugates associate with the nanoparticles.
  • a particular advantage of these complexes lies in the absence of hydrophobic cations such as cetyltrimethylammonium bromide (CTAB), considered to be cytotoxic.
  • CTAB cetyltrimethylammonium bromide
  • Another advantage of the association of these conjugates with hydrophobic nanoparticles lies in an improvement in the absorption of these conjugates on cell membranes, and therefore in an improvement in the penetration of these conjugates into living cells.
  • the conjugates according to the present invention can bind to various molecules, such as messenger and viral RNA (antisense and oligonucleotide clamp strategy), to DNA (triple helix strategy) or to proteins ( aptamer strategy).
  • messenger and viral RNA antisense and oligonucleotide clamp strategy
  • DNA triple helix strategy
  • proteins aptamer strategy
  • the fullerene derivative at Cg 0 which is advantageously used for the formation of conjugates according to the invention, has an absence of toxicity in mice, the lethal dose being greater than 500 mg / kg.
  • conjugates which are the subject of the present invention, and their complexes formed with nanoparticles can be used for therapeutic purposes, in order to totally or partially inhibit the expression of a given gene, for example by inhibiting the transcription of the gene or the translation of messenger RNA, either in the absence or in the presence of visible or ultraviolet light irradiation.
  • Such genes may in particular be genes responsible for or involved in pathologies of the cancer type, such as oncogenes, or genes of viruses such as the HIV virus.
  • the present invention due to the specificity of binding of the oligonucleotide has the advantage of being able to intervene very specifically in specific regions of genes whose sequence is at least partially known.
  • the present invention therefore relates to pharmaceutical compositions containing an effective amount of a conjugate or of a complex as described above, in combination with pharmacologically compatible excipients.
  • Such a composition will advantageously comprise from 1 ⁇ g to 10 mg of the conjugate which is the subject of the present invention.
  • the present invention further relates to a medicament containing such a conjugate or such a complex.
  • conjugates according to the present invention consists in the analysis of DNA fragments. To do this, the DNA preparations to be analyzed are placed in the presence of the conjugates, or their complexes, and are treated with low energy light, then the reaction products are demonstrated by methods known to man. of career.
  • the conjugates, or their complexes are administered by intravenous injection, by intradermal route or by local application.
  • the individual to whom these molecules have been administered can also be treated with low energy light.
  • the present invention also relates to a method for manufacturing a conjugate as described above, comprising activation of the fullerene and of the oligonucleotide, or of the nucleotide, allowing their covalent coupling.
  • a method comprises the following steps:
  • the final product is a conjugate having, in the case of a fullerene at Cg 0, the formula according to scheme III below.
  • FIGS. 1a to 1d respectively illustrate the conjugate used (FIG. 1a) and the target molecules hybridized to said conjugate, which are single-stranded DNA (FIG. 1d), a double stranded DNA (FIG. le) or a double stranded DNA having a loop (FIG. 1d).
  • the arrows represent the cut-off sites.
  • FIG. 2 is an electrophoresis gel of the structure having a loop, represented in FIG. 1d, placed in the presence of the conjugate represented on Figure la, without piperidine (wells 1 to 5) or in the presence of piperidine (wells 7 to 11), not irradiated
  • Wells 1 and 7 or irradiated with low energy light for 15 minutes (wells 2 and 8), 30 minutes (wells 3 and 9), 45 minutes (wells 4 and 10), and 60 minutes (wells 5 and 11 ).
  • the gel was analyzed using a phosphorimager.
  • Well 6 corresponds to the sequence of residues G obtained after treatment with dimethylsulfate and piperidine. The sequence in the cut-off region and the location of the guanine residues are indicated (the numbering starts from the 5 'end).
  • FIG. 3 is a graph in which the concentration in ⁇ M of oligo- fullerenes has been plotted on the abscissa and on the ordinate the percentage of adsorption, respectively without NaCl and with NaCl, in the case of the coupling of oligonucleotides - Fullerenes with polyalkylcyanoacrylate nanoparticles, in accordance with Example 3.
  • the yield of this reaction is of the order of 30 to 40%.
  • the conjugate has a brown-red color, is soluble in water and precipitates in ethanol or LiCl0 4 in acetone.
  • the three target molecules are: - an oligonucleotide of 20 nucleotides ( Figure lb); - a double stranded oligonucleotide of 26 base pairs ( Figure le); a oligonucleotide of 41 nucleotides partially double stranded and having a loop structure of five bases (FIG. 1d).
  • the complexes formed after the conjugate and the target molecules were irradiated using a Xenon lamp (1000 W) through a light absorbing filter at wavelengths less than 310 nm , in a buffer containing 10 mM cacodylate, pH 6, 50 mM NaCl, 50-100 nM of target molecule, with increasing concentrations of the conjugate (from 1 to 60 ⁇ M).
  • the three target molecules were labeled at the 5 ′ end with 32 P using gamma 32 P-ATP and polynucleotide kinase (marketed by Amersham).
  • FIG. 2 shows that the photo-cut induced by the conjugate takes place at well defined sites in the target molecules, contrary to the result obtained with unconjugated C 0 carboxylic acids, described above. It is observed that cuts take place mainly on guanines but also on thymines, although with lower efficiency.
  • the piperidine treatment slightly increases the intensity of the gel cut bands.
  • oligonucleotides to very hydrophobic groups, such as fullerenes C60 which makes it possible to increase their intracellular penetration.
  • Observations of fullerene oligonucleotides by transmission electron microscopy have shown that they are organized in the form of micelles 30 to 50 nm in diameter.
  • the adsorption of fullerene oligonucleotides to polyalkylcyanoacrylate nanoparticles was carried out. The objective was to combine these oligonucleotides chemically modified to nanoparticles, via hydrophobic interactions with the polymer matrix, without involving hydrophobic cations.

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PCT/FR1995/001649 1994-12-12 1995-12-12 Conjugues fullerene-oligonucleotide, ou fullerene-nucleotide, leurs complexes avec des nanoparticules et leurs utilisations theraputiques WO1996018635A1 (fr)

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Application Number Priority Date Filing Date Title
FR9414940A FR2727970A1 (fr) 1994-12-12 1994-12-12 Conjugues fullerene-oligonucleotide, ou fullerene-nucleotide leurs complexes avec des nanoparticules et leurs utilisations therapeutiques
FR94/14940 1994-12-12

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162725A1 (en) * 2020-02-16 2021-08-19 Butzloff Peter Robert Pivoting electrodynamic composition and medicament

Family Cites Families (1)

* Cited by examiner, † Cited by third party
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ATE239484T1 (de) * 1991-10-24 2003-05-15 Isis Pharmaceuticals Inc Derivatisierte oligonukleotide mit verbessertem aufnahmevermögen

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ANTIMICROB. AGENTS. CHEMOTHER., vol. 37, no. 8, pages 1707 - 1710 *
CHEM. PHYS. LETT., vol. 202, no. 5, pages 384 - 388 *
CHEMICAL ABSTRACTS, vol. 118, no. 10, 8 March 1993, Columbus, Ohio, US; abstract no. 88169a, P.M.AJAYAN ET AL.: "Distribution of Pentagons and Shapes in Carbon Nano-tubes and Nano-particöes" page 499; column 2; *
CHEMICAL ABSTRACTS, vol. 120, no. 5, 31 January 1994, Columbus, Ohio, US; abstract no. 45238w, R.F.SCHINAZI ET AL.: "Synthesis and Virucidal Activity of a Water-Soluble Configurationally Stable Derivatized C60 Fullerene." page 30; column 2; *
CHEMICAL ABSTRACTS, vol. 122, no. 1, 2 January 1995, Columbus, Ohio, US; abstract no. 358k, R.F.SCHINAZI ET AL.: "Anti-Human Immunodeficiency Virus, Toxicity in Cell Culture, and Tolerance in Mammals of a Water-Soluble Fullerene." page 36; column 1; *
PROC. - ELECTROCHEM. SOC., vol. 94, no. 24, pages 689 - 698 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162725A1 (en) * 2020-02-16 2021-08-19 Butzloff Peter Robert Pivoting electrodynamic composition and medicament

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FR2727970B1 (enrdf_load_stackoverflow) 1997-02-28
FR2727970A1 (fr) 1996-06-14

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