WO1995021931A1 - Composition contenant des acides nucleiques, preparation et utilisations - Google Patents
Composition contenant des acides nucleiques, preparation et utilisations Download PDFInfo
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- WO1995021931A1 WO1995021931A1 PCT/FR1995/000098 FR9500098W WO9521931A1 WO 1995021931 A1 WO1995021931 A1 WO 1995021931A1 FR 9500098 W FR9500098 W FR 9500098W WO 9521931 A1 WO9521931 A1 WO 9521931A1
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1135—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against oncogenes or tumor suppressor genes
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- 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
- A61K47/62—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 a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
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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
- A61K47/50—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
- A61K47/6917—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 lipoprotein vesicle, e.g. HDL or LDL proteins
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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
- A61K47/50—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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
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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
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
- A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
Definitions
- the present invention relates to compositions based on nucleic acids, their preparation and their use. More particularly, it relates to compositions comprising nucleic acids and oligopeptides and their use in gene therapy, in particular for the transfer of nucleic acids.
- Gene therapy consists of correcting a deficiency or an abnormality (mutation, aberrant expression, etc.) by introducing genetic information into the affected cell or organ.
- This genetic information can be introduced either in vitro into a cell extracted from the organ, the modified cell then being reintroduced into the organism, or directly in vivo into the appropriate tissue.
- Various techniques have been described for the transfer of this genetic information, among which various transfection techniques involving DNA and DEAE-dextran complexes (Pagano et al., J. Virol.
- viruses as vectors for gene transfer has emerged as a promising alternative to these physical transfection techniques.
- retroviruses RSV, HMS, MMS, etc.
- the HSV virus adeno-associated viruses
- adenoviruses adenoviruses
- nucleic acids prevent their passage through cell membranes. If it has been shown that naked nucleic acids are capable of crossing the plasma membrane ex vivo (see in particular application No. WO90 / 11092), the transfection efficiency remains quite low. In addition, naked nucleic acids have a short plasma half-life, due to their degradation by enzymes and their elimination through the urinary tract. Furthermore, if the recombinant viruses make it possible to improve the efficiency of transfer of nucleic acids, their use presents certain risks such as pathogenicity, transmission, replication, recombination, transformation, etc.
- the present invention provides an advantageous solution to these various problems.
- the Applicant has indeed shown that it is possible to form ion pairs between particular cationic oligopeptides and the phosphate groups of the nucleic acids, and that the complexes thus formed are stable, and are capable of penetrating cells or be encapsulated in transfer vectors such as liposomes, nanoparticles or low density lipoproteins (LDL) with high yields.
- transfer vectors such as liposomes, nanoparticles or low density lipoproteins (LDL) with high yields.
- a first object of the invention therefore resides in a composition comprising a nucleic acid and a cationic oligopeptide capable of forming secondary structures.
- the term secondary structure designates peptides capable of adopting a particular spatial conformation under physiological conditions, in contrast to peptides which do not exhibit any particular organization of their primary structure.
- the secondary structure can appear either in certain solvents, or in aqueous solution, or after complexation with the nucleic acid.
- oligopeptides used in the context of the invention are capable of forming ⁇ helices or ⁇ sheets.
- complexation of a nucleic acid with a polylysine has already been described in the prior art.
- the complexation rate and the stability of the complex formed with polylysine are relatively low, and these complexes cannot be encapsulated in transfer vectors in a satisfactory manner (see examples).
- the complexes according to the invention which involve cationic oligopeptides capable of forming secondary structures ( ⁇ helices, ⁇ sheets) exhibit high stability, can be obtained with yields close to 100%, and are capable of being encapsulated with high yields in transfer vectors.
- the compositions of the invention can be used on cells extracted from the body (ex vivo) for their re-administration, or directly in vivo.
- the oligopeptides used in the context of the present invention correspond to the formula (A 0 AyAyAo) n or (AoAyA ⁇ AyJn in which A Q is a hydrophobic amino acid, Ay is a hydrophilic amino acid, and n is a number integer greater than or equal to 4.
- a Q is a hydrophobic amino acid
- Ay is a hydrophilic amino acid
- n is a number integer greater than or equal to 4.
- the hydrophobic amino acid is chosen from leucine, valine, isoleucine and phenylalanine; and the hydrophilic amino acid is chosen from lysine, arginine and histidine.
- the capacity of the oligopeptides to form secondary structures can be verified by circular dichroism or by NMR, as indicated in the examples.
- the oligopeptide is chosen from oligopeptides of formula (LKKL) n, (LKLK) n, (LRRL) n, in which n is defined as above.
- n can vary between 4 and 100, preferably between 10 and 50.
- the value of n is adapted by a person skilled in the art depending on the length and the nature nucleic acid, oligopeptide composition, intended use, etc.
- the respective proportions of the oligopeptide and of the nucleic acid are preferably determined so that the ratio of positive charges of the oligopeptide / negative charges of nucleic acid is equal or greater than 1 (this ratio is designated R in the examples).
- R this ratio
- the longer the nucleic acid the higher the number of positive charges provided by the oligopeptide to obtain a maximum effect. This can result either by the use of oligopeptides in which the value of n is higher, or by the use of higher quantities of oligopeptides, or even by both.
- the oligopeptides used in the context of the present invention can be prepared by any technique known to a person skilled in the art. Preferably, they are synthesized chemically, using a peptide synthesizer, using any type of chemistry known to those skilled in the art (F-moc, T-boc, etc.). When the values of n are high, it is also possible to synthesize the oligopeptides into several fragments which are then assembled. Furthermore, according to the synthesis technique used (for example in the homogeneous phase), the oligopeptide obtained may not be a defined compound, but a mixture of oligopeptides having different lengths centered around an average. In this case, the value of n of the formula of the invention represents the average of the values of the n of the various constituents of the mixture. Appropriate synthetic methods are given in general molecular biology techniques and in the examples.
- nucleic acid includes both deoxyribonucleic acids and ribonucleic acids. They may be sequences of natural or artificial origin, and in particular genomic DNA, cDNA, mRNA, tRNA, rRNA, hybrid sequences or synthetic v . Semi-synthetic sequences. These nucleic acids ⁇ ⁇ can ⁇ be of human, animal, vegetable, bacterial, viral, etc. origin. They can be obtained by any technique known to those skilled in the art, and in particular by screening of banks, by chemical synthesis, or also by mixed methods including chemical or enzymatic modification of sequences obtained by screening of banks. They can also be incorporated into vectors, such as plasmid vectors.
- deoxyribonucleic acids With regard more particularly to deoxyribonucleic acids, they can be single or double stranded. These deoxyribonucleic acids can carry therapeutic genes, transcriptional regulatory sequences, antisense sequences, regions of binding to other cellular components, etc.
- therapeutic gene is understood in particular any gene coding for one or more proteins (or peptide or polypeptide) having pharmacological activity. These can be enzymes, hormones, growth factors, lymphokines, apolipoproteins, etc.
- antisense sequence is meant any sequence capable, directly or indirectly (after transcription into RNA) of reducing the expression levels of a desired protein, or even of suppressing them (EP 140 308).
- Antisense also includes sequences encoding ribozymes, which are capable of selectively destroying target RNAs (EP 321,201).
- RNA ribonucleic acids
- they may be antisense RNAs capable of at least partially blocking the translation of target mRNAs (cellular, viral, bacterial, etc.); or also ribozymes or nucleic acids capable of binding to another nucleic acid by the formation of a triple helix.
- compositions according to the invention can be used in vitro, ex vivo or in vivo.
- in vitro they can make it possible to transfer to cell lines desired nucleic acid sequences, for example for the purpose of expressing a recombinant protein or an antisense activity, or for the purpose of inhibiting a protein, by fixation of said protein. protein on nucleic acid.
- ex vivo they can be used for the therapeutic transfer of a nucleic acid into a cell originating from an organism, with a view to imparting to said cell new or enhanced properties, before its re-administration to an organism.
- they can be used for direct administration of nucleic acid.
- Another object of the invention therefore lies in the use of a cationic oligopeptide capable of forming secondary structures for the transfer of nucleic acids into cells. As indicated above, this transfer can be carried out in vitro, ex vivo or in vivo.
- compositions according to the invention can make it possible to transfer nucleic acids into various types of cells.
- these are animal cells, preferably human. They may in particular be hematopoietic, endothelial, myoblastic cells, etc. Furthermore, these can be both healthy cells and cells affected by dysfunctions (tumor, viral infection, etc.).
- the invention also relates to a method for transferring a nucleic acid into a cell, characterized in that said cell is cultured in the presence of the nucleic acid and a cationic oligopeptide capable of forming secondary structures.
- nucleic acid- oligopepti.de complexes of the present invention also allow the encapsulation of nucleic acids in transfer vectors with considerably improved yields.
- nucleic acids can in fact be combined with appropriate carriers or drug vectors.
- the encapsulation of nucleic acids in such transfer vectors makes it possible to protect them from serum nucleases, to facilitate their penetration into the cells where their pharmacological target is found, and to slow down their elimination.
- the major difficulty limiting the use of these vectors lies in the low yields of nucleic acid encapsulation.
- nucleic acid-oligopeptide complexes of the invention can be encapsulated in transfer vectors with high yields. More particularly, the encapsulation yields of the complexes of the invention in nanoparticles are greater than 50%, while they are less than 1% with naked nucleic acids, or with other oligopeptides which do not form secondary structures. (See examples).
- Another object of the invention therefore lies in the use of a cationic oligopeptide capable of forming secondary structures for the encapsulation of nucleic acids in a transfer vector.
- a subject of the invention is also the nucleic acid transfer vectors comprising a composition as defined above.
- vectors which are biocompatible, biodegradable, hydrophobic and of protein or polymeric nature.
- preferred vectors according to the invention are liposomes, nanoparticles or low density lipoproteins (LDL).
- Liposomes are phospholipid vesicles with an internal aqueous phase in which nucleic acids can be encapsulated.
- the synthesis of liposomes and their use for the transfer of nucleic acids is known in the prior art (WO91 / 06309, WO92 / 19752, WO92 / 19730).
- the use of complexes according to the invention makes it possible to improve the efficiency of encapsulation of nucleic acids in liposomes.
- Nanoparticles are small particles, generally less than 500 nm, capable of transporting or vectorizing an active ingredient (such as a nucleic acid) in cells or in the bloodstream.
- the present invention also makes it possible to considerably improve the yields of encapsulation of nucleic acids in nanoparticles.
- the nanoparticles according to the invention consist of polymers comprising a majority of degradable units such as polylactic acid, optionally copolymerized with polyethylene glycol.
- Other polymers usable in the nanoparticles have been described in the prior art (see for example EP 275 796; EP 520 889).
- the invention therefore also relates to a method of encapsulating nucleic acids in transfer vectors according to which the transfer vector or the constituent components, the nucleic acid and a cationic oligopeptide capable of forming secondary structures are brought into contact. , or optionally a nucleic acid - oligopeptide complex already formed, under conditions allowing the encapsulation of the nucleic acid in said transfer vector, then the transfer vector formed is recovered.
- the method according to the invention is preferably applied for the preparation of liposomes, nanoparticles or low density lipoproteins.
- the invention also relates to pharmaceutical compositions comprising a therapeutic nucleic acid and a cationic oligopeptide capable of forming secondary structures, optionally encapsulated in a transfer vector.
- This oligopeptide was synthesized as a salt of trifluoroacetic acid using an Applied Biosystem 431A peptide synthesizer, on an HMP resin (Applied Biosystem) and according to an F-MOC strategy. After synthesis, the peptide was released from the resin by treatment for 90 minutes in the presence of a TFA / water solution 95/5 (v / v), precipitated by addition of tert-butyl methyl ether, then purified by reverse phase HPLC on a column. Cl 8 100 A (Biorad RSL). The purity of the peptide obtained is greater than 95% and its solubility in water by 50 mg ml.
- This oligopeptide was synthesized in the form of a trifluoroacetic acid salt by following the protocol described above.
- the purity of the peptide obtained is greater than 90% and its solubility in water of 100 mg / ml. It has been shown that the polytetrapeptide LKLK, not structured in water, adopts a conformation in ⁇ sheets in saline solution or in the presence of nucleic acids, due to the interaction between phosphates and amino groups. Along a ⁇ sheet, the distance separating 2 positive charges is 6.9 A, which is compatible with the 6.2 A separating 2 phosphate groups from a single-stranded nucleic acid. This conformation should therefore improve the stability of the complex.
- This peptide (supplied by A. Brack, Center for Molecular Biophysics, La) is not structured in saline solution and was used as a control.
- the polylysine used is of commercial origin. This peptide is not structured in saline solution and was used as a control.
- Anti ras anti nucleic acids were prepared. These nucleic acids are oligonucleotides of 12 and 13 residues, synthesized by the company Eurogentec (Belgium). These oligonucleotides are directed against a sequence of the mutated ras mRNA at the twelfth codon.
- the nucleic acids used are the antisense (AS-Val), its inverse (IN V- Val: the sequence is identical but oriented in the opposite direction), as well as the antisense of normal ras mRNA (AS-Gly) and that a control nucleic acid comprising 2 unpaired nucleotides in the middle of the sequence (AS-mut2).
- the sequence of these nucleic acids is as follows:
- the nucleic acid (d (Tp) 15T) is composed of 16 thymidines. It is of commercial origin (Pharmacia).
- This example illustrates the formation of complexes between the antisense nucleic acids described in Example 2 and the oligopeptides described in Example 1, under different ionic strength and concentration conditions (all the nucleic acid concentrations are expressed as phosphate). H shows that very high complexation yields can be obtained, thus testifying to the stability of the complexes.
- the A / AO value is determined, making it possible to evaluate the fraction of free nucleic acid and, by difference, the complexed fraction.
- a ratio R 1, the concentration of oligopeptide expressed as lysine is therefore 10 " 4 M.
- the nucleic acid (10 ⁇ 4 M) and the oligopeptide (variable concentration) were brought into contact in a 50 mM Tris-HCl buffer pH 7.4. The solution was then centrifuged, and the absorbance at 256 nm determined in the supernatant. For each value of the R ratio tested, the A / AO value is determined as above.
- Example 4 Study of the encapsulation in a transfer vector of the nanoparticles.
- This example illustrates the very advantageous properties of the complexes of the invention, allowing the encapsulation of nucleic acid in transfer vectors with very high yields.
- Nanoparticles used are diblock copolymers consisting of a poly (D, L lactic acid) linked by an ester bond to a poly (ethylene glycol): PLAp (M) -PEG (N) where M and N are the average molecular weights (in kD) of PLA and PEG, respectively, and p, the percentage of L-lactic acid.
- the 2 types of nanoparticles used are PLA50 (30) -PEG (2) and PLA50 (30) -PEG (5). These copolymers can be synthesized by any technique known to a person skilled in the art (see for example EP 520 889).
- the nucleic acids were treated with phage T4 polynucleotide kinase (Biolabs) in the presence of ATP. ⁇ 32p (Amersham) in kinase buffer. After 30 min of incubation at 37 ° C., the nucleic acid was separated from the unreacted ATP by deposition on a Sephadex G25 column (Quick Spin) and centrifugation.
- This example describes the encapsulation of the INV-Vall3 nucleic acid in a PLA5Q (30) -PEG (2) nanoparticle in the presence or absence of an oligopeptide (LKKL) 10 .
- the polymer used (PLA50 (30) -PEG (2)) was dissolved in 1 ml of acetone at a concentration of 10 g 1.
- the organic solution obtained was then poured dropwise into 5 ml of an aqueous solution (50 mM Tris-HCl buffer, pH 7.4), under The polymer insoluble in the water / acetone mixture precipitates in the form of nanoparticles, trapping the nucleic acid-oligopeptide complex, then the acetone is removed by evaporation under partial vacuum, to a final volume of 2.5 ml.
- the nanoparticulate suspension was filtered through a Sartorius filter with a porosity of 1.2 ⁇ m, which acts as a screen for dispersion and injectability.
- the encapsulation yield corresponds to the percentage of nucleic acid encapsulated in the nanoparticles, relative to the total amount of nucleic acid present at the start.
- - LKKLn Propeller ⁇ synthesized in homogeneous phase in the form of a mixture of peptides of average molecular weight of 34900.
- - LKLKn Sheet ⁇ synthesized in homogeneous phase in the form of a mixture of peptides of average molecular weight of 7400.
- sphingosine a positively charged membrane lipid
- the nucleic acid (d (Tp) 15T) was mixed with the oligopeptide in solution in water.
- sphingosine it is dissolved in a water / ethanol mixture 50% v / v.
- concentrations used are indicated in the table below. 100 ⁇ l of a polylactic acid solution (PLA50) dissolved in l acetone at a concentration of 20 g / 1 were added to the mixture, as well as 300 ⁇ l of pure acetone (final concentration in PLA50: 5 g / 1).
- the mixture was poured drop by drop into a 2.5% (w / v) aqueous solution of pluronic F68 in order to precipitate the polymer in the form of a turbid nanoparticulate colloidal suspension.
- the turbidity was appreciated by the eye.
- the diameter of the nanoparticles (175 +/- 40 nm) was measured by quasi elastic scattering " of light on a BI 90 device (Brookhaven Instrument Corporation).
- the acetone was then evaporated in vacuo for one hour.
- the suspension was then filtered through an AP20 millipore filter (pore diameter: 1.5 ⁇ m), previously wetted with the 2.5% pluronic F68 solution.
- the encapsulation yield has been determined and is reported in the table below.
- This example illustrates the capacity of the compositions of the invention to transfer nucleic acids into cells.
- Cells used The nucleic acid transfer tests described in this example were carried out on a cell line originating from a human bladder carcinoma, designated T24 / EJ accessible to ATCC. The cells were cultured in MEM-EAGLE medium ("minimum essential medium", Biological Industries) supplemented with L-glutamine ((5 mM), streptomycin (50 u / ml), penicillin (50 u / ml), in the presence 7% fetal calf serum decomplemented 30 min at 60 ° C.
- MEM-EAGLE medium minimum essential medium
- L-glutamine ((5 mM)
- streptomycin 50 u / ml
- penicillin 50 u / ml
- the cells (1500 / well) were seeded in 96-well microplates, in the absence or presence of nucleic acid, whether or not encapsulated in nanoparticles, in a total volume of 100 ⁇ l. Each point was made in triplicate.
- the nucleic acid concentration used was adjusted by dilution in water or by concentration by centrifugation for 1 hour at 12,000 rpm. In this case, the suspension is centrifuged, the pellet weighed and then the volume adjusted.
- the efficiency of the transfer was determined by measuring the inhibition of cell proliferation induced by the antisense nucleic acid, after 72 or 96 hours of culture at 37 ° C. in the presence of 5% CO 2. For this, 2 methods were used:
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- Medical Informatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oncology (AREA)
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/687,551 US5856435A (en) | 1994-02-08 | 1995-01-27 | Nucleic acid-containing composition, its preparation and use |
JP7520999A JPH09508530A (ja) | 1994-02-08 | 1995-01-27 | 核酸を含む組成物、その調製および使用 |
AU15818/95A AU1581895A (en) | 1994-02-08 | 1995-01-27 | Nucleic acid-containing composition, its preparation and use |
EP95907715A EP0743984A1 (fr) | 1994-02-08 | 1995-01-27 | Composition contenant des acides nucleiques, preparation et utilisations |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR9401381A FR2715847B1 (fr) | 1994-02-08 | 1994-02-08 | Composition contenant des acides nucléiques, préparation et utilisations. |
FR94/01381 | 1994-02-08 |
Publications (1)
Publication Number | Publication Date |
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WO1995021931A1 true WO1995021931A1 (fr) | 1995-08-17 |
Family
ID=9459869
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/FR1995/000098 WO1995021931A1 (fr) | 1994-02-08 | 1995-01-27 | Composition contenant des acides nucleiques, preparation et utilisations |
Country Status (7)
Country | Link |
---|---|
US (1) | US5856435A (fr) |
EP (1) | EP0743984A1 (fr) |
JP (1) | JPH09508530A (fr) |
AU (1) | AU1581895A (fr) |
CA (1) | CA2182118A1 (fr) |
FR (1) | FR2715847B1 (fr) |
WO (1) | WO1995021931A1 (fr) |
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US5856435A (en) | 1999-01-05 |
AU1581895A (en) | 1995-08-29 |
CA2182118A1 (fr) | 1995-08-17 |
EP0743984A1 (fr) | 1996-11-27 |
FR2715847B1 (fr) | 1996-04-12 |
JPH09508530A (ja) | 1997-09-02 |
FR2715847A1 (fr) | 1995-08-11 |
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