EP1200461A2 - Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments - Google Patents

Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments

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Publication number
EP1200461A2
EP1200461A2 EP00949393A EP00949393A EP1200461A2 EP 1200461 A2 EP1200461 A2 EP 1200461A2 EP 00949393 A EP00949393 A EP 00949393A EP 00949393 A EP00949393 A EP 00949393A EP 1200461 A2 EP1200461 A2 EP 1200461A2
Authority
EP
European Patent Office
Prior art keywords
gly
polypeptide
dendrimer
dendrimers
bioactive
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00949393A
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German (de)
English (en)
Inventor
Antonio Verdini
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Laboratoires Servier SAS
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Laboratoires Servier SAS
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Publication date
Application filed by Laboratoires Servier SAS filed Critical Laboratoires Servier SAS
Publication of EP1200461A2 publication Critical patent/EP1200461A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • A61K47/62—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
    • A61K47/641—Branched, dendritic or hypercomb peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to polypeptide dendrimers their processes of synthesis and their use as carriers for the delivery of bioactive substances, including drugs, or as carriers of bacterial, viral and parasite antigens, gene- therapy compounds and diagnostic imaging contrast agents.
  • Prior art Dendrimers are highly branched polymers in which a number of primary branched chains (monodendrons) irradiating from a multifunctional core moiety originates structures and morphologies quite different from classical hyperbranched and star polymers.
  • dendrimers namely a) a core moiety, b) interior layers (generations) composed of branching units forming the monodendrons radially attached to the core, and c) an exterior of closely spaced surface groups generate, as the generations increase, spheroidal structures with well-developed internal hollows and channels.
  • the cavities and channels create a microenvironment that can be utilized for the entrapment or the covalent coupling of guest molecules.
  • PAMAM poiyamidoamine
  • dendrimers obtained by the divergent approach can hardly be achieved as they have very similar structures to their by-products.
  • the synthesis of dendrimers begins from the periphery and ends at the core by first preparing single monodendrons with the desired number of generations and then joining them to the core moiety. Dendrimers synthesized by this approach can be produced nearly pure since only a constant and low number of reactions are required for any generation-adding step. Dendrimers can be also obtained in fewer steps and higher yields, using pre-branched analogues of both cores (hypercores) and branching units (branched monomers) or, alternatively, following "double exponential" and mixed growth strategies of synthesis.
  • dendrimers namely spheroidal surfaces, internal voids and nanoscopic dimensions have suggested their use as host molecules capable of binding guest molecules either at the interior (dendrimers as endo- receptors) or at the surface (dendrimers as exo-receptors).
  • Various small molecular weight organic molecules have been entrapped into carboxylate- terminated hydrocarbon dendrimers.
  • Acetylsalycilic acid and 2,4 chlorophenoxyacetic acid have been encapsulated within, or near the surface of, PAMAM dendrimers of generation 4, 5 and 6 and the sequestering of 10-20 molecules of dopamine in the channels of PAMAM dendrimers of generation 6 has been studied by use of molecular dynamics calculations.
  • Gd (III) chelate of the PAMAM-thiourea-diethylenetriaminepentaacetic acid magnetic resonance imaging contrast agent (Gd(lll)-PAMAM-TU-DTPA) remains circulating in blood for longer periods of time than the monomeric chelate, the sixth generation chelate being more effective as contrast agent than chelate conjugates based on polylysine, albumin and dextran supports.
  • polypeptide monodendrons of generation 2 and 3 composed of lysyl residues (MAP, multiple antigen peptides), have been prepared as branched multivalent scaffolds for peptide conjugation and used as immunogens and immunodiagnostics.
  • MAP multiple antigen peptides
  • the author did not however mention the possibility to prepare polypeptide dendrimers of globular shape resembling high generation spheroidal poly(amidoamines) for the encapsulation of guest molecules in their internal cavities.
  • PAMAMs high carrying capacity.
  • the internal voids of PAMAMs are not big enough to encapsulate either a large number of low molecular weight molecules or a reasonable number of macromolecular guests like, for instance, insulin.
  • controlled dimensions preferably in the 10-100 nm range, to avoid rapid urinary clearance and RES (reticuloendothelial system) uptake.
  • a first aim of the present invention is that of providing water soluble polypeptide carriers with dendrimeric structures, spheroidal shapes and precisely defined dimensions (unimolecular dendrimeric carriers), with channels and cavities that can host bioactive substances and drug molecules with molecular weights up to 5-7 kDa.
  • a second aim of the present invention is that of providing polypeptide dendrimeric carriers whose gradual demolition in vivo, in blood or at the target cellular sites, occurs both by enzymatic hydrolysis (which can be controlled and modulated by insertion of D aminoacid residues into the backbone) and by UV irradiation if the carriers contain photolabile bonds.
  • a third aim of the present invention is that of providing loaded polypeptide dendrimeric carriers whose dimensions and surfaces are tailored to avoid RES uptake as well as rapid urinary clearance.
  • An additional aim of the present invention is the synthesis of polypeptide dendrimeric carriers with antigen moieties (peptides, oligonucleotides, saccharides and oligosaccharides deriving from relevant pathogenic agents) covalently linked to their surface reactive groups.
  • a further aim of the present invention is the derivatisation of the surface of the polypeptide dendrimeric carriers with biological receptor ligands such as folic acid, sialic acid, mannose, fat acids, vitamins, hormons, oligonucleotides, monoclonal antibodies, short peptides, proteins and oligonucleotides for cell targeting.
  • biological receptor ligands such as folic acid, sialic acid, mannose, fat acids, vitamins, hormons, oligonucleotides, monoclonal antibodies, short peptides, proteins and oligonucleotides for cell targeting.
  • a multifunctional core moiety ii. an exterior of closely spaced groups constituting the terminals of branched polypeptide chains (monodendrons) radially attached to the core that, in turn, form iii. interior layers (generations) of short peptide branching units (propagators) with characteristic hollows and channels, where each propagator contains a trifunctional aminoacid whose asymmetric carbon (the propagator branching point) is connected to two equal-length arms bearing identical terminal reactive groups and to a third arm (the propagator stem) bearing an activatable functional group, represented by formula (I):
  • K is a multifunctional core moiety
  • L is a polypeptide monodendron
  • p is the number of polypeptide monodendrons irradiating from the core moiety
  • M represents the outermost ramifications of the dendrimer.
  • polypeptide dendrimers the processes for their synthesis and the use as unimolecular carriers, according to the present invention, will be better illustrated in the following description.
  • the polypeptide dendrimers of this invention consist of highly branched polypeptide chains or monodendrons, deriving from repeated condensations of short peptide branching units or propagators, that irradiate outward from a multifunctional core moiety, having an exterior of closely spaced groups constituting the terminals of the monodendrons, and interior layers or generations of propagators with characteristic hollows and channels where each propagator contains a trifunctional aminoacid whose asymmetric carbon (the propagator branching point) is connected to two equal-length arms bearing identical terminal reactive groups and to a third arm (the propagator stem) bearing an activatable functional group.
  • the polypeptide dendrimers are represented by formula (I): K(-L) p -M (I) wherein: K is the multifunctional core moiety and K can be represented by the formulae:
  • aminoacid, peptide, nucleotide, oligonucleotide, saccharide, oligosaccharide, protein comprise either natural or synthetic analogues and derivatives.
  • a characteristic feature of the polypeptide dendrimers of the present invention is the limited stability of their backbone to plasma and cellular enzymes and, more important, the possibility of programming the stability towards enzymes in vivo by replacing L with D aminoacids. This property distinguishes the polypeptide dendrimers from PAMAM, polypropylamine, hydrocarbon, polyether, polythioether and silicon-based dendrimers that, being all stable to enzymatic hydrolysis, may accumulate non-specifically in the body creating toxicity problems.
  • polypeptide dendrimers can be prepared, in accordance with the present invention, by condensing to a core moiety with 2, 3 or 4 identical functional group, two, three or four polypeptide monodendrons, previously prepared by stepwise synthesis, using short three-branched peptide propagators as building blocks.
  • low-generations monodendrons can be condensed to a preformed dendrimer (expanded core) to obtain the final dendrimer.
  • polypeptide dendrimers of the present invention not only encapsulate guest molecules of a wide range of molecular weights but, surprisingly, show also an extraordinary solubility in water even when surface polar groups such as NH 2 , OH, and COOH are masked by hydrophobic moieties.
  • surface polar groups such as NH 2 , OH, and COOH are masked by hydrophobic moieties.
  • a first general process for the preparation of unimolecular polypeptide dendrimers consists in: 1 ) the synthesis of core moieties with at least two functional groups; 2) the divergent synthesis of single polypeptide monodendrons; 3) the covalent conjugation of the polypeptide monodendrons to the core moieties.
  • a second general process for the preparation of polypeptide dendrimers consists in: 1 ) the synthesis of core moieties with at least two functional groups; 2) the condensation of monodendrons of generation 1-3, protected at their termini with removable groups, to the core moieties; 3) the removal of protecting groups from the low generation dendrimers obtained in step 2 followed by the reiterated condensation of protected monodendrons to reach the target high generation dendrimers; and 4) the removal of protecting groups from the final dendrimer followed by surface modification, when necessary.
  • Protecting groups, condensing and deblocking agents, solvents and reaction times are selected considering not only the structure of both core moieties and propagators, but also the chemical and structural properties of guest molecules.
  • the objective of entrapping into polypeptide dendrimers molecules with molecular weights above 1 ,000 Da is obtained in two steps: 1) assembly of polypeptide monodendrons on solid supports (Solid-Phase Peptide Synthesis, SPPS), using short peptide derivatives as building blocks (divergent strategy) and 2) condensation, in aqueous phase and in the presence of guest molecules, of the polypeptide monodendrons to the core moiety by "chemical ligation” methods as currently applied for the synthesis of proteins (P.Lloyd-Williams, F. Albericio and E. Giralt, "Chemical Approaches to the Synthesis of Peptides and Proteins", 1997, CRC Press, Boca Raton, 175-200).
  • the objective of encapsulating into the polypeptide dendrimer molecules with molecular weight below 1 ,000 Da is obtained both by the above strategy of trapping guest molecules during dendrimer synthesis and also by first preparing "void carriers" that are subsequently filled up by diffusion of small guest molecules in their cavities.
  • the objective of preparing polypeptide dendrimers with photolabile bonds is obtained following the above methods and using monodendrons with one or more aminoacid residues of the backbone replaced by photolabile moieties.
  • the objective of preparing polypeptide carriers with guest molecules covalently linked at their interior is obtained by 1 ) preliminary entrapment of guest molecules into the dendrimer cavities by diffusion and 2) covalent coupling to the reactive groups of the dendrimer carrier.
  • the HPLC analysis was carried out with a Bruker LC21-C apparatus equipped with the UV Bruker LC313 detector, using Pico Tag Waters columns and acetonitrile-water buffers A) 10% (v/v) acetonitrile in 0.1 % TFA water and B) 60% (v/v) acetonitrile in 0.1 % TFA water; gradient (I) from 0 to 100% B in 25 min and (II) from 50 to 100% B in 25 min; flow, 1 ml/min, 220 nm detection.
  • This example describes the synthesis of a generation 4 dendrimer by condensation in liquid phase of a generation 4 monodendron derivative assembled on a solid-matrix, to a triamine core.
  • the synthesis was carried out on a Milligen 9050 machine, using a 0.5 cm (I.D.) column, loaded with 0.5 g of Fmoc-Gly-PEG-PS (Millipore) resin. Loading: 0.18 mmole/g.
  • the peptide monodendron was obtained by suspending the resin in 15 ml of TFA water (95/5, v/v) for 1 h at room temperature under stirring. After filtration, the resin was washed with 1 ml of TFA and the combined filtrates, after partial evaporation of TFA, were added to cold ethyl ether to precipitate the polypeptide. The mixture was kept at -20 °C for about 3 h. After filtration, the white product was dissolved in water and lyophilized three times. Yield: 420 mg. A dominating, broad HPLC peak was observed at 8.1 min, gradient (I), together with two very small peaks corresponding to products of the second and third cycle.
  • the product has been purified by Size Exclusion Chromatography (SEC) on Sephadex G-50, using 50% acetic acid as eluant.
  • SEC Size Exclusion Chromatography
  • the fractions containing the target peptide were lyophilized twice after dilution with water. Yield: 350 mg.
  • This example describes a three step synthesis of a generation 4 dendrimer prepared entirely in liquid-phase.
  • a generation 2 monodendron with NH 2 terminals protected by an acid labile group is condensed on a triamine core to obtain a generation 2 dendrimer.
  • the monodendron is again condensed to the free NH 2 terminals of the generation 2 dendrimer to obtain a generation 4 dendrimer.
  • the dendrimer NH 2 terminals are acetylated.
  • TEA 40 mmole
  • HOBt (8.8 mmole) and 1.12 ml of TEA (8.0 mmole) were dissolved in 30 ml of DMF at 0°C. The reaction was kept for 15 h at room temperature under stirring. After DMF evaporation, the residue was dissolved in 200 ml of methylethylketone.
  • the synthesis was carried out on a Milligen 9050 apparatus, using a 0.5 cm (I.D.) column, loaded with 0.1 g of Fmoc-Cys(Trt)-PEG-PS (Millipore) resin. Loading: 0.16 mmole/g.
  • 4-[4-(1-Fmoc-aminoethyl)-2-methoxy-5- nitrophenoxyjbutanoic acid was condensed to the cysteine(Trt) residue on the resin after Fmoc removal with 20% piperidine in DMF.
  • This example shows the stability of the polypeptide dendrimers described in Examples 1-3 to enzymatic hydrolysis in vitro.
  • Detection was by a Jasco Uvidec-100-ll detector. Eluant A was 0.1 % TFA in water; and eluant B was 0.1 % TFA in acetonitrile; gradient: from 0% B to 21 % B in 23 min.
  • the degradation in heparinated human plasma was studied using dendrimer concentrations of ca. 1.0 nmole/ml plasma at 37°C, as described above. The extent of degradation with time was obtained by comparing the area of the HPLC signals appearing at a given time to that registered initially. The half-life of the generation 4 dendrimer with free amino terminals is ca. 12 h against Leucine- aminopeptidase VI and ca. 8 h in human plasma.
  • EXAMPLE 5 This example illustrates the loading by diffusion of the Enkephalinase inhibitor L- Trp-L-Ala in a generation 6 polypeptide dendrimer prepared as in Example 1 ) and its release with time.
  • the dialysis was run against 100 ml of water for 48 h under slow stirring.
  • Increasing absorbance values observed during ca. 12 h of dialysis indicated a gradual release with time of the dipeptide by slow diffusion from the dendrimeric carrier.
  • a 28 o of the solution outside the dialysis cassette resulted slightly lower (-6%) than that of a reference solution prepared by dissolving 10 mg of dipeptide in 110 ml of water.
  • EXAMPLE 6 This example illustrates: a) the entrapment of heparin into a generation 7 polypeptide dendrimer containing photolabile bonds during condensation of the generation 7 monodendron to a trifunctional core carried out in the presence of heparin and b) the release of heparin by photolysis of the loaded dendrimer. 1 ). 1.12 g of sodium heparinate (obtained by depolimerization of ovine heparin, MW ca. 2,500 Da; activity, ca.180 lU/mg.) were added to the reagents used in Example 3.2 for the synthesis of the generation 7 dendrimer, at an apparent pH of 7.0. The monodendron condensation was protracted for 3 h at room temperature.
  • Rat Treatment t 0 1 h 2 h 3 h 4 h 24
  • rats 3-8 showed coagulation times close to those of rat 2, treated with heparin only.
  • Rats 9-14 treated with the non-irradiated dendrimer, showed an increase of coagulation times during four hours. At the first hour, the coagulation times are slightly less than that observed for rat 2 after two hours from heparin injection. The coagulation times for rats 9-14 becomes normal after 24 h.
  • This example reports: a) the absence of immunogenicity in mice of the generation 4 dendrimer obtained as described in Example 2) and b) its adjuvanticity when some of the NH 2 terminals are covalently linked to the octapeptide antigen Asn- Ala-Asn-Pro-Asn-Ala-Asn-Pro (a short segment of the immunodominant epitope of the Plasmodium falciparum Circumsporozoite Protein).
  • Plates were then saturated with PBS and 5% non-fat dry milk for 2 h at room temperature. After three washings (phosphate buffer, pH 7.4 and 0.05% Tween-20), sera that were serially diluted in PBS, 2.5% non-fat dry milk and 0.05% Tween 20 were added to the plates for 1 h at room temperature. After washings, rabbit anti-mice IgG-specific polyvalent immunoglobulins conjugated to alkaline phosphatase, diluted in PBS, 2.5% non-fat dry milk and 0.05% Tween 20 were added for 1 h. Plates were washed and the presence of enzyme evidenced with p- nitrophenylphosphate substrate.
  • Orn-Gly-Hl2l2l2l3 400.6 mg of N ⁇ CH2-CH2-NH-CO-CH(CH2-phenyl)-NH-Gly-Gly-Om-Gly[Gly-Gly-
  • mice In parallel, the same number of C57/8L/6 mice were injected with 50 ⁇ g of Asn-Ala-Asn-Pro-Asn-Ala- Asn-Pro dissolved in 50 ⁇ l of water. After three weeks, 25 and 250 ⁇ g of the same products were injected again to the two groups of mice. 10 days after, a sample of blood was taken from each mice as described before. The sera were tested by an ELISA test employing (Asn-Ala-Asn-Pro)4o as the antigen. (G. Del Giudice et al., J. Clin. Microbiol, 1997, 25, 91-96).
  • the antigen-dendrimer conjugate shows higher anti-Asn-Ala-Asn-Pro antibody titers (as the logarithmic geometric mean of antibody titers ⁇ S.E.M.) at week 45 (4.10 ⁇ 0.01 ) as compared to Asn-Ala-Asn-Pro- Asn-Ala-Asn-Pro antigen (2.81 ⁇ 08).
  • the polypeptide dendrimers of the present invention obtained by chemical synthesis, satisfy the foreseen objectives.
  • unimolecular polypeptide dendrimers can be obtained with the processes of synthesis described and, furthermore, the practicality of dendrimer loading and of controlled release of guest molecules in vivo by enzymatic hydrolysis and through the application of ultraviolet irradiation has been demonstrated.
  • Applications of the unimolecular carrier polypeptide dendrimers/guest molecules system in composition with pharmaceutically acceptable excipients in the medical field are widespread and potentially of extreme importance namely chemotherapy of cancer, anticoagulant and clot- dissolving drug therapy, antiviral therapy, vaccines, controlled release of hormones and related bioactive substances.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux dendrimères polypeptidiques ainsi que des procédés pour les synthétiser. Ces dendrimères polypeptidiques ont une structure constituée d'une fraction de noyaux multifonctionnelle à partir de laquelle des chaînes de polypeptides hautement ramifiée, formée de courtes unités de ramification de peptides, s'étendent radialement vers l'extérieur. Les branches le plus à l'extérieur entourent un volume de densité inférieure avec des cavités et des canaux dans lesquels des substances bioactives, utilisées en diagnostic et en thérapie, peuvent être piégées ou liées de manière covalente. Pour ces propriétés, les dendrimères de polypeptidiques sont particulièrement utiles dans de nombreux secteurs en biologie et en médecine en tant que porteurs pour l'administration de substances bioactives, y compris des médicaments, ou en tant que porteurs bactériens, viraux et d'antigènes parasites, de composés de thérapie génique et d'agents de contraste d'imagerie diagnostique.
EP00949393A 1999-07-23 2000-07-21 Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments Withdrawn EP1200461A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITFO990015 1999-07-23
IT1999FO000015A ITFO990015A1 (it) 1999-07-23 1999-07-23 "dendrimeri polipeptidici quali trasportatori unimolecolari di farmaci e sostanze biologicamente attive".
PCT/EP2000/007022 WO2001007469A2 (fr) 1999-07-23 2000-07-21 Dendrimeres polypeptidiques en tant que porteurs unimoleculaires d'agents de contraste d'imagerie diagnostique, de substances bioactives et de medicaments

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EP1200461A2 true EP1200461A2 (fr) 2002-05-02

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EP (1) EP1200461A2 (fr)
JP (1) JP2003506326A (fr)
CN (1) CN1364171A (fr)
AU (1) AU772167B2 (fr)
CA (1) CA2380178A1 (fr)
HU (1) HUP0201975A3 (fr)
IT (1) ITFO990015A1 (fr)
NO (1) NO20020333L (fr)
NZ (1) NZ517231A (fr)
PL (1) PL353273A1 (fr)
WO (1) WO2001007469A2 (fr)
ZA (1) ZA200201089B (fr)

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MY139353A (en) 2001-03-05 2009-09-30 Shell Int Research Process to prepare a lubricating base oil and a gas oil
AR032941A1 (es) 2001-03-05 2003-12-03 Shell Int Research Un procedimiento para preparar un aceite base lubricante y aceite base obtenido, con sus diversas utilizaciones
AR032932A1 (es) 2001-03-05 2003-12-03 Shell Int Research Procedimiento para preparar un aceite de base lubricante y un gas oil
WO2003037383A1 (fr) * 2001-10-29 2003-05-08 The Dow Chemical Company Systeme d'administration d'un medicament contenant un dendrimere antineoplasique
DE60302366T2 (de) 2002-07-18 2006-08-03 Shell Internationale Research Maatschappij B.V. Verfahren zur herstellung eines mirkokristallinen wachses und eines mitteldestillat-brennstoffs oder -kraftstoffs
EP1525890A1 (fr) 2003-10-02 2005-04-27 Complex Biosystems GmbH Complexes protéine-protéophore
WO2007061896A1 (fr) 2005-11-17 2007-05-31 Zogenix, Inc. Administration de preparations visqueuses par injection sans aiguille
HUP0700782A3 (en) * 2007-12-05 2009-11-30 Biostatin Gyogyszerkutato Fejl Novel peptides and amino acid derivatives, pharmaceutical compositions containing the same and use of the compounds
JP2011518881A (ja) 2008-04-28 2011-06-30 ゾゲニクス インコーポレーティッド 片頭痛の治療のための製剤
NZ591052A (en) * 2008-08-05 2012-11-30 Univ Queensland Antigen-presenting scaffolds

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WO1995000540A1 (fr) * 1993-06-18 1995-01-05 Robert Webber Vecteur et immunogene de synthese
WO1998032469A2 (fr) * 1997-01-29 1998-07-30 Nycomed Imaging As Polymeres

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PL353273A1 (en) 2003-11-03
JP2003506326A (ja) 2003-02-18
CN1364171A (zh) 2002-08-14
HUP0201975A2 (en) 2002-10-28
NZ517231A (en) 2003-05-30
WO2001007469A2 (fr) 2001-02-01
CA2380178A1 (fr) 2001-02-01
ZA200201089B (en) 2003-07-30
ITFO990015A1 (it) 2001-01-23
HUP0201975A3 (en) 2002-11-28
AU6276600A (en) 2001-02-13
WO2001007469A3 (fr) 2001-05-10
NO20020333D0 (no) 2002-01-22
NO20020333L (no) 2002-01-22
AU772167B2 (en) 2004-04-08

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