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WO2005011738A2 - Conjugues polymeres permettant d'etablir un diagnostic et d'effectuer une therapie - Google Patents

Conjugues polymeres permettant d'etablir un diagnostic et d'effectuer une therapie Download PDF

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WO2005011738A2
WO2005011738A2 PCT/IT2004/000422 IT2004000422W WO2005011738A2 WO 2005011738 A2 WO2005011738 A2 WO 2005011738A2 IT 2004000422 W IT2004000422 W IT 2004000422W WO 2005011738 A2 WO2005011738 A2 WO 2005011738A2
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conjugate
bfc
phosphine
pol2
peg
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WO2005011738A3 (fr
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Francesco Veronese
Ulderico Mazzi
Gianfranco Pasut
Roberta Visentin
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Universita degli Studi di Padova
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • A61K51/065—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules conjugates with carriers being macromolecules
    • 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
    • A61K47/56—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—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 organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/126—Linear polymers, e.g. dextran, inulin, PEG

Definitions

  • This invention relates to novel chelating agents comprising at least one polymer and at least a phosphorous atom in the form of a phosphine or phosphine oxide, to compositions and kits comprising them and to their uses in diagnostic and therapeutic methods.
  • Patent Documents
  • Chelating agents are often used in diagnostic and in therapeutic applications since they can bind specific metal ions and carry them in specific sites of the body.
  • Some metal ions for example Gd, 99m Tc, 6768 Ga, U1 ln, 62 Cu, which can be revealed by spectroscopic or scintigraphic methods are used in diagnostic methods, others, for example 90 Y, 186 188 Re, 153 Sm, m Lu, 64/67 Cu, can be used in therapeutic applications, like the treatment of tumours.
  • the labelled chelating agents often suffer of some disadvantages, such as the lack of thermodynamic and/or kinetic stability and specificity in localisation.
  • EP0659764 describes chelating agents comprising at least one phosphine.
  • PEGs poly(ethylene glycols)
  • PEGs poly(ethylene glycols)
  • derivatives thereof are having increase interest in chemical, biomedical, and other industrial applications due to their useful properties, such as, amphiphilic behaviour, solubility in aqueous and organic solvents, high purity, low polidispersivety, biological compatibility and since they can be activated for conjugation to other compounds such polymers have been employed for example, as drug carriers, matrices for liquid phase peptide or polynucleotides synthesis and to prepare conjugate with peptide and protein.
  • European Patent No. 0659764 describes chelating agents comprising at least one phosphine or one phosphine oxide phosphorous.
  • EP0659764 there is no suggestion to link a polymer to these chelating agents.
  • the skilled person would not have expected that such a conjugation could change the pharmacokinetic properties and in the meantime maintain the chelating properties necessary for diagnostic and therapeutic applications. It is apparent that there is a need of providing new alternative classes of diagnostic and therapeutic compounds capable to accumulate in certain tissues, and to remain in the blood pool for long periods of time.
  • a further problem concerning the preparation of radiopharmaceutical agents is the development of a suitable labelling procedure capable to afford the desired radiopharmaceuticals simply, possibly i n a o ne s pot r eaction b efore u se.
  • any radiochemicals are c haracterised b y a s hort half-life.
  • technetium when technetium is used as pertechnetate, it is combined with the chelating agent and must then be reduced by the addition of a suitable reducing agent; the complex comprising the technetium in reduced form must then be purified. This requires several steps, which are expensive and time consuming. Also since technetium, like other radiolabelling metals, has a short half-life, these multistep preparation processes cause a loss of specific radioactivity.
  • the present invention provides novel chelating agents that can be efficiently labelled with metal ions to produce radiopharmaceuticals for both diagnostic and therapeutic purposes.
  • the chelating agents according to the invention (also referred here as the "conjugates”) comprise a hydrophilic polymer conjugated directly or by means of other moieties to a chelating group able to chelate metal ions comprising at least one phosphine or one phosphine oxide phosphorous.
  • BFC is the chelating group, which is able to chelate a metal radioisotope, comprising at least one phosphine or one phosphine oxide phosphorous.
  • Pol2 is a hydrophilic water-soluble polymer, synthetic or naturally derived. Poll, Pol3 and BM may be present or absent,
  • Poll if present, is a polymer or a dendrimeric structure, which bears several side-chain fuctionalizable residues,
  • the chelating group has the formula: RlR2-P(O)r-(Alk-X-)-(Alk-X-)p-R' where: r is O or 1, p is 1 to 4, each group Alk is independently an alkyl group preferably comprising 1 to 4 carbons, optionally substituted by a one or more groups preferably selected among an oxy group, a hydroxy, an amino group, a carboxy group or a residue of an aminoacid,
  • R' is H or optionally substituted alkyl, or optionally substituted aryl or optionally substituted aryl-alkyl groups, such chelating group being conjugated to the other parts of the conjugate by a bond at any position of the chelating group, and preferably at an amine or carboxylic group or thiol group, or at any of the carbons of the backbone of the chelating group.
  • n 1, 2 and R" is an amino acid residue
  • R ls R 2 and R' have the meaning indicated above:
  • chelating groups comprising a phosphine phosphorous have reductive properties towards metals such as technetium, rhenium and copper when these are in their upper oxidation state (+7 for technetium and rhenium and +2 for copper, respectively).
  • the chelating group may be a phosphine moiety (monodentate BFC) or a phosphine group conjugated to a single natural or non natural amino acid (bidentate or tridentate BFC) as summarised in the formula VII-XII:
  • chelating agents may be suitable to bind metal ion moieties such as [Tc(CO) 3 ] + and [Re(CO) 3 ] + .
  • the phosphorous in polydentate chelating agents may be present as phosphine oxide as summarised in the formula XIII-XVII:
  • Preferred chelating groups are N-[N-(3-Diphenylphosphinopropionyl)glycyl]cysteine (PN 2 S) and
  • the conjugation between the chelating group and the other moieties of the conjugate can be made at any position of the chelating group; preferably conjugation involves a bond at a carboxylic or amino group present on the chelating group or at one of the carbons of the backbone of the chelating group.
  • the conjugation to Pol2 or to Poll, if present, may be direct or mediated by means of linker.
  • BM may be present or not, and if present it is a targeting molecule designed for the recognition of tumours, inflammatory sites and infection processes to exploit in diagnosis and therapy.
  • targeting molecules of the invention are peptides, monoclonal antibodies and antibody fragments, biotin, chemotherapeutic drugs and sugars.
  • Poll if present, is a polymer or a dendrimeric structure which bears several side-chain residues useful to attach covalently a plurality of BFC (n > 1, e.g., 2 to 200, and preferably 5 to 50), to obtain a polychelating compound.
  • Preferred hydrophilic polifunctional polymers include polyaspartic acid, polyglutamic acid, polyhydroxyethylaspartamide, polyhydroxyethylglutamide, poly(hydroxypropylmetacrylamide) and polylisine.
  • the polifunctional polymer has a molecular weight of 3000 to 9000 dalton.
  • the branching moiety is glutamic acid, ⁇ -glutamic acid, amino adipic acid or other amino bicarboxylic or tricarboxylic acids.
  • Preferred lipophilic polifunctional polymers include polyhydroxyl acids such as polylactic acid or polymalic acid.
  • Poll also possesses a terminal functional group, which can be used for the conjugation to Pol2 directly or by means of linker. Among the preferred functional groups are carboxylic, amino or hydroxyl groups.
  • the conjugation can be mediated by ester, amide, carbamate or other co alent bonds.
  • Pol3 if present, is a dendrimeric structure bearing several residues useful to covalently attach a plurality of BM (m>l, e.g., 2 to 200, and preferably 5 to 50), to obtain a polytargeting compound.
  • the branching moiety is glutamic acid, ⁇ -glutamic acid, amino adipic acid or other amino bicarboxylic or tricarboxylic acids.
  • Pol3 also possesses a terminal functional group for the conjugation to Pol2 directly or by means of linker. Among the preferred functional groups are carboxylic and amino groups. When Pol3 is directly bound to Pol2, the conjugation can be mediated by ester, amide, carbamate or other covalent bonds.
  • Pol2 is a hydrophilic water soluble polymer, synthetic or naturally derived, which possesses one or two terminal functional groups in order to be conjugated to Poll, Pol3, and BM (if they are present) and to at least one BFC.
  • Pol2 is a monofunctional polymer the only derivatizable group has to be conjugated to the block bearing the BFC moiety. Such conjugation may be directly or by means of linkers.
  • the preferred mono and bifunctional Pol2 are poly(ethylene glycol), polyvmylpirrolidone or polyacriloylmorpholine.
  • the polymer can have at least one reactive group suitable for conjugation. For instance the end group of the polymer can be activated according to know procedures (this holds for PEG-COOH, PEG-NH 2 ) and others (Sabine Herman, et al. J. of Bioactive and Compatible Polymers, Vol. 10 1995).
  • the polymer Pol2 has preferentially an average molecular weight of at least 1000, preferably of at least 4000, more preferably at least 10000, and even more preferably of at least 20000.
  • Pol2 is a polyethylene glycol) (PEG) derivative having an average molecular weight ranging from 1000 to 40000 Da. Some preferred Pol2 are PEG5000 and PEG20000.
  • the compounds according to the invention are suitable to complex metal ions, which can be used in therapeutic and diagnostic applications.
  • metals suitable in diagnostic applications are the ones which can be revealed by scintigraphic and spectroscopic methods (SPECT, PET, MRI, and others methods).
  • Metals used in diagnostic applications are for example Gd, 99m Tc,
  • radioisotopes such as 90 Y v , 186/188 Re,
  • a conjugate according to the invention can be prepared conjugating the chelating group to the other polymeric moieties of the conjugate according to know chemical routes such as activation of a carboxyl group of the chelating group through N-hydroxysuccinimid / N, N' dicyclohexyl- carbodiimid followed by coupling with a polymer comprising a reactive end-group such as an amine or an hydroxy and deprotection of any protecting group.
  • a typical labelling method for 99m Tc involves transchelation of the metal from its complex with an exchange ligand, such as gluconate, to the compounds according to the invention.
  • 99m Tc- gluconate is prepared following a reducing procedure of 99m TcO 4 " using Sn 2+ as reducing agent (B. Johannsen et al, Inorg. Chim. Acta, 210, 209-214, 1993).
  • the labelling method can avoid the use of an external reducing agent. It is assumed that the reducing properties of the phosphine derivatives are enhanced by the special supramolecular arrangement of these compounds, which have amphiphilic character. Surprisingly these phosphine compounds catalyse an intramolecular oxido-reduction in which the phosphine is oxidised to phosphine oxide and acts as a reducing agent in respect to pertechnetate. In a preferred method a solution of metal ion is added to the conjugate in a solid form.
  • the carboxylic group of PN 2 S(Trt) was activated by EDC/NHS and coupled with monomethoxy amino-poly(ethyleneglycol) (mPEG-NH 2 ) to obtain the desired product: mPEG 5 ooo-PN 2 S(Trt).
  • PN 2 S(Trt) (0,3 mmol; MW 660,76Da) dissolved in 10 ml of CH 2 C1 2 were cooled at 4°C and 51,80 mg of N-hydroxysuccinimid (NETS) (0,45 mmol; MW 115,19Da) and 172,53 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid-HCl (EDC) (0,9 mmol; MW 191,71Da) were added. The reaction was maintained under Argon atmosphere and allowed warming at room temperature.
  • NETS N-hydroxysuccinimid
  • EDC N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid-HCl
  • the carboxylic group of PN S(Trt) was activated by EDC/NHS and coupled with monomethoxy amino-poly(ethyleneglycol) (mPEG-NH 2 ) to obtain the wanted product: mPEG 2 oooo-PN 2 S(Trt).
  • the carboxylic group of (P)ON 2 S(Trt) was activated by EDC/NHS and coupled with monomethoxy amino-poly(ethyleneglycol) (mPEG-NH 2 ) to obtain the wanted product: mPEG 5 ooo-(P)ON 2 S.
  • the carboxylic group of (P)ON 2 S(Trt) was activated by EDC/NHS and coupled with monomethoxy amino-poly(ethyleneglycol) (mPEG-NH 2 ) to obtain the wanted product: mPEG 20 ooo-(P)ON 2 S.
  • HO-PEG 10 ooo-OH Activation of HO-PEG 10 ooo-OH lg of bifunctional poly(ethyleneglycol) (HO-PEG 10 ooo-OH; 0.1 mmol; MW 10 KDa) were dissolved in 20 mL of toluene and dehydrated by water-toluene azeotropic distillation.
  • the product PEG 1 oooo-(AD) 2 - (COOH) 4 (2) was repeatedly extracted from the aqueous solution with chloroform (5 x 50 mL). The organic phase was dried with Na 2 SO 4 , concentrated under vacuum to 5 mL, and added dropwise to 200 mL of diethyl ether. 2 was collected by filtration and dried under vacuum. The degree of functionalisation, evaluated by titration of the carboxylic groups with NaOH 0.01 N, was 95%.
  • Step 3 Activation of PEG 1 oooo-(L-2-aminoadipic) 2 -(COOH) 4 750 mg of 2 (0.072 mmol; MW 10374,3Da), were dissolved in 10 mL of anhydrous CH 2 C1 2 and the solution was cooled to 0°C. 24.9 mg of N-hydroxysuccinimide (0.216 mmol; MW 115,19 Da) and 44.6 mg of N,N'-dicyclohexylcarbodiimide (0.216 mmol; MW 206,33Da) were added under stirring. The mixture was allowed warm to room temperature and react for 12 hours.
  • Step 4 Preparation of PEG 1 oooo-(L-2-aminoadipic) 2 -[CONH-(CH 2 ) 6 -NH2] 100 ⁇ l of mono t-butil 1,6 diamine exan (0,48 mmol; MW 202,3Da; d 20 0,972) were dissolved in DMF and, under costant stirring, 650 mg of 3 (0,06 mmol; MW 10763 Da) was added. After 3 hours reaction mixture was treated with 10 ml o f a solution composed as follows: 50%TFA, 49%CH 2 C1 2 , 1% water.
  • Step 5 Coupling of PN 2 S(Trt) to PEG 10 ooo-(L-2-aminoadipic) 2 -[CONH-(CH 2 ) 6 -NH 2 ] 4
  • Carboxylic group of PN 2 S(Trt) were activated by EDC/NHS and coupled with PEG-AD 2 - [CONH-(CH 2 ) 6 -NH 2 ] 4 to obtain the wanted product: PEG ⁇ 00 oo-(AD) 2 -[CONH-(CH 2 ) 6 - PN 2 S(Trt)] 4 .
  • PN 2 S(Trt) (0,24 mmol; MW 660,76 Da) dissolved in 5 ml of CH 2 C1 2 were cooled at 4°C and 41,47 mg of N-hydroxysuccinimid (NHS) (0,36 mmol; MW 115,19 Da) and 138 mg of N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid-HCl (EDC) (0,72 mmol; MW 191,71Da) were added.
  • NHS N-hydroxysuccinimid
  • EDC N'-(3-dimethylaminopropyl)-N-ethylcarbodiimid-HCl
  • Example 8 Preparation of PEG 5 ooo-(P)ON 2 S
  • amphiphilic compounds PEG 5 ooo-PN 2 S and PEG 2 oooo-PN 2 S were evaluated by light scattering technique.
  • a solid sample of the amphiphilic compound was directly dissolved in phosphate buffer (pH 4, 7.4, 10) and the analysis was performed at 496 nm keeping the temperature constant at 25° C.
  • Example 9 Self-association in aqueous solution of PEG 5 ooo-PN 2 S
  • PEG 5 ooo-PN 2 S (20 mg) was dissolved in phosphate buffer (1 mL). At all considered pH values, the compound self-associates in micelles showing similar mean diameter at pH 7.4 and 10 (387.9 nm and 391.6 nm, respectively) and being significantly smaller at pH 4 (175.2 nm).
  • Example 10 Self-association in aqueous solution of PEG 20000 -PN 2 S
  • PEG 2 oooo-PN 2 S (80 mg) was dissolved in phosphate buffer (1 mL). At all considered pH values, the compound self-associates in micelles showing similar mean diameter at pH 7.4 and 10 (2757.6 nm and 2591.9 nm, respectively) and slightly bigger at pH 4 (3029.1 nm).
  • the detritylated amphiphilic conjugates of Examples 6 and 7 PEG 5 ooo-PN 2 S and PEG20 000 -PN 2 S can be labeled with 99m Tc by transchelation of the metal from its complex with an exchange ligand, such as gluconate.
  • 99m Tc- gluconate prepared by adding 100 ⁇ L of freshly e luted 99m TcO 4 " (5-10 mCi) to 10 ⁇ l di Na- gluconato 0.01 M and 1 ⁇ l di SnCl 2 0.1 M (HC1 0.1M), must be purified by Sep-pak chromatography to eliminate undesirable hydrolized oxides which can be absorbed unspecifically by PEG chains.
  • Example 11 Labeling of PEG 500 o-PN 2 S via 99m Tc-gluconate
  • the detritylated amphiphilic conjugates of Examples 6 and 7 PEG 5 ooo-PN 2 S and PEG 20 ooo-PN 2 S can be alternatively labeled with 99m Tc exploiting the reductive properties of phosphine phosphorous and avoiding the need of an external reductive agent.
  • the pertechnetate s olution i s p referably a dded t o a so lid s ample o f t he a mphiphilic c ompound, t o favour the binding interaction between the reducing-coordinating BFC and TcO 4 " before micelles formation.
  • Example 13 Labeling of PEG 5 ooo-PN 2 S via TcO 4 "
  • Example 14 Labeling of PEG 20 ooo-PN 2 S with 99m Tc via TcO 4 "
  • Example 13 The same procedure was followed as for Example 13, except for the following changes: PEG 2 oooo-PN 2 S 8 mg, incubation at 37° C. Quantitative yield in a single labeled species.
  • the amphiphilic conjugates PEG 5 ooo-PN 2 S and PEG 2 oooo-PN 2 S reduce 99m TcO " and coordinate reduced 99m Tc species in mild conditions, in a really short time and with quantitative yields.
  • the free BFC PN 2 S by itself is able to reduce TcO " due to the redox potential of phosphine phosphorous, but the reaction is kinetically not favoured and it is not useful in the time scale of technetium decay. Instead, the reduction of TcO 4 " by the amphiphilic conjugates is fast and complete in a short time (10-15 minutes).
  • the labeling procedure of the present invention is in agreement with a catalytic process mediated by micellar aggregate formation.
  • the solution of a metal radioisotope in its upper oxidation state is added to the solid amphiphilic compound bearing the most suitable chelating agent, micelle formation catalyses metal reduction and coordination.
  • the amphiphilic compound associates in micelles, the radioactive metal is loaded into the lipophilic core and it undergoes reduction reaction, mediated by phosphorous, and coordination reaction, mediated alternatively by the PN 2 S or the (P)ON 2 S set.
  • the inclusion into micelle core enhances the reductive properties of phosphorous and favours coordination.
  • no radiolabeled impurities or free pertechnetate are detectable indicating that the reduction is followed immediately by coordination.
  • analogous amphiphilic compounds bearing a phosphine oxide instead of the phosphine phosphorous thus missing reductive properties, can be labeled with 99m Tc via gluconate.
  • Example 15 Labeling of PEG SO oo-(P)°N 2 S via Tc-gluconate
  • the TcO 3+ core is coordinated by the (P)ON 2 S set with the phosphine oxide oxygen bound to the metal centre instead of the phosphine phosphorous.
  • the labeled amphiphilic conjugates of Examples 11-15 are very stable as demonstrated by the fact that when micellar aggregates dissociated into their unimers no radiolabeled impurities or free radiometal species are detectable.
  • the labeled amphiphilic conjugates are intended to be use as radiopharmaceuticals for diagnostic and therapeutic purposes. In vivo studies were performed to evaluate the biodistribution and stability of labeled compounds of Examples 13 and 14 after intravenous administration.
  • a normal Swiss mouse was injected into the tail vein with a diluted solution of the labeled compound prepared in Example 13 (pH 7, NaOH 0.1N). Scintigraphic images of the mouse were collected for 40 minutes with a YAP-camera (F. Vittori, T. Malatesta, F. de Notaristefani, Transactions on Nuclear Science, Vol. 44, No. 1, 47-53, 1997) and showed a rapid and efficient clearance from t he b loodstream m ainly b y t he urinary s ystem, a lso c onfirmed b y t he ex- vivo counting of activity in organs and tissues.
  • Example 14 The biodistribution of the labeled compound prepared in Example 14 were evaluated under the same conditions as those for Example 16, except for the image acquisition time which was extended to 4 hours. Scintigraphic images of the mouse showed a slow clearance from the blood pool which correlated with a high retention of activity in all organs and tissues, also confirmed by the ex-vivo counting of activity in organs and tissues.
  • Example 19 Complexation of PEG 2 oooo-PN 2 S with 18S/187 Rhenium The same procedure was followed as for Example 18, except for the following changes: PEG 2000 0-PN2S 400 mg in 6 mL of dichlorometane, ReOCl 3 (PPh 3 ) 2 16 mg. Yield: 68%.
  • Example 20 Complexation of PEG S ooo-(P)ON 2 S with 185/187 Rhenium

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Abstract

L'invention concerne des polymères réactifs pouvant être conjugués, directement ou au moyen de liants et/ou d'autres polymères avec des agents de chélation, qui comprennent au moins un atome phosphoreux sous forme de phosphine ou d'oxyde de phosphine (ou de précurseurs de celui-ci) afin de former des conjugués utilisés dans des applications diagnostiques et thérapeutiques. L'invention concerne, en particulier, des conjugués comprenant un polymère hydrophile lié directement ou au moyen d'autres fractions, à au moins un groupe de chélation capable de chélater des radio-isotopes métalliques comprenant au moins une phosphine ou un oxyde de phosphine phosphoreux. Ces groupes de chélation peuvent être conjugués au polymère hydrophile directement ou via un ou plusieurs liant(s) et/ou un ou plusieurs polymère(s) supplémentaire(s). L'utilisation de ces polymères supplémentaires permet d'augmenter la charge d'agent de chélation. Les liants sont, de préférence, sélectionnés dans des groupes alkyle ou des groupes aromatiques ou des peptides clivables ou d'autres séquences biodégradable. De plus, une ou plusieurs molécule(s) de ciblage peut/peuvent être liée(s ) au polymère hydrophile directement ou au moyen de liants et/ou d'autres polymères. Du fait de leur structure polymère, les conjugués de l'invention possèdent une spécificité améliorée envers certains tissus, tels que les tumeurs, les tissus enflammés et le foie. Cette spécificité peut également être accrue par adjonction de fractions de ciblage telles que des anticorps ou des sucres. Ces conjugués peuvent être formulés afin de rester dans la circulation sanguine pendant une durée appropriée pour des applications diagnostiques et thérapeutiques. Ils possèdent, en outre, une stabilité thermodynamique et cinétique, permettant de conserver intact l'agent de chélation métallique dans des conditions physiques. L'invention concerne également une méthode très simple et très efficace permettant d'étiqueter des substances radiopharmaceutiques, ce qui permet d'éviter l'utilisation d'un agent de réduction supplémentaire. En conséquence, des ions métalliques du type technétium ou rhénium peuvent être ajoutés sous forme de pertechnétate ou pherrhénate aux agents de chélation comprenant un polymère et une phosphine. On a ainsi découvert de manière surprenante que des agents de chélation peuvent agir comme agents de réduction du métal et que l'utilisation d'un agent de réduction supplémentaire n'est pas nécessaire, ce qui permet de préparer des kits simples comprenant un composant (a) constitué de l'agent de chélation polymère et un composant (b) constitué de l'ion métallique dans son état d'oxydation le plus élevé. Ces deux composants peuvent être conservés séparément et combinés ensemble juste avant leur utilisation afin de produire le complexe métallique sans avoir recours à une étape de réduction et de purification.
PCT/IT2004/000422 2003-07-31 2004-07-29 Conjugues polymeres permettant d'etablir un diagnostic et d'effectuer une therapie Ceased WO2005011738A2 (fr)

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IT2003PD000174A ITPD20030174A1 (it) 2003-07-31 2003-07-31 Coniugati polimerici per diagnostica e terapia
ITPD2003A000174 2003-07-31

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US20110065680A1 (en) * 2008-03-10 2011-03-17 Roger Alberto Metal Complexes
EP2557155A4 (fr) * 2010-04-06 2016-03-09 Ihi Corp Dérivé du complexe métal-salen et son procédé de fabrication
US9902690B2 (en) 2013-12-27 2018-02-27 Novus International, Inc. Ethoxylated surfactants
US10584306B2 (en) 2017-08-11 2020-03-10 Board Of Regents Of The University Of Oklahoma Surfactant microemulsions

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JP2640293B2 (ja) * 1990-05-30 1997-08-13 ドイチエス クレープスフオルシユングスツエントルム ステイフツング デス アフエントリヒエン レヒトス ポリエーテル置換抗腫瘍剤
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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110065680A1 (en) * 2008-03-10 2011-03-17 Roger Alberto Metal Complexes
US8961924B2 (en) * 2008-03-10 2015-02-24 University Of Zurich Metal complexes
EP2557155A4 (fr) * 2010-04-06 2016-03-09 Ihi Corp Dérivé du complexe métal-salen et son procédé de fabrication
US9603940B2 (en) 2010-04-06 2017-03-28 Ihi Corporation Metal salen complex derivative and process for production thereof
US9902690B2 (en) 2013-12-27 2018-02-27 Novus International, Inc. Ethoxylated surfactants
US10584306B2 (en) 2017-08-11 2020-03-10 Board Of Regents Of The University Of Oklahoma Surfactant microemulsions

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WO2005011738A3 (fr) 2005-04-14

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