WO1998041540A1 - Ligands radiomarques du recepteur de la somatostatine pour le diagnostic et la theraphie - Google Patents
Ligands radiomarques du recepteur de la somatostatine pour le diagnostic et la theraphie Download PDFInfo
- Publication number
- WO1998041540A1 WO1998041540A1 PCT/AT1998/000065 AT9800065W WO9841540A1 WO 1998041540 A1 WO1998041540 A1 WO 1998041540A1 AT 9800065 W AT9800065 W AT 9800065W WO 9841540 A1 WO9841540 A1 WO 9841540A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- carrier substance
- diagnosis
- peptide
- compound
- metal
- Prior art date
Links
- HEFYZANMMCMMGH-UHFFFAOYSA-N C#CC1=Cc2ccccc2C#CC1 Chemical compound C#CC1=Cc2ccccc2C#CC1 HEFYZANMMCMMGH-UHFFFAOYSA-N 0.000 description 1
- 0 C=*1c(cccc2)c2C(C#C)=C1 Chemical compound C=*1c(cccc2)c2C(C#C)=C1 0.000 description 1
Classifications
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
-
- 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
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/083—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins the peptide being octreotide or a somatostatin-receptor-binding peptide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Definitions
- the invention relates to a carrier substance for metal compounds for diagnosis and / or destruction of tumor tissue, which selectively binds the substance to the somatostatin-binding surface receptors of the affected cells, a macrocyclic chelating agent being bound to a somatostatin 14 agonist
- peptides such as (D) Phe-Cys-Tyr- (D) Trp-Lys-Thr-Cys-Thr (ol) (Tyr 3 -Octreotide, 2) and m In-DTPA- (D) Phe-Cys-Phe- (D) Trp-Lys-Thr-Cys-Thr (ol) ((DTPA) - (D) Phe 1 -Octreotide, 3) used to localize malignancies such as neuroendocrine tumors, breast cancer and lymphomas
- Radioiodinated NDP vasoactive intestinal peptide, 4
- This radioligand ie 123 I-VIP
- ie 123 I-VIP not only binds to neuroendocrine tumors with high affinity, but also especially on a variety of adenocarcinomas that cannot be visualized with 111 In-DTPA- (D) Phe 1 octreotide.
- somatostatin receptors So far, five different human somatostatin receptors (hSSTRl-5) and two different VIP receptors have been characterized and cloned. Using transfected peptide receptors, the SSTR3 subtype has been found to be the most widely used among somatostatin receptors Binding site for somatostatin in the tumor tissue is. It was also shown that VIP binds to SSTR3 and that the binding of somatostatin and VIP is cross-competitive to primary tumor cells.
- the binding of peptides to tumor receptors can not only be used to diagnose the location of tumors and their metastases.
- the 111 In-DTPA (D) Phe 1 octreotide used for diagnostic purposes has already been used in high doses as a receptor ligand for targeted radiotherapy.
- EP 0 714 911 A2 shows that a conjugate of an octapeptide with the common name octreotide and a macrocyclic chelator 1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' -tetraacetic acid (DOTA ), a radionuclide can complex so that it can be used in vivo for the therapy of tumors.
- This patent is limited to the therapeutic use of said substance.
- Octreotide only binds to some of the high affinity somatostatin 14 subtype receptors that have now been found.
- 111 In-DTPA- (D) Phe 1 -octreotide is also taken up in kidney, liver and spleen, which leads to an unnecessarily high radiation exposure of these organs.
- the invention is based on the object of creating a carrier molecule of the type mentioned at the outset which has the broadest possible somatostatin 14 receptor subtype recognition profile (hSSTR2-5) and has little stress on healthy body tissue and thus has better biodistribution.
- the effect would be a higher dose in the tumor tissue and a lower radiation exposure of the healthy tissue, especially of the spleen and kidney.
- the invention solves this problem in that as a somatostatin 14 agonist
- (D) ßNal-Cys-Tyr- (D) Trp-Lys-Val-Cys-Thr-NHR 1 (I) is bound to the macrocyclic chelating agent via its C or N terminus (example 1).
- This octapeptide is known under the name "lanreotide", but not in connection with a macrocyclic chelating agent.
- the peptide of the invention can be labeled with salts of radionuclides in metal-free buffers at elevated temperature (Examples 2-4). The high labeling efficiency is that The peptide of the invention forms a stable chelate with In, 90 Y or 67/68 Ga under physiological conditions.
- these chelates are in human serum or in the presence of a 10,000-fold excess of diethylenetriamine-pentaacetic acid (DTPA)
- DTPA diethylenetriamine-pentaacetic acid
- the peptide of the invention also forms stable chelates with rare earths ( 161 Tb, 153 Sm, etc.).
- EP 0 714911A2 covers the use of DOTA octreotide in a form labeled with 90 Y or 161 Tb and with radionuclides which emit alpha, beta particles or Auger electrons.
- radionuclides which capture an isomeric transition by making (such as 99m Tc)
- electrons ie 67 Ga, In ⁇ n
- positron proposed 68 Ga
- the peptide of the invention can be based on
- 1 1 1 1 ⁇ 7 / ⁇ R must be marked stable with In or Ga and is therefore not only suitable for therapy, but also for use as a radio diagnostic agent (both for SPECT and PET).
- the octapeptide according to the invention has a broad somatostatin receptor recognition profile.
- the radioactively labeled peptide with K values in the low nanomolar range binds to SSTR2, SSTR3, SSTR4 and also SSTR5 (Example 5).
- the radiolabeled ligand also shows high affinity binding for PC3 and DU145 prostate cancer cells, PANC1 and HT29 adenocarcinoma cells, A431 epithelial cells, ZR75-1 and T47D breast cancer cells and for 518A2 melanoma cells.
- the peptide also binds to a number of primary tumors such as breast cancer, melanoma, adenocarcinoma, lymphoma, liver cell tumor, thyroid tumor and various neuroendocrine tumors.
- the most important somatostatin receptor expressed in the tumor appears to be SSTR3, which is a target R for the peptide of the invention (Example 6).
- SSTR3 is a target R for the peptide of the invention (Example 6).
- the experiments have shown that the binding behavior of the octapeptide on the one hand and that of the octapeptide associated with the macrocyclic chelating agent on the other hand is somewhat was different, which may be due to the different lipophilicity of the octapeptide in the unbound or bound state.
- heavy metal atoms or metal ions with atomic numbers 20-32, 42-44, 45 and 57 to 83 can also be used for the medical imaging diagnosis.
- Paramagnetic metals or metal ions with atomic numbers 21-29, 42, 44 or 57-71, in particular Gd 3+ , Mn 2+ or Dy 3+ can be used for a magnetic resonance display.
- Alkali, alkaline earth or transition metals or metal ions, in particular Na + , K + , Ca 2+ , Fe 2 + / 3 + , Zn 2+ and Mn 2+ can also be used for pharmaceutical purposes.
- the compound 1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' tetraacetic acid (DOTA) was advantageously used as the chelating agent.
- the conjugate resulting from Lanreotide and DOTA is relatively lipophilic and shows slower blood clearance and higher tumor accumulation than other somatostatin 14 analogues in humans. Due to the hydrophilicity of DOTA, the lipophilicity of the octapeptide used is reduced, which means that the tumors can be better displayed on the one hand, and on the other hand a lower absorption of this substance is achieved in the non-diseased organs, i.e. the non-target organs such as the spleen and kidney.
- the lu In-labeled peptide of the invention was directly compared to ⁇ ⁇ In-DTPA- (D) Phe 1 octreotide.
- intravenous application of the peptide of the invention (3 mCi, 6 nmol) compared to the lu In-DTPA- (D) Phe 1 -octreotide, there was a higher tumor uptake, a lower retention in the kidneys and a reduced uptake in the spleen (example 8th).
- the diagnosis as a radionuclide ⁇ n In or Ga 67/68 be bound to the chelating agent, which has the advantage that this radionuclide Gamma radiation emitted, which is suitable for diagnosis, with less radiation exposure for the body.
- the radionuclide 90 Y can be bound to the chelating agent, which is known to emit beta radiation which serves to destroy the tumor cells, the effect of the radionuclide essentially being restricted to the diseased cells due to the specific binding of the octapeptide ).
- a "cocktail" of radioisotopes (such as 86 Y-labeled peptide and 90 Y-labeled peptide) or radionuclides (such as U1 In -labeled peptide and 90 Y-labeled peptide) for simultaneous diagnosis and radiotherapy can also be produced.
- radioisotopes such as 86 Y-labeled peptide and 90 Y-labeled peptide
- radionuclides such as U1 In -labeled peptide and 90 Y-labeled peptide
- the radioactively labeled peptide can be used repeatedly to evaluate somatostatin receptor-positive tumor diseases or endocrinological diseases.
- DOTA l, 4,7,10-tetraazacyclododecane-N, N ⁇ N ', N'-tetraacetic acid
- BOC tert-butyloxycarbonyl 80 mg of DOTA, 74 mg of N-hydroxysuccinimide and 80 mg of [ ⁇ -Boc-Lys 5 ] lanreotide are dissolved in 15 mL H 2 O and 30 mL N, N-dimethylformamide. One hundred mg of NjN'-dicyclohexylcarbodiimide are added and the resulting solution is stirred at room temperature for 16 hours.
- the product, [ ⁇ -DOTA- (D) - ßNal 1 , ⁇ -Boc-Lys 5 ] -lanreotide, is isolated and isolated on a silica gel 60 column using methylene chloride: methanol: 50% acetic acid (9: 1: 0.125 - »7: 3: 1) cleaned as a solvent.
- the Boc-protected group is cleaved from the [ ⁇ -DOTA- (D) -ßNal 1 , ⁇ -Boc-Lys 5 ] - lanreotide product using 30 mL methylene chloride and 2 mL trifluoroacetic acid (30 minutes at room temperature).
- the peptide of the invention is dissolved in 0.2 mol / L ammonium acetate buffer (metal-free, pH 7) and incubated with m InCl 3 (carrier-free, Me ++ ⁇ 0.1 ⁇ g / mCi, ⁇ 1 ⁇ g / mL) in 0.05 mol / L HC1 .
- m InCl 3 carrier-free, Me ++ ⁇ 0.1 ⁇ g / mCi, ⁇ 1 ⁇ g / mL
- a ratio of 0.5 mCi ⁇ ⁇ In: 1 nmol DOTA lanotide is produced and the reaction mixture is boiled at 100 ° C. for 30 minutes. An aliquot is checked for purity by means of thin layer chromatography. The radiochemical purity of the product is typically> 99%. If it is less, the product is cleaned with reversed phase LC or HPLC.
- radioligand is taken up in a solution of 0.075 mol / L NaCl, 0.05 mol / 1 NHUOAc, 0.2 mol / L ascorbic acid and 0.1% human serum albumin and sterilized by filtration through a 0.2 ⁇ m membrane.
- Example 3 Radiolabeling of the peptide with 90 Y
- the labeled and unlabelled substance of the invention was examined in saturation studies and in competition studies in vitro for its binding to various tumor cells (primary tumors, immortal cells) and also to the somatostatin receptor subtypes SSTR1-SSTR5.
- the subtype receptors were expressed on COS-7 cells using cDNA samples.
- Comparative studies were carried out with other somatostatin receptor agonists.
- 125 I-Tyr n -somatostatin-14 was also used as the radioligand.
- the data below clearly show that there is a significant difference in binding to the SSTR3 as well as the SSTR4 between the peptide of the invention and the n ⁇ In-DTPA- (D) Phe 1 -ctreotide.
- Receptor subtypes hSSTR1 to hSSTR ⁇ Receptor subtypes hSSTR1 to hSSTR ⁇ .
- Gastric cancer colon and rectal cancer
- Skin cancer Breast cancer
- Pancreas thyroid tumors, lymphomas, lung cancer, various neuroendocrine tumors such as carcinoids, gastrinomas, pheochromocytomas; Prostate cancer, glandular cancer, and the daughter tumors of these tumors.
- the biodistribution and dosimetry of ⁇ n In-labeled peptide of the invention was compared with the biodistribution and dosimetry of 1 I 1 In-DTPA (D) Phe 1 octreotide.
- Approx. 3 mCi of one or the other substance was administered intravenously at intervals of approx. 6-8 weeks.
- blood samples, urine samples and stool samples were examined for their radioactivity at different times.
- the gamma radiation was recorded using a gamma camera, the measuring points being applied up to 144 hours after application.
- the gamma camera images included whole-body images in anterior and posterior projection, as well as single-photon emission tomography (SPET) for precise tumor localization and size estimation.
- SPET single-photon emission tomography
- FIG. 1A From FIG. 1A it can be seen that the substance of the invention is excreted from the body somewhat more slowly than 111 In-DTPA- (D) Phe 1 octreotide.
- the uptake of the peptide of the invention in the tumor is significantly higher in direct comparison (see FIG. 1B). It is also important that, compared to III In-DTPA- (D) Phe'-octreotide, the peptide of the invention a priori shows a significantly lower uptake in the spleen (FIG. IC) and kidneys (FIG. 1D). This biodistribution forms the basis for effective radiotherapy with the 90 Y-labeled peptide of the invention, since these organs are critical to radiation exposure. literature
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- Health & Medical Sciences (AREA)
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- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
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- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002284581A CA2284581A1 (fr) | 1997-03-14 | 1998-03-12 | Ligands radiomarques du recepteur de la somatostatine pour le diagnostic et la theraphie |
AU66021/98A AU6602198A (en) | 1997-03-14 | 1998-03-12 | Radiolabelled somatostatin receptor ligands for diagnosis and therapy |
EP98907750A EP0975670A1 (fr) | 1997-03-14 | 1998-03-12 | Ligands radiomarques du recepteur de la somatostatine pour le diagnostic et la theraphie |
JP53994098A JP2001515494A (ja) | 1997-03-14 | 1998-03-12 | 診断及び治療のための放射能標識したソマトスタチン受容体リガンド |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT0045197A AT405906B (de) | 1997-03-14 | 1997-03-14 | Radiomarkierte somatostatin rezeptor-liganden zur diagnose und therapie |
ATA451/97 | 1997-03-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998041540A1 true WO1998041540A1 (fr) | 1998-09-24 |
Family
ID=3490974
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/AT1998/000065 WO1998041540A1 (fr) | 1997-03-14 | 1998-03-12 | Ligands radiomarques du recepteur de la somatostatine pour le diagnostic et la theraphie |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP0975670A1 (fr) |
JP (1) | JP2001515494A (fr) |
AT (1) | AT405906B (fr) |
AU (1) | AU6602198A (fr) |
CA (1) | CA2284581A1 (fr) |
WO (1) | WO1998041540A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001051095A2 (fr) * | 2000-01-13 | 2001-07-19 | Schering Aktiengesellschaft | Derives paramagnetiques de type dota, agents pharmaceutiques les contenant, procedes permettant de les preparer et leur utilisation pour l'imagerie par resonance magnetique de necroses et de l'infarctus |
US6358491B1 (en) | 1999-08-27 | 2002-03-19 | Berlex Laboratories, Inc. | Somatostatin analogs |
WO2003014157A2 (fr) * | 2001-08-03 | 2003-02-20 | Bracco Imaging S.P.A. | Conjugues peptidiques, leurs derives a complexes metalliques et leur utilisation dans l'imagerie par resonance magnetique (irm) |
EP1358890A1 (fr) * | 2002-05-03 | 2003-11-05 | BioSynthema, Inc | Dérivés benzothiényle de la somatostatine, sélectifs pour certains récepteurs de la somatostatine |
EP1416971A1 (fr) * | 1999-08-16 | 2004-05-12 | UAB Research Foundation | Imagerie de transfert genique et ses utilisations |
US7122622B2 (en) | 2002-04-16 | 2006-10-17 | Biosynthema Inc. | Peptide compounds having improved binding affinity to somatostatin receptors |
US10322191B2 (en) | 2014-06-30 | 2019-06-18 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0588754A1 (fr) * | 1992-09-15 | 1994-03-23 | The Ohio State University Research Foundation | Application de la cinétique de peptide/récepteur de cellule en utilisant des congénères de samotastatine radiomarquée en cours de la détection et différenciation de tissu néoplastique in situ et in vivo |
EP0714911A2 (fr) * | 1994-09-06 | 1996-06-05 | Sandoz Ltd. | analogues de somatostatine contenant des agents de chélation et leur compositions radio-marquées |
WO1996039161A1 (fr) * | 1995-06-05 | 1996-12-12 | The Administrators Of The Tulane Educational Fund | Analogues de la somatostatine contenant plusieurs de tyrosines |
-
1997
- 1997-03-14 AT AT0045197A patent/AT405906B/de not_active IP Right Cessation
-
1998
- 1998-03-12 EP EP98907750A patent/EP0975670A1/fr not_active Withdrawn
- 1998-03-12 JP JP53994098A patent/JP2001515494A/ja active Pending
- 1998-03-12 CA CA002284581A patent/CA2284581A1/fr not_active Abandoned
- 1998-03-12 AU AU66021/98A patent/AU6602198A/en not_active Abandoned
- 1998-03-12 WO PCT/AT1998/000065 patent/WO1998041540A1/fr not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0588754A1 (fr) * | 1992-09-15 | 1994-03-23 | The Ohio State University Research Foundation | Application de la cinétique de peptide/récepteur de cellule en utilisant des congénères de samotastatine radiomarquée en cours de la détection et différenciation de tissu néoplastique in situ et in vivo |
EP0714911A2 (fr) * | 1994-09-06 | 1996-06-05 | Sandoz Ltd. | analogues de somatostatine contenant des agents de chélation et leur compositions radio-marquées |
WO1996039161A1 (fr) * | 1995-06-05 | 1996-12-12 | The Administrators Of The Tulane Educational Fund | Analogues de la somatostatine contenant plusieurs de tyrosines |
Non-Patent Citations (2)
Title |
---|
PLESS J ET AL: "(111IN-DTPA-D-PHE1)-OCTREOTIDE (SDZ 215-811) TO IMAGE SOMATOSTATIN RECEPTOR POSITIVE TUMORS", PEPTIDES: CHEMISTRY AND BIOLOGY, CAMBRIDGE, JUNE 16 - 21, 1991, no. SYMP. 12, 16 June 1991 (1991-06-16), SMITH J A;RIVIER J E, pages 106 - 108, XP000371753 * |
WECKBERGER G. ET AL: "SOMATOSTATIN ANALOGS FOR DIAGNOSIS AND TREATMENT OF CANCER", PHARMACOLOGY AND THERAPEUTICS, vol. 60, no. 2, 1993, pages 245 - 264, XP002072560 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1416971A1 (fr) * | 1999-08-16 | 2004-05-12 | UAB Research Foundation | Imagerie de transfert genique et ses utilisations |
EP1416971A4 (fr) * | 1999-08-16 | 2004-05-12 | Uab Research Foundation | Imagerie de transfert genique et ses utilisations |
US6358491B1 (en) | 1999-08-27 | 2002-03-19 | Berlex Laboratories, Inc. | Somatostatin analogs |
WO2001051095A3 (fr) * | 2000-01-13 | 2002-11-28 | Schering Ag | Derives paramagnetiques de type dota, agents pharmaceutiques les contenant, procedes permettant de les preparer et leur utilisation pour l'imagerie par resonance magnetique de necroses et de l'infarctus |
WO2001051095A2 (fr) * | 2000-01-13 | 2001-07-19 | Schering Aktiengesellschaft | Derives paramagnetiques de type dota, agents pharmaceutiques les contenant, procedes permettant de les preparer et leur utilisation pour l'imagerie par resonance magnetique de necroses et de l'infarctus |
DE10002939C1 (de) * | 2000-01-13 | 2001-09-20 | Schering Ag | Paramagnetische DOTA-Derivate, Verfahren zu ihrer Herstellung und ihre Verwendung für die Herstellung von pharmazeutischen Mitteln |
WO2003014157A2 (fr) * | 2001-08-03 | 2003-02-20 | Bracco Imaging S.P.A. | Conjugues peptidiques, leurs derives a complexes metalliques et leur utilisation dans l'imagerie par resonance magnetique (irm) |
WO2003014157A3 (fr) * | 2001-08-03 | 2003-11-13 | Bracco Imaging Spa | Conjugues peptidiques, leurs derives a complexes metalliques et leur utilisation dans l'imagerie par resonance magnetique (irm) |
US7122622B2 (en) | 2002-04-16 | 2006-10-17 | Biosynthema Inc. | Peptide compounds having improved binding affinity to somatostatin receptors |
EP1358890A1 (fr) * | 2002-05-03 | 2003-11-05 | BioSynthema, Inc | Dérivés benzothiényle de la somatostatine, sélectifs pour certains récepteurs de la somatostatine |
WO2003092744A3 (fr) * | 2002-05-03 | 2004-04-01 | Biosynthema Inc | Compose peptidique presentant une meilleure affinite de liaison avec les recepteurs de la somatostatine |
US10322191B2 (en) | 2014-06-30 | 2019-06-18 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
US10624967B2 (en) | 2014-06-30 | 2020-04-21 | Tarveda Therapeutics, Inc. | Targeted conjugates and particles and formulations thereof |
US11458206B2 (en) | 2014-06-30 | 2022-10-04 | Tva (Abc), Llc | Targeted conjugates and particles and formulations thereof |
Also Published As
Publication number | Publication date |
---|---|
CA2284581A1 (fr) | 1998-09-24 |
ATA45197A (de) | 1999-05-15 |
AU6602198A (en) | 1998-10-12 |
EP0975670A1 (fr) | 2000-02-02 |
JP2001515494A (ja) | 2001-09-18 |
AT405906B (de) | 1999-12-27 |
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