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Diagnostic or therapeutic somatostatin or bombesin analog conjugates and uses thereof

By linking bioactive peptides with connectors to maintain their activity and utilizing hydrophilic polymers to improve distribution, the problems of therapeutic toxicity and radiolabeling in tumor imaging are solved, enabling tumor-specific targeting and rapid excretion, thereby improving therapeutic efficacy and reducing toxicity.

Inactive Publication Date: 2005-03-02
THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Furthermore, although iodination and astatine (see Vaidyanathan et al., Nucl. Med. Biol. 27(4): 329-337, 2000) are used in imaging and in possible adjuvant therapy with increased expression of factors specific for bioactive peptides Holds great promise for related diseases, but the problem is that currently available methods for labeling many peptide analogs are problematic
A further problem is the loss of binding affinity when iodination of tyrosines close to the pharmacophore

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0115] Preparation of the Dicesium Salt of (+)-Methotrexate (Methotrexate)

[0116] Methotrexate (0.75 mmol) was dissolved in 200 ml of water to which cesium bicarbonate (1.5 mmol) was added. The yellow solution was stirred for 4 hours, evaporated under reduced pressure, and the oily residue was dissolved in ethanol. Evaporate 3 times from absolute ethanol to remove residual water.

Embodiment 2

[0118] 2-Bromo-acetyl-D-tert-butyl-Ser-D-tert-butyl-Ser-D-tert-butyl-Ser-D-tert-butyl-Ser-D-tert-butyl-Ser-ε-tert-butyl Butoxycarbonyl-Lys-D-tert-Butyl-Tyr-D-tert-Butyl-Tyr-S-Trityl-Cys-Phe-D-Trp-ε-tert-Butoxycarbonyl-Lys-tert-Butyl Preparation of base-Thr-S-trityl-Cys-tert-butyl-Thr-Rink-amide-resin

[0119]Rink-amide MBHA polystyrene resin (0.25 mmol) [4-(2',4'-dimethoxyphenyl-Fmoc-(aminomethyl)phenoxyacetamido-norleucyl-methyl Diphenylmethylamine resin, 100-200 mesh, Novabiochem, San Diego, CA)] was added to the reaction vessel of a CS136 automated peptide synthesizer (CS Bio, Inc., San Carlos, CA) and swelled in DMF for approx. 1 hour. The resin was filtered and an excess of 20% piperidine in DMF was added and mixed for 2 minutes. The resin was filtered and again excess 20% piperidine was added and mixed for 20 minutes to ensure complete removal of the resin's Fmoc groups. After deprotection, the resin was washed 4 times with DMF, then the first protected amino acids, ...

Embodiment 3

[0122] Methotrexate-acetyl-D-tert-butyl-Ser-D-tert-butyl-Ser-D-tert-butyl-Ser-D-tert-butyl-Ser-D-tert-butyl-Ser-ε-tert-butyloxy ylcarbonyl-Lys-D-tert-butyl-Tyr-D-tert-butyl-Tyr-S-trityl-Cys-Phe-D-Trp-ε-tert-butoxycarbonyl-Lys-tert-butyl- Preparation of Thr-S-trityl-Cys-tert-butyl-Thr-Rink-amide-resin

[0123] The dicesium salt of methotrexate (0.75 mmol) prepared in Example 1 was dissolved in DMSO and added to the peptidyl resin prepared in Example 2 (0.25 mmol) in a round bottom flask. While heating in a water bath (40°C, 18 hours), the suspension was mixed gently, filtered and washed with copious DMF followed by methanol. After the final filtration, the derivatized resin was air dried overnight.

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Abstract

Disclosed are peptide agents and uses thereof that are analogs of biologically active peptides such as somatostatin and bombesin. The compounds of the invention have the general formula X-Y-Z-Q, where X is a cytotoxic agent, therapeutic agent, detectable label or chelating group, and Q is a biologically active peptide. In peptide agents of the invention Y is optionally a hydrophilic polymer or peptide, and Z is a linking peptide bonded to Q at the amino terminus of Q, having two, three, four, or five, amino acid residues selected to link X to Q, while retaining the biological activity of Q. Methods of using these peptide agents in the diagnosis and treatment of diseases are also disclosed.

Description

Field of Invention [0001] The present invention relates to somatostatin and bombesin analogs and uses thereof for targeting compounds useful in the detection, diagnosis or treatment of disease. Background technique [0002] The toxic side effects of many treatments, including standard treatments for cancer, effectively limit the amount of agents that can be administered to a patient. Additionally, many agents cause organ-specific toxicity, further limiting the dose that can be delivered to target tissues. For example, the cardiotoxicity of many members of the anthracycline family reduces the maximum therapeutic dose available for this group of chemotherapeutic agents. Targeted drug delivery of various detectable or therapeutic agents can reduce toxicity in normal tissues and increase the efficacy of treatments by providing concentrated local effects in specific tissues. [0003] Somatostatin, bombesin, or other bioactive peptide analogs have been used to detect tumor cells...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61BA61K47/48A61B1/00A61KA61K31/165A61K31/4745A61K31/519A61K38/00A61K38/08A61K38/10A61K38/31A61K47/42A61K49/00A61K51/00A61K51/08A61P1/00A61P9/00A61P11/00A61P13/08A61P15/00A61P25/00A61P27/02A61P35/00C07K7/06C07K7/08C07K14/655
CPCA61K51/083A61K47/48176A61K47/48215A61K47/48246A61K51/088A61K47/60A61K47/58A61K47/64A61P1/00A61P11/00A61P13/08A61P15/00A61P25/00A61P27/02A61P35/00A61P9/00A61K38/16
Owner THE ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND