WO2020031136A1 - Protéines de type théranostiques sanps conjuguées à des peptides de ciblage de l'intégrine et du pmsa et thérapie du cancer de la prostate - Google Patents

Protéines de type théranostiques sanps conjuguées à des peptides de ciblage de l'intégrine et du pmsa et thérapie du cancer de la prostate Download PDF

Info

Publication number
WO2020031136A1
WO2020031136A1 PCT/IB2019/056768 IB2019056768W WO2020031136A1 WO 2020031136 A1 WO2020031136 A1 WO 2020031136A1 IB 2019056768 W IB2019056768 W IB 2019056768W WO 2020031136 A1 WO2020031136 A1 WO 2020031136A1
Authority
WO
WIPO (PCT)
Prior art keywords
sanps
composition according
ligand
nanoparticles
particles
Prior art date
Application number
PCT/IB2019/056768
Other languages
English (en)
Inventor
Igor GENNADIEVICH SIVOV
Andrey OLEGOVICH TATARENKO
Olafs SLŪTIŅŠ
Original Assignee
Integrative Medicine Clinic, Sia
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Integrative Medicine Clinic, Sia filed Critical Integrative Medicine Clinic, Sia
Publication of WO2020031136A1 publication Critical patent/WO2020031136A1/fr

Links

Classifications

    • 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
    • A61K47/69—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
    • A61K47/6901—Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001193—Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR
    • A61K39/001195—Prostate specific membrane antigen [PSMA]
    • 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
    • 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
    • A61K47/66—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 the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • 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
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1203—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules in a form not provided for by groups A61K51/1206 - A61K51/1296, e.g. cells, cell fragments, viruses, virus capsides, ghosts, red blood cells, viral vectors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/525—Virus
    • A61K2039/5258—Virus-like particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10023—Virus like particles [VLP]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/10011—Adenoviridae
    • C12N2710/10041—Use of virus, viral particle or viral elements as a vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32123—Virus like particles [VLP]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2770/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses positive-sense
    • C12N2770/00011—Details
    • C12N2770/32011—Picornaviridae
    • C12N2770/32111—Aphthovirus, e.g. footandmouth disease virus
    • C12N2770/32141—Use of virus, viral particle or viral elements as a vector
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2795/00—Bacteriophages
    • C12N2795/00011—Details
    • C12N2795/18011—Details ssRNA Bacteriophages positive-sense
    • C12N2795/18111—Leviviridae
    • C12N2795/18123—Virus like particles [VLP]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2795/00—Bacteriophages
    • C12N2795/00011—Details
    • C12N2795/18011—Details ssRNA Bacteriophages positive-sense
    • C12N2795/18111—Leviviridae
    • C12N2795/18141—Use of virus, viral particle or viral elements as a vector

Definitions

  • the invention applies to the field of medicine and molecular biology and may be used for long-lasting therapy of cancer with adjuvant effect using SANPs-theranostics (SANPs - self assembled nano particles).
  • SANPs-theranostics SANPs-theranostics
  • researchers should develop perspective technologies of creation of new SANPs-theranostics and hold their pre-clinical and clinical trials, results of theranostics usage prove it.
  • Cancer therapy largely depends on the introduction of cytotoxic drugs, which affect both cancerous and healthy cells due to limited selectivity of the drugs and wide spread of cytotoxic molecules throughout the body. Integration of targeted therapy and diagnostics have created a new field of treatment called theranostics.
  • the main task of the discipline is the potential ability to track the progress of target delivery of drugs or other pharmaceutically acceptable derivatives using molecular imaging in the study subjects.
  • SANPs "theranostic-alike" drug was held as as AbraxaneTM or TaxolTM which are used in medical diagnostics, but the cargo SANPs are salts of monovalent thallium isotopes.
  • This invention relates to the method of making SANPs-theranostics with adjuvant effect turned to therapy and diagnostic of prostate cancer and possible ways of usage.
  • a composition of self assembled nanoparticles comprising: a) a ligand of conjugation binding to membrane antigen of prostate (PSMA); b) a ligand of conjugation binding to integrin anb3, c) a biologically active agent; and d) nanoparticles.
  • PSMA membrane antigen of prostate
  • integrin anb3
  • a biologically active agent a biologically active agent
  • nanoparticles examples of the PSMA, anb3 targeted nanoparticles are disclosed in US patent application publication No. US 2014/023591 and in the publication of Hassan M. Shallal et. al.
  • Peptide (Gly) 3 - iRGD was prepared by automatic solid-phase synthesis from 9-fluorenyl (methoxycarbonyl) - amino acids (ChemPep -USA), (433A synthesizer, Applied Biosystems, Fast Moc Method).
  • the formation of S-S-bridges was performed by oxidation 12 as described in the publication of Andreau [Andreu D., Alberico F., Sole N.A., Munson M.C., Ferrer M., Barany G.// Methods Mol.
  • the peptide was purified by reverse phase HPLC (Cl 8 column Triart, 2lx250mm, 10 pm, YMC, Switzerland, workstation Agilent 1100, Agilent, USA) in a concentration gradient CH3CN (BioSolve, Israel) in water in the presence of 0.1% acetic acid.
  • Reversed-Phase Analytical HPLC C18 column Triart, 2. lx50mm, 2.0pm (YMC), workstation Agilent 1200 with UV - and mass spectrometric detection, the purity of peptide drug is not less than 95%.
  • the ligand of conjugation binding to PSMA is attached to a nanoparticle, wherein a biologically active agent is encapsulated in the nanoparticle or wherein the ligand of conjugation binding to integrin anb3 is attached to the nanoparticle.
  • the therapeutic nanoparticle of the drug is a capsid of MS2 bacteriophage (total particle size
  • thallium salts Tl +
  • the capsid is modified: ligands, iRGD peptides are attached to its surface, which ensure the capture of nanoparticles by receptors of target tumor cells.
  • the experimental data demonstrated the feasibility of replacing the bacteriophage MS2 capsid used in the drug with the capsid of another virus, which expands the possibilities of technology development and ensures non-infringement.
  • the use of thallium salts as a therapeutic agent is associated with their high toxicity and the absence of the fundamental possibility of the development of drug resistance against these compounds.
  • the amount of thallium (10 ng) included in one therapeutic dose of the drug / biotechnology is extremely small to have a toxic effect on the body in general. For instance:
  • the dose of the isotope ⁇ 01 Tl for radionuclide diagnostics is 0.10 - 0.15 ng / kg;
  • Biotechnology has a cytotoxic effect. Its use entails a risk of metabolic disorders called tumor lysis syndrome (TLS). These disorders arise as a result of the rapid destruction of tumor cells and an abrupt release of intracellular ions, nucleic acids, proteins and metabolites thereof into the extracellular environment, which is accompanied by increased levels of uric acid, potassium, phosphorus and urea, as well as a decrease in calcium level in the blood.
  • TLS tumor lysis syndrome
  • the biologically active agent is monovalent thallium compound, preferably thallium salt.
  • the composition may be used in treatment of cancer, especially prostate cancer, and in treatment of solid tumors.
  • the biologically active agent may be selected from a group consisting of: actinomycin D; ametantrone; 9-aminocamptothecin; aminoglutethimide; amsacrine; anastrozole; antagonists of purine and pyrimidine; anthracyclines; aromatase linkers; asparaginase; antiestrogens; bendamustine; bexarotene; biolimus A9; bleomycin; buserelin; busulfan; calicheamicin; camptothecin; derivatives of camptothecin; capecitabine; carboplatin; carmustin; chlorambucil; cisplatin; cladribine; cyclophosphamide; cytarabine; cytosine- arabinoside; alkylating cytostatics; dacarbazine; dactinomycin; daunorubicin; 5'-deoxy-5- fluorouridine;, docetaxel
  • the ligand of conjugation binding to PSMA is an organic molecule from class of inhibitors of enzymatic activity, and the nanoparticle contains a radioactive probe in concentration from 10 7 to 10 9 .
  • the ligand of conjugation binding to PSMA is heterodimeric glutamate urea or N -acetyl -L-aspartyl -L-glutamate .
  • the nanoparticles have a diameter in the range from about 30 nm to about 50 nm.
  • the composition of the nanoparticles may has a value of IC50 in the range of from about 10 6 to about 10 9 .
  • the compositions of the nanoparticles may have a value of IC50 in the range from about 5 x 10 6 to about 5 x 10 9 .
  • a method for the treatment or prevention of tumor of a subject including the stage of introduction to the subject an aforementioned composition, so that the introduction of the composition of the nanoparticles is effective for treatment or prevention of the tumor.
  • the tumor is a prostate cancer or metastasis of prostate cancer.
  • composition is administered to the subject for therapy purposes.
  • the composition is administered simultaneously or part thereof consecutively.
  • the subject may be a human.
  • a pharmaceutical composition may contain the aforementioned composition and a pharmaceutically suitable excipient.
  • the present invention provides a modification of any SANPs to obtain the SANPs-"theranostic-alike" medication with adjuvant effect and enhancing of the effectiveness of therapy and diagnosis of prostate cancer.
  • the invention provides the ability of long-lasting usage of SANPs- theranostics in therapy and diagnosis of prostate cancer.
  • this invention provides the ability of long-lasting usage of any described to date SANPs-theranostics in gene therapy.
  • any described embodiment of this invention unless otherwise noted or required is a SANPs-theranostic, including drugs with display that has different nature, for example, from low molecular weight compounds or fragments of nucleic acids (aptamers).
  • this invention provides the ability of long-lasting usage of any described to date SANPs-theranostics in oncotherapy and their usage in combination with gene therapeutic SNAPs-theranostics which have similar structure.
  • this invention provides antigens which have biological activity after application of SANPs-theranostics, which use antigens specific to prostate cancer (e.g. but not exclusively, mutant ras-peptides, mucin 1 or p53).
  • compositions e.g., but not only vaccines Sipuleucel-T (Provenge) or PROSTVAC
  • pharmaceutical compositions containing SANPs- theranostics.
  • this invention provides compositions of SANPs-theranostics with antigens specific to prostate cancer (e.g. but not exclusively, mutant ras-peptides, mucin-l or p53 or vaccine Sipuleucel-T (Provenge) or PROSTVAC).
  • kits, arrays containing any product in combination with SANPs- theranostics and antigens specific to prostate cancer e.g. but not exclusively, mutant ras- peptides, mucin 1 or p53.
  • this invention provides a method of treating prostate cancer or suppressing tumor growth foreseeing the introduction of individual compositions that contain SANPs-theranostics with directing ligands and filled with cytostatic compounds and isotopes: technetium-99, iodine-l23 or -131, thallium-20l, gallium-67, fluorine-l8, indium- 111, but not exclusively.
  • this invention provides the therapeutic method and composition for the treatment or alleviate prostate cancer or inflammatory processes which are mediated by viruses and expressing cells of prostate.
  • this invention provides a method of diagnosis of stated above pathological processes using SANPs-theranostics foreseeing "carrier” of quantum dots (compounds of monovalent thallium with selenium).
  • this invention provides a diagnostic or prognostic kit that contains the components described above using the SANPs-theranostics filled with diagnostic metabolites that are specific for tumor cells of prostate cancer and isotopes (radionuclide theranostics using technicia-99, iodine-l23 and -131, thallium-20l, gallium-67, fluorine-l8, indium-l 11, but not exclusively) or quantum dots (compounds of monovalent thallium with selenium).
  • this invention provides a method of testing possible antitumor agents or medications for prostate cancer therapy by trial which indicates ability or its lack of the medication or agent to inhibit intracellular pathological processes.
  • Fig. 1 The scheme for obtaining the structure of S ANPs, which, by way of example, are chemically modified MW-particles with covalently attached peptides PSA141 (PSA-l FLTPKKLQCV), PSA146 (P-2 KLQCVDLHV) and PSA154 (PSA-3 VISNDVCAQV) and GRFLTGGTGRLLRIS .
  • Fig. 2 Forming of antibodies of different specificity in rabbits in response to the introduction of two drugs of bacteriophage MS2 with covalently attached peptides PSA141 (PSA-l FLTPKKLQCV) under designation A in Fig. 2, PSA146 (P-2 KLQCVDLHV) under designation B in Fig. 2 and PSA154 (PSA-3 VISNDVCAQV) under designation C in Fig. 2, and phage MS2 with GRFLTGGTGRLLRIS under designation D in Fig. 2, but only one of which is filled with Tl + (average concentration is 2000 ions Tl + ).
  • PSA141 PSA-l FLTPKKLQCV
  • PSA146 P-2 KLQCVDLHV
  • PSA154 PSA-3 VISNDVCAQV
  • phage MS2 with GRFLTGGTGRLLRIS under designation D in Fig. 2, but only one of which is filled with Tl + (average concentration is 2000 ions Tl + ).
  • Fig. 3 Forming of reaction of delayed-type hypersensitivity as redness diameter in rabbits in response to introduction of two drugs of bacteriophage MS2 with covalently attached peptides PSA141 (PSA-l FLTPKKLQCV), PSA146 (P-2 KLQCVDLHV) and PSA154 (PSA-3 VISNDVCAQV) and phage MS2 with GRFLTGGTGRLLRIS, but only one of which is filled with approximate 2000 ions Tl + .
  • the photo of Fig. 3 shows the measure method for the area of allergic inflammation.
  • the schematic record of the area of the allergic reaction of delayed hypersensitivity skin relationship ratios (DHS; in mm) to the modifying BSA (bovine serum albumin) by the specified peptide epitope injection as well-known to those skilled is art.
  • DHS delayed hypersensitivity skin relationship ratios
  • Fig. 4 Forming of antibodies of different specificity in rabbits in response to introduction of two drugs: one is bacteriophage MS2 with covalently attached peptides PSA141 (PSA-l FLTPKKLQCV) under designation E in Fig. 4, PSA146 (P-2 KLQCVDLHV) under designation F in Fig. 4 and PSA154 (PSA-3 VISNDVCAQV) filled with TINO3 (average concentration is 2000 ions Tl + ) under designation G in Fig. 4, and the other are particles of ferritin with GRFLTGGTGRLLRIS under designation H in Fig. 4.
  • PSA141 PSA-l FLTPKKLQCV
  • PSA146 P-2 KLQCVDLHV
  • PSA154 PSA-3 VISNDVCAQV
  • TINO3 average concentration is 2000 ions Tl +
  • G in Fig. 4 and the other are particles of ferritin with GRFLTGGTGRLLRIS under designation H in Fig. 4.
  • Figure 5 Forming of the reaction of delayed-type hypersensitivity in rabbits in response to introduction of two drugs: one is bacteriophage MS2 with covalently attached peptides PSA141 (PSA-l FLTPKK-LQCV), PSA146 (P-2 KLQCVDLHV) and PSA154 (PSA-3 VISNDVCAQV) filled with TINO3 (average concentration is 2000 ions Tl + ) and the other are particles of ferritin with GRFLTGGTGRLLRIS.
  • DHS delayed hypersensitivity skin relationship ratios
  • BSA bovine serum albumin
  • Fig. 6 The formation of antibodies of different specificity in rabbits in response to introduction of drugs: one are particles of bacteriophage MS2, filled with TINO3 (average concentration is 2000 ions Tl + ) under designation I in Fig. 6 and the other particles of ferritin with PSA141 peptides (PSA-l FLTPKK-LQCV) under designation J in Fig. 6, PSA146 (P- 2 KLQCVDLHV) under designation K in Fig. 6, PSA154 (PSA-3 VISNDVCAQV) under designation L in Fig. 6 and GRFLTGGTGRLLRIS under designation M in Fig. 6.
  • PSA-l FLTPKK-LQCV the other particles of ferritin with PSA141 peptides
  • PSA146 P- 2 KLQCVDLHV
  • K in Fig. 6 PSA154 (PSA-3 VISNDVCAQV) under designation L in Fig. 6
  • GRFLTGGTGRLLRIS under designation M in Fig. 6.
  • Fig. 7 Forming of reaction of delayed-type hypersensitivity in rabbits in response to introduction of two drugs: one is particle of a bacteriophage MS2, filled with TINO3 (average concentration is 2000 ions Tl + ) and the other are particles of ferritin with PSA141 peptides (PSA-l FLTPKK-LQCV), PSA146 (P-2 KLQCVDLHV), PSA154 (PSA-3 VISNDVCAQV) and GRFLTGGTGRLLRIS.
  • DHS delayed hypersensitivity skin relationship ratios
  • BSA bovine serum albumin
  • Fig. 9 Therapeutic efficacy of chemically modified bacteriophage MS2 bacteriophage particles, VLP FMDV, AVV virus or ferritin with covalently attached peptides PSA141 (PSA-l FLTPKK-LQCV), PSA146 (P-2 KLQCVDLHV), PSA154 (PSA-3 VISNDVCAQV) and GRFLTGGTGRLLRIS filled with TINO3 (average concentration is 2000 ions Tl + ) in Nude PC3 -xenograft mice.
  • the ratio tumor sizes measurement with Leica Application Suite Live Image Builder for Nude mouse are well-known to those skilled in the art.
  • This invention provides new methods of obtaining SANPs-theranostics which can be long term used for treatment of prostate cancer with adjuvant effect. But adjuvant effect is only to the antigens of the tumor.
  • As a filling can be used different monovalent thallium compounds known as salts of metal, including radionuclides and also, perhaps, quantum dots, primarily, the complexes TlSe or Tl 2 Se.
  • the principle of creating SANPs-theranostics can be applied for diagnostics, for example, reservoirs of viral infections caused by a variety of viruses - causative agents.
  • AAV is an abbreviation for adeno-associated virus.
  • VLP FMDV is an abbreviation for virus-like particles (VLP) of foot-and-mouth disease virus (FMDV).
  • SANPs Self- Assembled Nano Particles
  • SANPs Self- Assembled Nano Particles
  • peptides which can form numerous nanostructures because there are many different types of interactions between links of the polypeptide chain, for example, electrostatic, hydrophobic, or due to forming of hydrogen bonds.
  • Peptide nanomaterials that are the result of self-assemblage into stable structures have potential application as tools for medication delivery and/or encapsulation.
  • SANPs of this invention are natural reservoirs that represent theirselves as natural virions of viruses and virus-like particles formed like virions but without nucleic acid which are empty virions and reservoirs formed by known natural proteins.
  • MMT-particles is SANPs, such as phage MS2, virus AAV, VLP FMDV and the particles of ferritin, but not only, filled with the pharmaceutically acceptable derivatives, such as salts of thallium, but not only.
  • iRGD is cyclic polypeptide containing L-arginine, glycine and L-aspartic acid (order in the polypeptide is shown).
  • this sequence (RGD sequence or RGD-peptide) is a common recognition element and protein-protein interaction of cellular proteins with integrins a n b3 and aib 5 .
  • RGD-containing peptides are often used in cell biology and biotechnology due to the property to specifically bind with the specified integrins.
  • Tl is the chemical symbol of thallium.
  • thallium (Tl) is referred as a salt of monovalent thallium or radioactive isotope or a component of complex compounds with selenium (Se).
  • Ras is a superfamily of Ras-proteins which are small GTPhases and it includes Ras, Rho, Arf, G-protein, Rab and Ran.
  • the Ras-superfamily includes more than a hundred structurally similar human proteins, there are more than ten human proteins of Ras. Ras are membrane- bound proteins engaged in one of the first steps of signal transmission from outside of the cell and, as a rule, regulate the reproduction of cells.
  • P53 is a transcription factor that regulates cell cycle and functions as a suppressor of malignancy.
  • PSMA is a specific membrane antigen of prostate. It is carboxypeptidase and is relatively unique in its ability to function as N-acetylated a-related dipeptidase and hydrolase g- glucamine (i.e. folate).
  • Polypeptide and “protein” are used interchangeably and mean any compound by a peptide bond the chain of amino acids, regardless of length. According to accepted in the biochemistry of designations of amino acids, peptide structure "KLQCVDLHV” means heteropolymer with the sequence of amino acid residues NH 2 - lysyl - leucyl - glutamyl - cysteyl - valyl - aspartyl - leucyl - histidyl - valyl - COOH.
  • A“covalent bond” is called compound atoms by using a common (shared between them) electron pairs. In this case, refers to the ability of atoms connect with other atoms.
  • atoms combine their electrons as if in common "piggy Bank" which is formed by atomic shells of individual atoms. This new wrapper has possibly completed the number of electrons and replaces the atoms of their own incomplete atomic shell.
  • carrier is SANPs nanoparticle with chemically modified surface and containing in its volume a cytostatic, or a pharmaceutically acceptable derivative.
  • ligand refers to PSMA acceptor.
  • a ligand is a chemical compound (often, but not always, a small molecule) that forms a complex with a particular biomolecule (most often a cell receptor, integrin). This binding occurs with forming of the so-called “coordination" donor-acceptor bond with polypeptides on the surface of SANPs-nanoparticles act as Lewis base, so they are donors of electronic pairs.
  • ligands may also be suitable targets for the SANPs-theranostic and such targets are also covered by the present invention.
  • enzymes PSMA like.
  • pharmaceutically acceptable derivative means any pharmaceutically acceptable salt, solvate, prodrug and/or their compounds according to the invention which when administered to the recipient, can provide (directly or indirectly) the cytotoxic action or its consequences.
  • pharmaceutically acceptable derivatives are recognized by the person skilled in the art without undue experimentation. Nevertheless, we make reference to the teaching of medicinal chemistry and the cure Burger's 5th Edition, Vol 1 : Principles and Practice, which is incorporated herein by reference to the extent to which such derivatives.
  • Preferred pharmaceutically acceptable derivatives are salts of heavy metals and containing organic compounds. Particularly preferred pharmaceutically acceptable derivatives are salts of thallium or platinum.
  • “Pharmaceutical compositions” are compositions that include a quantity (e.g., a unit dosage) of one or more described compounds together with one or more non-toxic pharmaceutically acceptable additives, including carriers, diluents and/or adjuvants, and optionally other biologically active ingredients. Such pharmaceutical compositions can be obtained by standard methods of pharmaceutical compositions, such as described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa. (19 edition).
  • Therapeutically effective dosages can be determined stepwise by combinations of approaches such as: (i) characterization of effective doses of the composition or compounds in the analyses carried out on cell cultures in vitro criteria of tumor growth and/or survival of cells as a testimony, followed by
  • subject means any animal, including mammals and particularly humans.
  • standard conditions of conjugation refers to the conditions of joining of the peptide (-s) that allow you to create a covalent bond between the peptide and the surface of the SANPs.
  • conjugation conditions with higher efficiency can be used to provide at least 85% of points on the surface of the carrier.
  • Quantum dots are nano-sized (less than 10 nm) probes with high quantum yield, high photostability and fluorescence emission ability. Energy of quantum dots can be transferred to the surrounding molecules of 0 2 that leads to formation of superoxide anion (radical) having a high cytotoxicity. Quantum dots can be synthesized in aqueous solutions and are obtained for specific targets in the pathological region.
  • Example 1 Obtaining of preparative quantities of SANPs.
  • IB Receiving of adeno-associated virus (AAV) and virus-like particles of FMDV (VLP FMDV) carried out in the laboratory of diseases of pigs (Federal Centre for animal health, Russia) according to protocols RF patents N°N° 2335542 and 2332233, respectively.
  • AAV adeno-associated virus
  • VLP FMDV virus-like particles of FMDV
  • Example 2 Filling SANPs (bacteriophage MS2, virus AAV, VLP FMDV and ferritin particles) of thallium salts (receiving MBT-particles) and control of these processes.
  • SANPs bacteria MS2, virus AAV, VLP FMDV and ferritin particles
  • the grid was subjected to contrast staining in uranyl acetate and analyzed by for 35 min and washed three times by immersing the grids in lead citrate for 7 min.
  • the Mesh was observed on transmission electron microscope JEM-1400 operating at an accelerating voltage of 80 kV using magnification > ⁇ 8000.
  • the peptide was removed from resin by treatment with a mixture of trifluoroacetic acid, tri-(isopropyl)-silane, 3,6- dioxa-l,8-octanedithiol and water (in volume ratio of 94: 1 :2,5:2.5) and precipitated methyl tert-butyl ether.
  • Precipitate of the peptide was dissolved in 10% aqueous acetonitrile with 0.1% trifluoroacetic acid, and the resulting solution was subjected to purification by HPLC on the column Zorbax SB-C8, 21,2x250 mm, 7 pm in a concentration gradient of acetonitrile in 0.1% aqueous solution of trifluoroacetic acid.
  • the fraction containing the target peptide were collected and evaporated under vacuum, and then carried out the removal of the protective Acm groups of cysteine residues with simultaneous disulfide bridge formation by a known method (Fernando Albericio et al.
  • Example 5 The definition of sensitivity of endothelial cell cultures and cultures of prostate cancer cells to modified MBT-particles (e.g., nitrate, but not exclusively), and agglutination of the cells of the modified virions of the phage MS2 and VLP FMDV.
  • modified MBT-particles e.g., nitrate, but not exclusively
  • Example 6 Determination of the sensitivity of animals to MBT-particles with modified surface.
  • mice The study was performed on 310 white noninbred mice and 160 white noninbred rats.
  • weight of mice was 18.0-22.0 g weight rats 170-250 g.
  • Cages with animals were in a separate room.
  • Light regime 12 hours light, 12 hours darkness.
  • Mode of ventilation 100%, without recirculation, with a shift of about 15 volumes of the room per hour, C0 2 concentration ⁇ 0,15% ammonia ⁇ 0,001 mg/1.
  • the animals received ad libitum a high-grade specialized food for rats and mice, 2 hours before the introduction of the MBT- particles, the animals were deprived of food.
  • Composition of surface-modified MBT- particles with radioactive 201 Tl was administered orally by adding sterile drug particles in drinking water.
  • the remaining conditions of animals consistent with good laboratory practices (GLP, General Guidelines for Submitting a Proposal to ECVAM for the Evaluation of the Readiness of a Test Method to Enter the ECVAM Prevalidation and/or Validation Process, and "OECD series on principles of good laboratory practice and compliance monitoring").
  • GLP General Guidelines for Submitting a Proposal to ECVAM for the Evaluation of the Readiness of a Test Method to Enter the ECVAM Prevalidation and/or Validation Process, and "OECD series on principles of good laboratory practice and compliance monitoring”
  • Example 7 Determination of the effectiveness of the compositions of the nanoparticles on model of xenograft mice, according to the Xenograft Tumor Assay Protocol, Iruela-Arispe Lab (ETniversity of California, Los Angeles).
  • Cell line PC3 was administered to 128“nude” healthy adult female mice (line NCRNU- F). In order to strengthen the relevant activity of the cells of PC3 line, pre-grown under conditions known to specialists. Cells were collected and injected into mice subcutaneously. Mixture for injection contained 5-l5xl0 6 cells in the buffer with penicillin and streptomycin, and the combination of 17P-valerate-estradiol (15 mg) and 300 m ⁇ Matrigel. In a period of 2 months, the surviving mice were selected for analysis of the engraftment of the tumor. The resulting model was considered positive according to histological analysis, immunofluorescence and PCR, in comparison with the control.
  • composition of surface-modified MBT-particles with radioactive 201 Tl in the amount of 10 10 particles were orally administered by adding sterile drug particles in drinking water.
  • the medication was administered to three groups of mice with imbedded tumors (tumor sizes was 5, 7 and 10 mm 3 ), two control groups with tumors treated with cisplatin at therapeutic dose, and intact animals.
  • tumor sizes was 5, 7 and 10 mm 3
  • two control groups with tumors treated with cisplatin at therapeutic dose
  • intact animals were administered to three groups of mice with imbedded tumors (tumor sizes was 5, 7 and 10 mm 3 ), two control groups with tumors treated with cisplatin at therapeutic dose, and intact animals.
  • the disappearance of the cell line PC3 in xenograft mice treated with MBT-particles was observed by 12 days after the first dose.
  • Example 8 Determination of the titer of antibodies to antigens of nanoparticles and tumor (PSMA) in mice treated MBT-particles according to protocol E. Kolsch, A. J. S. Davies, E. Leuchars.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Cell Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Dispersion Chemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne le domaine de la médecine et de la biologie moléculaire et peut être utilisée pour une thérapie de longue durée du cancer avec un effet adjuvant à l'aide de SANPs-théranostiques (SANPs-nano-particules auto-assemblées). L'invention concerne une composition de nanoparticules auto-assemblées comprenant : a) un ligand de conjugaison se liant à un antigène membranaire de la prostate (PSMA) ; b) un ligand de conjugaison se liant à l'intégrine αvβ3, c) un agent biologiquement actif ; et d) des nanoparticules, l'agent biologiquement actif étant un composé de thallium monovalent, de préférence un sel de thallium.
PCT/IB2019/056768 2018-08-09 2019-08-08 Protéines de type théranostiques sanps conjuguées à des peptides de ciblage de l'intégrine et du pmsa et thérapie du cancer de la prostate WO2020031136A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2018/055990 2018-08-09
PCT/IB2018/055990 WO2020030954A1 (fr) 2018-08-09 2018-08-09 Protéines sanp de type théragnostique conjuguées à des peptides de ciblage de l'intégrine et de la pmsa et thérapie du cancer de la prostate

Publications (1)

Publication Number Publication Date
WO2020031136A1 true WO2020031136A1 (fr) 2020-02-13

Family

ID=63557655

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/IB2018/055990 WO2020030954A1 (fr) 2018-08-09 2018-08-09 Protéines sanp de type théragnostique conjuguées à des peptides de ciblage de l'intégrine et de la pmsa et thérapie du cancer de la prostate
PCT/IB2019/056768 WO2020031136A1 (fr) 2018-08-09 2019-08-08 Protéines de type théranostiques sanps conjuguées à des peptides de ciblage de l'intégrine et du pmsa et thérapie du cancer de la prostate

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/055990 WO2020030954A1 (fr) 2018-08-09 2018-08-09 Protéines sanp de type théragnostique conjuguées à des peptides de ciblage de l'intégrine et de la pmsa et thérapie du cancer de la prostate

Country Status (1)

Country Link
WO (2) WO2020030954A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2022523702A (ja) 2019-01-28 2022-04-26 ミトコンドリア エモーション， インク． トランス－４－ヒドロキシシクロヘキシルフェニルアミドマイトフュージン活性化物質及びその使用方法
EP3917508A4 (fr) 2019-01-28 2022-12-21 Mitochondria Emotion, Inc. Activateurs de la mitofusine et leurs procédés d'utilisation
EP4141110A1 (fr) 2020-04-24 2023-03-01 Obshchestvo S Ogranichennoy Otvetstvennost'yu "Ingenik" Procédé de production de particules de bactériophages de la famille levivirus

Citations (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU681837A1 (ru) 1978-02-13 1980-12-23 Ленинградский институт ядерной физики им. Б.П.Константинова Способ иммобилизации белковых молекул
US5401636A (en) 1992-10-21 1995-03-28 E. I. Du Pont De Nemours And Company Enhanced sensitivity agglutination assays multivalent ligands
US5541417A (en) 1995-05-18 1996-07-30 Abbott Laboratories Quantative agglutination reaction analysis method
WO1997035021A2 (fr) * 1996-03-20 1997-09-25 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Peptide d'oligo-epitope de l'antigene prostatique specifique
US5800996A (en) 1996-05-03 1998-09-01 The Perkin Elmer Corporation Energy transfer dyes with enchanced fluorescence
RU2305270C2 (ru) 2005-05-18 2007-08-27 Андрей Алексеевич Климов Способ флуоресцентной наноскопии (варианты)
RU2335542C2 (ru) 2003-06-13 2008-10-10 Джэпэн Эз Репрезентед Бай Президент Оф Нэшнл Сентер Фор Джериэтрикс Энд Джеронтолоджи Аденоассоциированный вирусный вектор для лечения болезни альцгеймера, его применение для получения терапевтических средств, а также способ лечения болезни альцгеймера с помощью данного вектора
RU2341785C1 (ru) 2007-04-23 2008-12-20 Валерий Николаевич Конопский Способ регистрации биологических, химических и биохимических процессов на границе жидкость-фотонный кристалл и устройство для его осуществления
US7488792B2 (en) 2002-08-28 2009-02-10 Burnham Institute For Medical Research Collagen-binding molecules that selectively home to tumor vasculature and methods of using same
RU2359030C1 (ru) 2008-03-19 2009-06-20 Общество С Ограниченной Ответственностью "Лаборатория Клеточных Технологий" Способ получения эндотелиальных клеток из эмбриональных стволовых клеток человека (варианты)
RU2377017C2 (ru) 1999-02-01 2009-12-27 Чилдренз Хоспитал Лос-Анджелес Способы ингибирования роста опухолей головного мозга с помощью антагонистов интегринов
US20100322862A1 (en) 2009-06-22 2010-12-23 Burnham Institute For Medical Research Methods and compositions using peptides and proteins with c-terminal elements
RU2442142C2 (ru) 2009-08-27 2012-02-10 Валерий Николаевич Конопский Способ измерения показателя преломления и устройство для его осуществления
WO2012109611A2 (fr) * 2011-02-11 2012-08-16 Washington University Agents pet/spect pour applications en imagerie biomédicale
US8367621B2 (en) 2008-01-18 2013-02-05 Sanford-Burnham Medical Research Institute Methods and compositions related to internalizing RGD peptides
RU2493251C1 (ru) 2012-07-16 2013-09-20 Федеральное государственное бюджетное учреждение науки Институт биологии гена Российской академии наук Линия клеток cho[v3d], секретирующих рекомбинантный фактор роста эндотелия сосудов (vegf) человека, изоформа а165, с экзогенным 3×ded-эпитопом
US20140023591A1 (en) 2012-04-13 2014-01-23 Case Western Reserve University Heteromultivalent nanoparticle compositions
US20140271470A1 (en) * 2013-03-13 2014-09-18 Laurel O. Sillerud Targeted theranostics for metastatic prostate cancer
US8987173B2 (en) 2005-08-01 2015-03-24 Cornell Research Foundation, Inc. Compositions and methods for monitoring and altering protein folding and solubility
US20150194577A1 (en) 2014-01-06 2015-07-09 Nanoco Technologies Ltd. Cadmium-free Quantum Dot Nanoparticles
US9441026B2 (en) 2009-01-18 2016-09-13 The Board Of Trustees Of The Leland Standford Junior University Polypeptides targeting vascular endothelial growth factor receptor-2 and alpha V beta 3 integrin
US9446157B2 (en) 2011-06-15 2016-09-20 Cancer Targeted Technology Llc Chelated PSMA inhibitors
US9468672B2 (en) 2012-05-04 2016-10-18 Pfizer Inc. Prostate-associated antigens and vaccine-based immunotherapy regimens
WO2016183223A2 (fr) * 2015-05-11 2016-11-17 Georgia State University Research Foundation, Inc. Agents de contraste protéiques ciblés, procédés de fabrication et utilisations de ces agents de contraste
US20160339113A1 (en) 2013-07-09 2016-11-24 President And Fellows Of Harvard College Microvessel endothelial cell surface markers and uses thereof
US9550000B2 (en) 2011-09-09 2017-01-24 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US20170066719A1 (en) 2015-09-09 2017-03-09 On Target Laboratories, LLC Psma-targeted nir dyes and their uses
WO2017052419A1 (fr) 2015-09-22 2017-03-30 Общество С Ограниченной Ответственностью "Биотехнология" Procédé d'activation de l'apoptose de cellules à signalisation multiple des tumeurs malignes solides
US9655980B2 (en) 2012-08-01 2017-05-23 University of Pittsburgh—of the Commonwealth System of Higher Education Theranostic platform for targeted cancer therapy and drug delivery monitoring
US9687573B2 (en) 2013-03-13 2017-06-27 Biosphere Medical, Inc. Compositions and associated methods for radioisotope-binding microparticles
US9687569B2 (en) 2012-08-16 2017-06-27 University Of Washington Through Its Center For Commercialization Theranostic nanoparticle and methods for making and using the nanoparticle
US9724035B2 (en) 2012-10-31 2017-08-08 The Regents Of The University Of California In vivo visualization of lymphatic tissue
US20170226141A1 (en) 2014-08-06 2017-08-10 The Johns Hopkins University Prodrugs of prostate specific membrane antigen (psma) inhibitor
WO2017137953A1 (fr) * 2016-02-10 2017-08-17 Pfizer Inc. Nanoparticules thérapeutiques comprenant un agent thérapeutique, et procédés de fabrication et méthodes d'utilisation de ces dernières
US9745631B2 (en) 2011-12-20 2017-08-29 Dana-Farber Cancer Institute, Inc. Methods for diagnosing and treating oncogenic kras-associated cancer

Patent Citations (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU681837A1 (ru) 1978-02-13 1980-12-23 Ленинградский институт ядерной физики им. Б.П.Константинова Способ иммобилизации белковых молекул
US5401636A (en) 1992-10-21 1995-03-28 E. I. Du Pont De Nemours And Company Enhanced sensitivity agglutination assays multivalent ligands
US5541417A (en) 1995-05-18 1996-07-30 Abbott Laboratories Quantative agglutination reaction analysis method
WO1997035021A2 (fr) * 1996-03-20 1997-09-25 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Peptide d'oligo-epitope de l'antigene prostatique specifique
US5800996A (en) 1996-05-03 1998-09-01 The Perkin Elmer Corporation Energy transfer dyes with enchanced fluorescence
RU2377017C2 (ru) 1999-02-01 2009-12-27 Чилдренз Хоспитал Лос-Анджелес Способы ингибирования роста опухолей головного мозга с помощью антагонистов интегринов
US7488792B2 (en) 2002-08-28 2009-02-10 Burnham Institute For Medical Research Collagen-binding molecules that selectively home to tumor vasculature and methods of using same
RU2335542C2 (ru) 2003-06-13 2008-10-10 Джэпэн Эз Репрезентед Бай Президент Оф Нэшнл Сентер Фор Джериэтрикс Энд Джеронтолоджи Аденоассоциированный вирусный вектор для лечения болезни альцгеймера, его применение для получения терапевтических средств, а также способ лечения болезни альцгеймера с помощью данного вектора
RU2305270C2 (ru) 2005-05-18 2007-08-27 Андрей Алексеевич Климов Способ флуоресцентной наноскопии (варианты)
US8987173B2 (en) 2005-08-01 2015-03-24 Cornell Research Foundation, Inc. Compositions and methods for monitoring and altering protein folding and solubility
RU2341785C1 (ru) 2007-04-23 2008-12-20 Валерий Николаевич Конопский Способ регистрации биологических, химических и биохимических процессов на границе жидкость-фотонный кристалл и устройство для его осуществления
US8367621B2 (en) 2008-01-18 2013-02-05 Sanford-Burnham Medical Research Institute Methods and compositions related to internalizing RGD peptides
US20130343989A1 (en) 2008-01-18 2013-12-26 Sanford-Burnham Medical Research Institute Methods and Compositions Related to Internalizing RGD Peptides
RU2359030C1 (ru) 2008-03-19 2009-06-20 Общество С Ограниченной Ответственностью "Лаборатория Клеточных Технологий" Способ получения эндотелиальных клеток из эмбриональных стволовых клеток человека (варианты)
US9441026B2 (en) 2009-01-18 2016-09-13 The Board Of Trustees Of The Leland Standford Junior University Polypeptides targeting vascular endothelial growth factor receptor-2 and alpha V beta 3 integrin
US20100322862A1 (en) 2009-06-22 2010-12-23 Burnham Institute For Medical Research Methods and compositions using peptides and proteins with c-terminal elements
RU2442142C2 (ru) 2009-08-27 2012-02-10 Валерий Николаевич Конопский Способ измерения показателя преломления и устройство для его осуществления
US9579408B2 (en) 2011-02-11 2017-02-28 Washington University PET/SPECT agents for applications in biomedical imaging
WO2012109611A2 (fr) * 2011-02-11 2012-08-16 Washington University Agents pet/spect pour applications en imagerie biomédicale
US9446157B2 (en) 2011-06-15 2016-09-20 Cancer Targeted Technology Llc Chelated PSMA inhibitors
US9550000B2 (en) 2011-09-09 2017-01-24 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9745631B2 (en) 2011-12-20 2017-08-29 Dana-Farber Cancer Institute, Inc. Methods for diagnosing and treating oncogenic kras-associated cancer
US20140023591A1 (en) 2012-04-13 2014-01-23 Case Western Reserve University Heteromultivalent nanoparticle compositions
US9468672B2 (en) 2012-05-04 2016-10-18 Pfizer Inc. Prostate-associated antigens and vaccine-based immunotherapy regimens
RU2493251C1 (ru) 2012-07-16 2013-09-20 Федеральное государственное бюджетное учреждение науки Институт биологии гена Российской академии наук Линия клеток cho[v3d], секретирующих рекомбинантный фактор роста эндотелия сосудов (vegf) человека, изоформа а165, с экзогенным 3×ded-эпитопом
US9655980B2 (en) 2012-08-01 2017-05-23 University of Pittsburgh—of the Commonwealth System of Higher Education Theranostic platform for targeted cancer therapy and drug delivery monitoring
US9687569B2 (en) 2012-08-16 2017-06-27 University Of Washington Through Its Center For Commercialization Theranostic nanoparticle and methods for making and using the nanoparticle
US9724035B2 (en) 2012-10-31 2017-08-08 The Regents Of The University Of California In vivo visualization of lymphatic tissue
US20140271470A1 (en) * 2013-03-13 2014-09-18 Laurel O. Sillerud Targeted theranostics for metastatic prostate cancer
US9687573B2 (en) 2013-03-13 2017-06-27 Biosphere Medical, Inc. Compositions and associated methods for radioisotope-binding microparticles
US20160339113A1 (en) 2013-07-09 2016-11-24 President And Fellows Of Harvard College Microvessel endothelial cell surface markers and uses thereof
US20150194577A1 (en) 2014-01-06 2015-07-09 Nanoco Technologies Ltd. Cadmium-free Quantum Dot Nanoparticles
US20170226141A1 (en) 2014-08-06 2017-08-10 The Johns Hopkins University Prodrugs of prostate specific membrane antigen (psma) inhibitor
WO2016183223A2 (fr) * 2015-05-11 2016-11-17 Georgia State University Research Foundation, Inc. Agents de contraste protéiques ciblés, procédés de fabrication et utilisations de ces agents de contraste
US20170066719A1 (en) 2015-09-09 2017-03-09 On Target Laboratories, LLC Psma-targeted nir dyes and their uses
WO2017052419A1 (fr) 2015-09-22 2017-03-30 Общество С Ограниченной Ответственностью "Биотехнология" Procédé d'activation de l'apoptose de cellules à signalisation multiple des tumeurs malignes solides
WO2017137953A1 (fr) * 2016-02-10 2017-08-17 Pfizer Inc. Nanoparticules thérapeutiques comprenant un agent thérapeutique, et procédés de fabrication et méthodes d'utilisation de ces dernières

Non-Patent Citations (23)

* Cited by examiner, † Cited by third party
Title
"Current Protocols in Molecular Biology", 1987
"Handbook of Experimental Immunology", 1991, ACADEMIC PRESS, INC.
"Molecular Cloning: A Laboratory Manual", 1989, MACK PUBLISHING CO.
"Oligonucleotide Synthesis", 1984
ALESHINA E. YU.PYNDYK N.MOISA A. A.SANZHAKOV M. A.HARYBIN O. N.NIKOLAEV E. N.KOLESANOVA E. F.: "Synthesis of a fragment of P-amyloid 5RHDSGY10 and its isomers", BIOMED. CHEMISTRY, vol. 54, no. 2, 2008, pages 154 - 166
ANDREU D.ALBERICO F.SOLE N.A.MUNSONM.C.FERRER M.BARANY G., METHODS MOL. BIOL., vol. 35, 1994, pages 91 - 169
BRAKKE M. K.: "Methods in Virology", vol. 2, 1967, ACADEMIC PRESS, article "Density-gradient centrifugation", pages: 93 - 118
CHUN-CHIEH CHEN ET AL: "Chemically activatable viral capsid functionalized for cancer targeting", NANOMEDICINE, vol. 11, no. 4, 1 February 2016 (2016-02-01), GB, pages 377 - 390, XP055421845, ISSN: 1743-5889, DOI: 10.2217/nnm.15.207 *
DI ZHANG ET AL.: "A Thallium Transport FLIPR-Based Assay for the Identification of KCC2-Positive Modulators", JOURNAL OF BIOMOLECULAR SCREENING, vol. 1, 2010, pages 177 - 184
E. KOLSCHA. J. S. DAVIESE. LEUCHARSJOSE E. BELIZARIO: "The immune response to phage fd in normal and thymus-deprived animals of a low responding inbred strain and in genetically thymusless mice// Eur", JOURNAL OF IMMUNOLOGY, vol. l, no. 3, June 1971 (1971-06-01), pages 210 - 213
ELIX C. ET AL.: "The role of peroxisome proliferator-activated receptor gamma in prostate cancer", ASIAN JOURNAL OF ANDROLOGY, vol. 19, 2017, pages 1 - 6
F. CHEN ET AL: "Theranostic Nanoparticles", THE JOURNAL OF NUCLEAR MEDICINE, vol. 55, no. 12, 20 November 2014 (2014-11-20), US, pages 1919 - 1922, XP055582254, ISSN: 0161-5505, DOI: 10.2967/jnumed.114.146019 *
FERNANDO ALBERICIO ET AL.: "Fmoc Solid Phase Peptide Synthesis: A Practical Approach", 2000, OXFORD UNIVERSITY PRESS, article "Preparation and handling of peptides containing methionine and cysteine"
GRATIA A: "Numerical Relations between Lysogenic Bacteria and Particles of Bacteriophage", ANN. INST. PASTEUR, vol. 57, 1936, pages 652
HASSAN M. SHALLAL ET AL: "Heterobivalent Agents Targeting PSMA and Integrin-[alpha] v β 3", BIOCONJUGATE CHEMISTRY, vol. 25, no. 2, 19 February 2014 (2014-02-19), pages 393 - 405, XP055214872, ISSN: 1043-1802, DOI: 10.1021/bc4005377 *
HASSAN M. SHALLAL, HETEROBIVALENT AGENTS TARGEING PSMA INTEGRIN-[ALPHA]V&BGR: 3, ISSN: 1043-1802
HEGER Z. ET AL.: "Apoferritin applications in nanomedicine", NANOMEDICINE (LOND., vol. 9, no. 14, 2014, pages 2233 - 2245
IMMUNODEFICIENT MOUSE MODELS: AN OVERVIEW THE OPEN IMMUNOLOGY JOURNAL, vol. 2, 2009, pages 79 - 85
J. L. CRISP ET AL.: "Dual targeting of integrin avØ and matrix metalloproteinase-2 for optical imaging of tumors and chemotherapeutic delivery", MOL CANCER THER., 2014
KNYAZHEV V.A.SIVOV, I.G.SERGIENKO V.I.: "RNA-transduction of non-infectious virions of phage MS2: Molecular genetics", MICROBIOLOGY AND VIROLOGY, vol. 3, 2002, pages 56 - 63
M. H. V. VAN REGENMORTELS. MULLER: "Synthetic peptides as antigens", 1999, ELSEVIER, pages: 88 - 90
ZHIHANG CHEN ET AL: "PSMA-Targeted Theranostic Nanoplex for Prostate Cancer Therapy", ACS NANO, vol. 6, no. 9, 9 August 2012 (2012-08-09), US, pages 7752 - 7762, XP055583220, ISSN: 1936-0851, DOI: 10.1021/nn301725w *
ZHIHANG CHEN, PSMA-TARGETED THERANOSTIC NANOPLEX FOR PROSTATE CANCER THERAPY, ISSN: 1936-0851

Also Published As

Publication number Publication date
WO2020030954A1 (fr) 2020-02-13

Similar Documents

Publication Publication Date Title
Tekade Biomaterials and bionanotechnology
CN102869384B (zh) 使用带有c-端元件的肽和蛋白质的方法和组合物
Bogdanov Jr et al. Gold nanoparticles stabilized with MPEG-grafted poly (l-lysine): in vitro and in vivo evaluation of a potential theranostic agent
JP2021503492A (ja) 放射線療法と組み合わせて癌を治療するための粒子
WO2020031136A1 (fr) Protéines de type théranostiques sanps conjuguées à des peptides de ciblage de l'intégrine et du pmsa et thérapie du cancer de la prostate
Li et al. Nanomedicine embraces cancer radio-immunotherapy: mechanism, design, recent advances, and clinical translation
Kanthi et al. Nanotherapeutic shots through the heart of plaque
US20060270030A1 (en) Multimodally altered cells as a form for administering active substances and as diagnostic particles
JP2001510812A (ja) フィブリンクロットの検出法
RU2599462C1 (ru) Способ полисигнальной активации апоптоза клеток злокачественных солидных опухолей
WO2012105801A2 (fr) Nanoparticule revêtue d'un ligand introduit avec une chaîne hydrophobe longue et son procédé de préparation
US20210113715A1 (en) Targeted nanoparticles for diagnosing, detecting and treating cancer
CN109420177A (zh) 用于有效体内递送dna纳米结构至动脉粥样硬化斑块的材料和方法
JP7128528B2 (ja) 標的投与のための放射性標識物質
KR101467676B1 (ko) 암 표적용 펩타이드 및 이의 의학적 용도
Wang et al. Nano-integrated cascade antioxidases opsonized by albumin bypass the blood–brain barrier for treatment of ischemia-reperfusion injury
WO2013106824A1 (fr) Agents ciblant les récepteurs des éphrines
Krekorian et al. Characterization of intrinsically radiolabeled poly (lactic-co-glycolic acid) nanoparticles for ex vivo autologous cell labeling and in vivo tracking
TWI682937B (zh) 經官能化以供癌症靶向之化學活化的奈米蛋白殼體
Mehata et al. Radionanotheranostics for breast cancer diagnosis and therapy: Recent advances and future opportunities
JP5645085B2 (ja) マクロ分子を放射性標識化するための方法
NL2027653B1 (en) Targeting system with improved uptake
Schnitzler et al. Surmounting the endothelial barrier for delivery of drugs and imaging tracers
WO2023014975A1 (fr) Procédés de marquage de substance biologique et d'imagerie médicale
JP2023511073A (ja) 好中球エラスターゼ結合ペプチドおよびその組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19773915

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19773915

Country of ref document: EP

Kind code of ref document: A1