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WO2012000791A2 - Agent de diagnostic permettant de localiser un tissu malade - Google Patents

Agent de diagnostic permettant de localiser un tissu malade Download PDF

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Publication number
WO2012000791A2
WO2012000791A2 PCT/EP2011/059924 EP2011059924W WO2012000791A2 WO 2012000791 A2 WO2012000791 A2 WO 2012000791A2 EP 2011059924 W EP2011059924 W EP 2011059924W WO 2012000791 A2 WO2012000791 A2 WO 2012000791A2
Authority
WO
WIPO (PCT)
Prior art keywords
biomolecule
aptamer
peptide
diseased tissue
agent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2011/059924
Other languages
German (de)
English (en)
Other versions
WO2012000791A3 (fr
Inventor
Hartmuth C. Kolb
Ursus KRÜGER
Oliver Lade
Arno Steckenborn
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Siemens AG
Siemens Corp
Original Assignee
Siemens AG
Siemens Corp
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 Siemens AG, Siemens Corp filed Critical Siemens AG
Publication of WO2012000791A2 publication Critical patent/WO2012000791A2/fr
Publication of WO2012000791A3 publication Critical patent/WO2012000791A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers
    • 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
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody

Definitions

  • the invention relates to a diagnostic for the localization of a diseased tissue and a biomolecule for the production of such a diagnostic agent.
  • biochemical analyzes of blood, other body fluids and tissue samples are used to characterize diseases. It examines the presence and amount of molecules that are typical of a particular disease. In addition to foreign substances, the body's own substances are detected, which are formed, for example, only in the event of infection by viruses or bacteria.
  • tumor cells often form large amounts of certain proteins, particularly cellular Vietnamese Nos., IL-12, IL-12, IL-12, IL-12, IL-12, etc.
  • Many of the proteins that are made specifically from diseased cells are surface molecules that are anchored in the membrane which he ⁇ diseased cells. These surface molecules can be detected by appropriate diagnostic methods. For this purpose, usually cells from tissue or blood samples are examined with antibodies that bind to specific, specific for a disease surface molecules.
  • Such in vitro studies can diagnose the presence of a disease. But it is not possible to determine the exact location of the diseased tissue. For this purpose, imaging techniques such as X-ray, ultrasound, and nuclear spin tomography are typically used. In particular, ectopic cell aggregates, such as tumors, or swellings of individual organs can be located with them. However, does a diseased tissue show no marked morphological abnormalities, or is it relatively small, it can easily be overlooked in traditional studies.
  • the invention is therefore based on the object of providing a diagnostic kit with which a diseased tissue can be detected specifically and independently of its size.
  • a diagnostic for the localization of a diseased tissue comprising an agent A and an agent B.
  • Agent A has a complex comprising an aptamer and a linking molecule
  • Agent B has a biomolecule.
  • diagnostic refers to medicines that are used to detect, identify, and / or locate diseases in a patient's body.
  • the most important applications of the diagnostic agent according to the invention are in oncology, cardiology and neuro ⁇ logy.
  • Conventional radiological diagnostics contain ge ⁇ ′lich gamma- or beta-emitting nuclides, for example Xenon 133, "technetium, gallium 68, or 18 fluorine.
  • radionuclides are typically about chelating agents like diethylene triamine pentaacetate (DTPA), 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA) or ethylenediaminetetraacetate (EDTA) to mono- or polysaccharides, so-called tracers.
  • DTPA diethylene triamine pentaacetate
  • DOTA 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid
  • EDTA ethylenediaminetetraacetate
  • the nuclides are, depending on the nature of their radiation, by means of scintigraphy, single photon emission computed tomography (SPECT) or positron emission tomography (PET) is detected. Because of their non-physiological component parts ⁇ conventional radionuclide-containing diagnostic JE but side effects such as anaphylactic or allergic re ⁇ actions that cause a patient's body.
  • the diagnostic agent of the invention comprises two separated ge ⁇ agents, agent A and agent B.
  • agent A comprises a molecule which binds to the diseased tissue and is present as a com plex with ⁇ a connecting molecule. This complex can be designed in particular as a conjugate.
  • the agent B in turn has a radioactively labeled biomolecule. In this way, both functions are separated, and the molecules ⁇ le, according to their respective function, can be optimally selected. Both agents can simultaneously administered to the patient, however, preferably one after the ⁇ .
  • aptamer refers to short, single-stranded nucleic lein Textre oligomers that can accommodate both RNA and DNA molecules to ⁇ . Depending on their respective sequence aptamers form diverse structures and bind to Zielmo ⁇ leküle of various classes. This results in a specific structural compatibility between an aptamer and its target molecule, similar to antigen-antibody binding.
  • the structural compatibility of the molecules via electrostatic interactions, ionic Bin ⁇ compounds, van der Waals interactions, hydrogen bonds and so-called. stacking interactions between the aromatic rings of the bases of nucleic acids.
  • Aptamers that bind to a specific target molecule are identified and produced by in vitro selection and amplification techniques known as SELEX processes (Systematic Evolution of Ligands by Exponential Enrichment).
  • Aptamers comprise regularly 8-220 nucleic ⁇ otide, preferably 20 to 60 nucleotides. However, it is also possible to use aptamers with up to 500 nucleotides. They can be produced synthetically or obtained by enzymatic degradation of genomic DNA (Kulbachinskiy AV, 2007).
  • aptamers can be identified that bind a specific Zielmole ⁇ kül. This can be both larger biomolecules, such as proteins, as well as to individual chemical ele ⁇ ments. In addition, aptamers bind almost all classes of substances, so that aptamers can also be identified that recognize and bind to specific protein modifications, such as fatty acid or sugar modifications.
  • Each cell carries on its surface, anchored in its cell membrane, a multitude of different molecules, most of which belong to the class of proteins. Besides Mole ⁇ cules with basic biological functions that are found in almost every cell, many molecules only by cells of a particular tissue or a particular cell type can be expressed. In addition, cells that are infested with pathogens or have impaired cell functions, such as tumor cells, form their own molecules. Many of these disease-specific molecules are membrane bound and Queen ⁇ NEN be detected on the surface of the respective cell. By choosing an aptamer, with one, for one Morbid tissue characterizing molecule interacts, the detective ⁇ ter det specific to the diseased tissue.
  • the aptamer is selected so that the bond between the aptamer and the target molecule is a linear chalient Koef-, so-called.
  • KD value of ⁇ 100 nM, preferably ⁇ 10 nM, most preferably of 7.5 nM having. With such an aptamer even a few cells of a diseased tissue can be specifically detected.
  • diseased tissue refers to cells, parts of organs or whole organs that do not or not fully fulfill their physiological function. These include, for example, viruses or bacteria infected cells, hypertrophic tissue, inflamed tissue and organs, hyperplasti ⁇ MOORISH and neoplastic tissue, such as ulcers, tumors and cancers. Diseased cells often form proteins whose expression is indicative of a particular disease, for example, because they are derived from the genetic material of a virus or bacterium. When these molecules are cell surface molecules, they are anchored to the cell membrane. By specifically binding a surface molecule of a diseased tissue, the aptamer enables a reliable localization of this tissue.
  • linking molecule includes chemical Verbindun ⁇ gen suitable ren to interagie- with a biomolecule. It is due to chemical interactions between the linker molecule and the biomolecule to form a stable binding of the two molecules, similar to an antigen-antibody Interaction.
  • short-chain peptides, sugar compounds and chemical at ⁇ particular natural compounds, as well as aptamers are therefore geeig ⁇ net as the compound molecules.
  • compound molecules are advantageous, which consist of body-like components are built so that they can be metabolized by endogenous mechanisms.
  • biomolecule includes molecules of biological origin or are made up of natural ingredients and have the ability to specifically interact with other Mole ⁇ cules and retain them.
  • the biomolecule is chosen so that it binds to the complex of agent A, without interacting with other molecules. It is preferred that the biomolecule binds to the compound molecule. This is chosen so that it is not similar to any other common molecule in a patient's body. The biomolecule binds then only the connection molecule, so that a strong positive signal arises with at the same time low background signals.
  • the organic ⁇ molecule is chosen so that the bond between the organic ⁇ molecule and the target molecule is a linear coefficient called. KD value of ⁇ 100 nM, preferably ⁇ 10 nM, most be ⁇ vorzugt of 7, 5 nM.
  • the biomolecule binds to the complexes of the agent A, which are attached to the diseased tissue and serves to determine the Positi ⁇ on these complexes or the diseased tissue.
  • the detection of the biomolecule takes place via its radio ⁇ active marker with an 11 C carbon atom.
  • positrons also referred to as ⁇ + radiation, are formed. If the positrons hit an electron, they form two photons, which move away from each other at an angle of 180 °, ie exactly in the opposite direction. The photons can be detected and used to calculate the position of the positron emission, or of the 11 C carbon atom.
  • An advantage of the use of an aptamer, and a d e ⁇ labeled biomolecule is that both are composed of responsibilitiesei ⁇ antigenic components, namely nucleic acids and amino acids, whereby they are compatible to the organism. Both the aptamer and the biomolecule and its individual nucleic acids or amino acids are non-toxic, they can naturally metabolized, degraded and are ⁇ eliminated. By using an integrated X1 C carbon atom, it is also possible to prevent a ra- 1
  • diooxider impurity such as fluorine, xenon, or 68 gallium
  • diooxider impurity such as fluorine, xenon, or 68 gallium
  • carbon is an element that occurs in the body and can naturally be metabolised.
  • Another advantage of the diagnostic is the favorable signal / background ratio during detection.
  • the agent A After the agent A has been administered to the patient, the ent ⁇ contained complexes are distributed in the body and bind by the binding specificity of the aptamer to the diseased tissue. Free, unbound complexes, on the other hand, are rapidly metabolised and excreted from the organism because they can be degraded by endogenous enzymes.
  • the patient is administered the agent B, which binds extremely selek ⁇ tively and with high binding specificity to the complex. This causes a non-specific attachment in the body of the prevents patients, and there is a strong and specifi ⁇ cal signal at the position of the diseased tissue, whereas the background signal is minimized.
  • the distribution of biomolecules by high selectivity Particularly efficiently so that the time between Verabrei ⁇ chen of the agent B and the detection can be shortened. Both result in that the dose of agent B can be minimized and the radiation exposure for the patient is reduced.
  • the biomolecule With a particularly high affinity and specificity of the biomolecule for the complex of agent A, the biomolecule can be chosen to be metabolized faster than the complex. In this case, both agents can be administered at extremely short intervals or optionally simultaneously.
  • the biomolecule is selected from the group consisting of peptides, aptamers and micro-antibodies. These biomolecules are all made up of body-like components, such as nucleic acids or amino acids, and are therefore particularly well tolerated by the patient.
  • the biomolecule is a peptide and the 11 C carbon atom is the carbonyl carbon atom of one of the amino acids.
  • the carbonyl groups are part of the peptide bonds between the amino acids and are located inside the peptide. This ensures that the 11 C-carbon atom is not cleaved by the peptide from ⁇ how it would be possible for example in a side chain of the amino acids.
  • the 11 C carbon atom is the carbonyl carbon atom of the N-terminal amino acid of the peptide.
  • This embodiment is particularly preferred because the peptide can be used directly after the on ⁇ bring the 11 C-labeled amino acid.
  • 11 C-carbon has a half-life of only about 20 Minu ⁇ th, so that the radiation dose must be chosen the higher, the more time is between the synthesis of the peptide and its ⁇ ner use. If the 11 C-labeling with the N-terminal amino acid and thus in the last step of the synthesis is applied, the peptide can be used immediately after its synthesis.
  • the peptide has at least one D-amino acid.
  • D-amino acid With the exception of glycine, all amino acids have a chiral center at their alpha carbon atom and can therefore exist as configurational isomers, namely as the D or L amino acid. Endogenous peptides and proteins are largely out
  • a further possibility for influencing the pharmacological clearance of the peptide consists of replacing individual amino acids of the peptide with non-natural amino acids having similar chemical properties.
  • the non-natural amino acids are metabolized more slowly because the body's own proteolytic enzymes are specially adapted to the degradation of natural amino acids.
  • the non-natural amino acids should be chosen so that the binding affinity of the peptide is not altered.
  • other chemical Mo ⁇ dtechniken individual amino acids of the peptide are possible to influence the half-life of the peptide specifically.
  • the terminal amino group of the peptide may be replaced by an isonitrile group. Such modes ⁇ fication reduces, mediated by the amino group, in ⁇ ter syndrome with proteolytic enzymes without altering the bond between the peptide and the complex.
  • the biomolecule is an aptamer and the amino acid is coupled via a peptide bond to a free amino group of a nucleotide of the aptamer.
  • the labeling of the aptamer with an 11 C carbon atom via an amino acid is particularly advantageous because it does not require the use of any of the conventional complexing agents, such as DTPA or DOTA.
  • the resulting complex of aptamer and amino acid comprises endogenous Mole ⁇ molecules, whereby it is particularly compatible with the organism. Both the aptamer and its individual nucleic acids, and the amino acid are non-toxic, they can natuer metabolized ⁇ Lich, be broken down and excreted.
  • Another object of the invention is the use of a biomolecule for the preparation of a diagnostic agent for the detection of a diseased tissue.
  • the biomolecule binds to a complex comprising an aptamer and a dacasmo ⁇ lekül and the aptamer to the diseased tissue (18) binds the biomolecule is suitable, even a few cells ei ⁇ nes diseased tissue in a patient's body to locate. Characterized in that the biomolecule has an amino acid with egg nem ⁇ ⁇ C-carbon atom, it may be PET detek- advantage.
  • PET is an established method for detecting the radiation of radioactive elements and determining their position (Massoud TF, Gambhir SS, 2003). With the aid of detector devices arranged annularly around the patient, sectional images are created on which the decay events are represented in their spatial distribution in the interior of the body. PET also makes it possible to determine the amount of labeled Mo ⁇ lekülen quantitatively in a tissue.
  • the biomolecule is selected from the group consisting of peptides, aptamers and micro-antibodies. These molecules are built up from body-like components and are therefore particularly well tolerated by the patient.
  • the biomolecule is a peptide and the 11 C carbon atom is the carbonyl carbon atom of one of the amino acids, preferably the N-terminal amino acid of the peptide.
  • the biomolecule is an aptamer and the amino acid is linked to the aptamer via a peptide bond with a free amino group of a nucleotide.
  • Also disclosed is a method of localizing diseased tissue in an organism comprising the steps of: a) administering to the organism an agent A comprising a complex or conjugate comprising an aptamer and a linking molecule, b) administering an agent B with a biomolecule, the bin to the complex or conjugate ⁇ det, to the organism, and c) detecting the biomolecule in the organism by means of positron emission tomography
  • the aptamer binds to the diseased tissue and the biomolecule has one amino acid
  • the diagnostic agent according to the invention is therefore ideal for monitoring the course and success of a treatment, so-called therapy monitoring.
  • FIG. 1 shows schematically a complex of an aptamer 6 4 and a linker molecule 5 to which a biomolecule 1, NaEM ⁇ Lich a peptide is attached.
  • the complex 6 is bound to a pathological tissue 18.
  • Peptide 1 comprises 8
  • Amino acids 2 of which the N-terminal amino acid 3 is radiolabeled with ei ⁇ nem 11 C carbon atom.
  • the radioactive label is represented by an asterisk (*).
  • the specific binding affinity between the complex 6 and the diseased tissue 18 is due to the chemical interactions between the aptamer 4 and the surface of the diseased tissue 18. These interactions are determined by the nucleic acid sequence of aptamer 4.
  • an aptamer 4 is identified that interacts with a surface molecule of the diseased tissue ⁇ bes 18th Subsequently, the aptamer 4 is coupled to a linker molecule 5 which is adapted to be bound by egg ⁇ nem peptide 1 extremely selectively and with high affinity.
  • Peptide 1 which has an 11 C-labeled amino acid 3, is used to produce an agent B. Peptide 1 can then by the decay of the 11 C-carbon atom toge ⁇ positron surrounded by positron emission tomography (PET) can be detected. The location of the positron emission corresponding to the location of Complex 6, and therefore that of the sick ⁇ exemplary fabric 18, to which the complex is bound. 6
  • agent B is administered to the patient.
  • the peptides 1 bind rapidly to the complex plexes 6 because they do not interact with other molecules in the patient's body. In this way, they accumulate on the cells of the diseased tissue 18. This accumulation becomes visible in a positron emission tomography (PET), so that the distribution of the complex 6 or the position of the diseased tissue 18 in the body of the patient are determined can.
  • PET positron emission tomography
  • FIG. 2 shows a schematic illustration (greatly simplified according to Faller A, Schünke M, The body of man,
  • the circulation system 10 includes various organs schematically represented, such as the lungs 12, heart 13, liver 14, 15 intestine and kidney 16 and the main wires 11 which these organs ver ⁇ bind. Left of center of the circulatory system 10 is additionally ⁇ a diseased tissue 18, for example, a tumor or an inflammation, shown, are attached to the already Komple ⁇ xe. 6
  • the peptide 1 is represented by triangles, ent ⁇ long of the veins 11 and bound to the complexes 6 on the diseased tissue 18 shown.
  • the degradation products 17 of the complex 6 and the peptide 1 are represented by individual lines within the outline of the kidney 16.
  • the distribution of the peptide 1 in the circulatory system 10 comprises four phases, which are listed along the top-down view.
  • Phase I Peptide 1 is injected into the circulatory system 10 of the organism.
  • Phase II is via the blood circulatory system 10 Peptide 1 in the organs 12, 13, 14, 15, and 16 of the body transported ⁇ advantage.
  • Phase III The circulating peptide 1 specifically binds to the complexes 6, which are already at the pathological tissue 18 ⁇ superimposed.
  • Phase IV Unbound peptide 1 is rapidly metabolised and enzymatically degraded.
  • the organism not failed ⁇ det between the body's own molecules and the peptide 1, because it is composed of amino acids 2, 3, corresponding to the stressesei ⁇ antigenic molecules.
  • the degradation products 17 of the peptide 1 and the amino acids 2, 3 accumulate predominantly in the kidney 16, from where they are excreted via the bladder and the ureter.
  • Massoud TF, Gambhir SS Molecular imaging in living subjects: seeing fundamental biological processes in a new light; Genes Dev. 2003 Mar 1; 17 (5): 545-80.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical & Material Sciences (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne un agent de diagnostic permettant de localiser un tissu malade (18) et comprenant un agent A avec un complexe (6) comportant un aptamère (4) et une molécule de liaison (5), et un agent B avec une biomolécule (1) qui se lie au complexe (6). L'aptamère (4) se lie au tissu malade (18) et la biomolécule (1) comprend un acide aminé (2) avec un atome de carbone 11 (11C). L'invention concerne également l'utilisation d'une biomolécule (1) pour produire un tel agent de diagnostic.
PCT/EP2011/059924 2010-06-30 2011-06-15 Agent de diagnostic permettant de localiser un tissu malade Ceased WO2012000791A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102010026057.6 2010-06-30
DE201010026057 DE102010026057A1 (de) 2010-06-30 2010-06-30 Diagnostikum zur Lokalisation eines krankhaften Gewebes

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WO2012000791A2 true WO2012000791A2 (fr) 2012-01-05
WO2012000791A3 WO2012000791A3 (fr) 2012-04-19

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

Family Cites Families (2)

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Publication number Priority date Publication date Assignee Title
CN101511389A (zh) * 2005-10-04 2009-08-19 皇家飞利浦电子股份有限公司 使用[3+2]叠氮化物-炔环加成的靶向成像和/或治疗
WO2009045579A2 (fr) * 2007-06-14 2009-04-09 The Regents Of The University Of California Sondes d'imagerie multimodes pour imagerie et thérapie in vivo ciblées et non ciblées

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102009035645A1 (de) 2009-07-29 2011-02-03 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markiertren Peptids
DE102009035648B3 (de) 2009-07-29 2011-03-17 Siemens Aktiengesellschaft Verfahren zur Herstellung eines radioaktiv markierten Carboxylats sowie die Verwendung einer Mikroelektrode zur elektrochemischen Synthese eines radioaktiv markierten Carboxylats

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FALLER A, SCHÜNKE M: "Der Körper des Menschen", 2008, THIEME-VERLAG
KULBACHINSKIY AV: "Methods for selection of aptamers to protein targets", BIOCHEMISTRY (MOSC), vol. 72, no. 13, December 2007 (2007-12-01), pages 1505 - 18, XP002593035, DOI: doi:10.1134/S000629790713007X
MASSOUD TF, GAMBHIR SS: "Molecular imaging in living subjects: seeing fundamental biological processes in a new light", GENES DEV., vol. 17, no. 5, 1 March 2003 (2003-03-01), pages 545 - 80, XP007905304, DOI: doi:10.1101/gad.1047403
NEUNDORF I, RENNERT R, FRANKE J, KÖZLE I, BERGMANN R: "Detailed analysis concerning the biodistribution and metabolism of human calcitonin-derived cell-penetrating peptides", BIOCONJUG CHEM., vol. 19, no. 8, August 2008 (2008-08-01), pages 1596 - 603, XP002575961, DOI: doi:10.1021/bc800149f

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DE102010026057A1 (de) 2012-01-05

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