WO2021032784A1 - Isotope du platine combiné à des agents de ciblage osseux destinés à être utilisés dans des médicaments anticancéreux - Google Patents

Isotope du platine combiné à des agents de ciblage osseux destinés à être utilisés dans des médicaments anticancéreux Download PDF

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WO2021032784A1
WO2021032784A1 PCT/EP2020/073212 EP2020073212W WO2021032784A1 WO 2021032784 A1 WO2021032784 A1 WO 2021032784A1 EP 2020073212 W EP2020073212 W EP 2020073212W WO 2021032784 A1 WO2021032784 A1 WO 2021032784A1
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bone
ligand
use according
platinum
mice
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Sander Cornelis Gerardus Leeuwenburgh
Robin Abraham NADAR
Otto Christiaan BOERMAN
Nicola MARGIOTTA
Karlijn CODÉE-VAN DER SCHILDEN
Sander DE GROOT
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Nuclear Research And Consultancy Group
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0489—Phosphates or phosphonates, e.g. bone-seeking phosphonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/42—Phosphorus; Compounds thereof
    • 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
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/548—Phosphates or phosphonates, e.g. bone-seeking
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage

Definitions

  • the present invention relates to novel compounds containing a platinum isotope and a bone targeting agent capable of associating with bone tissue and the application of the compounds in the treatment of cancers such as bone cancer.
  • Bone metastases are often affected by malignant cancers, which then become the primary cause of mortality. Distant metastases are the leading cause of death for both breast and prostate cancer patients, with 65-75% and 90% of these patients developing bone metastases in advanced stages, respectively. Bone metastases are often associated with accelerated bone resorption leading to complications such as skeletal-related events (SREs), bone pain or hypercalcemia.
  • SREs skeletal-related events
  • Current treatments for bone metastases are limited.
  • Bisphosphonates (BP) and denosumab are most commonly used for palliative treatment to prevent or limit SREs. Although such treatments inhibit osteoclast activity and prevent the progression of metastases, they do not kill cancer cells effectively and do not improve the quality of life substantially. Consequently, the development of effective therapies to treat bone metastases is still a major clinical challenge.
  • Cancer cells modulate the bone microenvironment to support tumor growth and accelerate tumor progression.
  • the elimination of cancer cells from bone metastases is crucial for treatment efficacy, which requires precise and efficient delivery of antitumor therapeutics to bone metastases.
  • Targeted drug delivery aims at selective and effective accumulation of pharmacologically active compounds at desired target site(s), thus minimizing undesired side effects and maximizing therapeutic efficacy.
  • platinum-based (Pt) drugs belong to a class of radiosensitizer that influence the nature or repair of DNA damage.
  • Platinum-based (Pt) drugs are a specific class of chemotherapeutic drugs which exhibit antitumor properties by interacting with DNA and suppressing its replication. Pt-based drugs are known to induce systemic toxicity, while the lack of tumor specificity restricts their application for long-term treatment. Consequently, there remains a need for improved compounds and their preparation in the treatment of various cancers such a bone cancers.
  • Margiotta et al. formulated various anticancer Pt-bisphosphonate complexes to deliver Pt to bone (40-42), since BPs exhibit a strong affinity for hydroxyapatite bone mineral (43). Recent advances in imaging technologies allow for early detection of malignant tissues directly in bone marrow (54-56) or detection of indirect tumor activity related to bone remodeling (57,
  • the present inventors have focused on the design of radioactive chemotherapeutics based on 195m pt which exhibit diagnostic, chemo- and radiotherapeutic efficacy to facilitate effective treatment of bone metastases.
  • the high metabolic activity of metastatic bone offers the opportunity for bone tumor-targeting of bone-seeking 195m Pt-based therapeutics.
  • Nadar et al. (Nadar et al, Clin. Exp. Metastasis 2017, 34, 491-524, page 514) have disclosed and discussed the use of 195m pt-BP as a theranostic agent, but only combined the chemotherapeutic effect of Pt with the gamma radiation of the 195m pt isotope as a diagnostic in SPECT imaging.
  • radioactive Pt isotopes preferably 1 95m pt or i93m p t , more preferably 195m pt in bone tissue-targeting agents further enhances the therapeutic/diagnostic properties of Pt-based drugs.
  • the use of Pt-isotope containing compounds combines the chemotherapeutic effects of Pt with the radiotherapeutic effects of the Pt isotope.
  • the combination of the Pt isotope with a bone tissue-targeting agent delivers the Pt isotope at the desired location (bone of high metabolic activity), where the Pt can exert its function as a chemotherapeutic in (synergistic) combination with its radiotherapeutic function as the Pt isotope as the 195m pt radionuclide emits Auger electrons.
  • these compounds have also diagnostic applications, as 195m pt or 193m pt emits gamma rays that can be detected outside the patient. This gamma emission allows SPECT imaging.
  • SPECT imaging provides for the detection of the location and distribution of the compound in the patient.
  • the compound of the invention thus provides information on cancer location and/or distribution of the compound in the body and/or compound targeting efficiency.
  • Fig. 4. In vivo phenotypic effects of Pt-BP in zebrafish embryos.
  • Fig. 8 Biodistribution profile of 195m pt-BP and 195m Pt(N03)2(en) in vivo.
  • Fig. 9 Quantification of 195m pt-BP and 195m Pt(N03)2(en) biodistribution in vivo.
  • Fig. 10 Spatial distribution of Pt in bone.
  • FIG. 11 Biodistribution profile of 195m pt-BP and 195m Pt-Cisplatin in vivo (bone tumor-bearing mice).
  • Fig. 13 Representative histological images of tumor regions in metastatic mice model.
  • Fig. 14 Representative histochemical and immunohistochemical images of tibial lesions in a prostate cancer cell-induced bone metastasis model 14 days after treatment.
  • the present invention hence pertains in a first aspect to a compound comprising a Pt isotope, preferably 195m pt or 193m pt, more preferably 195m pt isotope, the compound further comprising a bone-seeking agent preferably capable of targeting bone of high metabolic activity.
  • the invention provides a compound that is a complex or a conjugate of a Pt-isotope in combination with a bone-seeking (or bone-targeting) agent that is capable of associating with bone.
  • the bone seeking agent is preferably a compound or complex that is bone seeking, i.e. when administered to a subject, there is a tendency of association with bone (or mineralized tissue) more than with other tissues of the subject.
  • the compound of the present invention preferably displays the following functionalities and advantages: the compound is targeted to bone (or mineralized tissue) of high metabolic activity; the compound dissociates in the cell environment; the compound upon dissociation is capable of releasing a Pt-isotope compound/molecule, which is similar or identical to platinum-based chemotherapeutic molecules.
  • Platinum-based chemotherapeutic molecules have a tendency to bind to DNA or cell nucleus material.
  • the activated Pt-isotope is close enough to cellular DNA to cause severe damage to the DNA by Auger electrons and/or gamma rays, and kill the cell.
  • the present invention solves a major problem with Pt-based chemotherapeutics.
  • Pt-based chemotherapeutics are generally delivered systemically, thereby causing serious side-effects in various organs unaffected by cancer, since the chemotherapeutic affects also healthy cells.
  • the invention encompasses any Pt-isotope capable of emitting Auger electrons, there is a preference for 195m Pt.or 193m pt, more preferably 195m pt. It is thought, without being limiting, by the present inventors that the use of 195m pt would cause additional damage, not only to cancer cells but also to healthy cells and induce or enhance unwanted side effects.
  • the in-cell dissociation/activation of the compound of the invention in combination with the 195m Pt can bring the compound to the desired location (DNA in mineralised tissue such as bone) where the Pt can exert a chemotherapeutic effect and the Auger electrons and/or gamma rays of the 195m pt isotope exert a radiotherapeutic/diagnostic effect.
  • the present invention thus demonstrates that significant advantages are being achieved with this radiation therapy wherein the radiation damage is preferentially brought to the location that needs to be affected.
  • the short range of Auger electrons causes that only cells with the Auger emitter at the right location in the cell will be harmed.
  • this is achieved by targeting the bone and targeting the DNA after which the Auger emitter is close enough to the cell nucleus material and DNA to be effective, considering the very short range at which Auger emitters are damaging. If the compound does not enter the cell, it nevertheless may be effective, provided the emitter is located in proximity of the cell or nucleus of interest. At larger distances, the Auger emitter range of damage is typically too short to affect the cell.
  • the compound of the present invention is radiotherapeutically active by killing cancer cells.
  • bone seeking agents include phosphorus-containing compounds such as those which contain C-O-P bonds (phosphates such as those described in U.S. Patent No. 4,582,700), P-O-P bonds (pyrophosphates or polyphosphates such as those described in U.S. Patent No. 4,016,249), C-C-P bonds (phosphonates such as those described in U.S. Patent Nos. 4,233,284 and 4,642,229), P-C-P bonds (diphosphonates or bisphosphonates such as those described in U.S. Patent No. 4,233,284), P-N-P bonds (imidodiphosphonates such as those described in U.S. Patent No. 3,974,268), or combinations or derivatives thereof.
  • C-O-P bonds phosphates such as those described in U.S. Patent No. 4,582,700
  • P-O-P bonds pyrophosphates or polyphosphates such as those described in U.S. Patent No. 4,016,249
  • the targeting agents may be used in a variety of forms, e.g., mono-, di- and polyphosphonates.
  • phosphonates particularly examples are methylene diphosphonate (MDP), 4,5-diamino-1-hydroxypentane-1 ,1-diphosphonate, 3-amino-1-hydroxypropane-1 ,1- diphosphonate (ADP) and 2-amino-1-hydroxyethane-1 ,1-diyl-bisphosphonate (AHBP).
  • MDP methylene diphosphonate
  • ADP 3-amino-1-hydroxypropane-1 ,1- diphosphonate
  • AHBP 2-amino-1-hydroxyethane-1 ,1-diyl-bisphosphonate
  • a typical Example in the context of the present invention are pyrophosphates and phosphonates, preferably bisphosphonates.
  • Bisphosphonates and pyrophosphates have been described as expressing similar behavior for the local delivery of Pt-containing compounds and these ligands influenced the loading and release of platinum.
  • Nanoparticles retaining these bisphosphonates or pyrophosphates ligands at their surface release chemotherapeutically active residues of the Pt compounds.
  • these Pt-loaded nanocarriers not only deliver their payload at the tumor sites in a controlled manner, but also improve the cytotoxicity of the unmodified complexes that can thus be considered as platinum prodrugs.
  • the Pt may be complexed, bound or conjugated via covalent, ionic and/or coordination bonds to the targeting agent.
  • the compound may contain other ligands, ions etc.
  • the compound can comprise a ligand ( or a chelate).
  • a nitrogen containing ligand there is a preference for a nitrogen containing ligand.
  • the ligand may be a monodentate, bidentate tridentate or tetradentate.
  • nitrogen-containing bidentate ligand There is a preference for a nitrogen-containing bidentate ligand.
  • Suitable and preferred are ligands selected from the group consisting of ethylenediamine (en), diazabicyclo [2.2.2] octane (DABCO), N,N,N' ,N'-tetramethyl ethylenediamine (TMEDA) , N,N,N' ,N '-tetraethyl ethylenediamine (TEEDA) ,1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), 2,2’-bipyridine (bipy), 5- or 6 membered aliphatic cyclic diamines such as 1,2-cyclohexanediamine, 1,4-cyclohexanediamine, 1,3- cyclopentanediamine, 1 ,4-cycloheptanediamine.
  • DABCO diazabicyclo [2.2.2] octane
  • TEDA N,N
  • the ligands and/or targeting agents may be protonated or quaternized to improve solubility, for instance under physiological conditions.
  • the compound can have the formula (I): wherein Pt comprises a Pt isotope, preferably 195m Pt.or 193m pt, more preferably 195m Pt.; wherein R1 is C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C5-C6 (het)aryl, preferably substituted with a (quaternized) amine group; wherein R2 is OH, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, C5-C6 (het)aryl, preferably an OH group; wherein L1 , L2, L3, L4 are monodentate ligands; wherein L1 together with L2 and/or L3 together with L4 are independently a bidentate ligand; or wherein L1-L4 are a quadridentate ligand, capable of forming a coordination complex with Pt
  • the Pt in formula I comprises a Pt isotope, preferably 195m Pt.or 193m pt, more preferably 195m pt isotope. Not all Pt atoms in a composition the compound of formula I will be 195m pt. There will be a fraction in conjunction with other Pt isotopes, and the fraction may diminish due to decay of the 195m Pt. this is an inherent feature of radioactive isotopes.
  • the Pt in formula I may further contain Pt as a stable element or other Pt isotopes,.
  • a fraction of the Pt will be 195m Pt, depending on the 195m pt specific activity of Pt used for the synthesis of the compound, and wherein the 195m pt fraction may reduce over time due to nuclear decay of the
  • the ligand is ethylenediamine (en).
  • the compound of the invention further finds use as a medicament, a theranostic, chemotherapeutic and/or a diagnostic agent, in particular in the field of bone cancer.
  • the bone cancer can be a primary bone cancer, a metastatic bone cancer.
  • the use of the compound for bone cancer is foreseen in the treatment of bone cancers selected from the group consisting of osteosarcoma, chondrosarcoma, Ewing tumor, giant cell tumor of bone, chordoma or wherein the bone cancer is metastasized from primary tumors such as prostate, breast, kidney, lung and thyroid primary tumors.
  • the use of the compound is foreseen in a pharmaceutical comprising which may comprise suitable and common additives such as carriers, diluents, excipients etc.
  • the present inventors have designed, synthesized and tested novel radioactive Pt-BP ( 195m Pt- BP) complexes to enable targeted delivery of 195m pt to bone of high metabolic activity.
  • Pt release from Pt-BP complexes was investigated at physiological (pH 7.4) and acidic conditions (pH 5.25). This latter condition mimics the acidic cancer environment.
  • the objective of the study was to evaluate Pt-BP as potential therapeutic (Pt) or theranostic agent ( 195m pt) to selectively deliver Pt or 195m pt to metabolic active region of bone. All experiments were performed with five animals per group to reach statistical significance. Mice were randomized into different groups before administration of pt/ 195m pt compounds.
  • ratios are depicted as mean ⁇ standard deviation.
  • the statistical analyses were performed using GraphPad Prism (version 6.0) software. Two-way analysis of variance (ANOVA) with a Bonferroni (multiple comparisons) post-hoc test was used to determine the differences among the two groups. For ratios, paired t-test was used to determine the differences among the two groups. For the ototoxicity assay, one-way analysis of variance (ANOVA) was performed followed by the Dunnett’s method for multiple comparisons.
  • the zebrafish (Danio rerio) strains were kept under standard conditions (28 °C in E3 buffer) until 48 hours post fertilization (hpf). All animal experiments were conducted at larval stages before the point of independent feeding and were in agreement with the animal protection law (Tierstoff contradict).
  • Na2SC>4 and Ba(OH)2 were purchased from Sigma-Aldrich.
  • 2-amino-1-hydroxyethane-1,1-diyl- bisphosphonic acid (AHBP-FU) was prepared following procedures reported previously (40). Milli-Q water was used to dissolve the compounds. All other reagents were purchased from Sigma-Aldrich and used without further purification.
  • Kl potassium iodide
  • Electrospray Ionisation-Mass Spectrometry was carried out to measure the molecular weight of the obtained Pt(N0 3 ) 2 (en) using an electrospray interface and ion trap mass spectrometer (1100 Series LC/MSD Trap system Agilent, Palo Alto, CA): Anal.
  • the 195m Pt was produced as previously reported (E. A. Aalbersberg, B. J. de Wit-van der Veen, O. Zwaagstra, K. Codee-van der Schilden, E. Vegt, W. V. Vogel, Preclinical imaging characteristics and quantification of Platinum- 195m SPECT. EurJ Nucl Med Mol Imaging 44, 1347-1354 (2017).)
  • the specific activity of 195m Pt(N03)2(en) was 48,5 MBq/mg Pt.
  • the radionuclide purity of 195m Pt(NC>3)2(en) as received from NRG (Petten, The Netherlands) is reported in Table S1.
  • 31 P NMR spectra were recorded on a Bruker Avance III 700 MHz instrument. Standard pulse sequences were used for 31 P ⁇ 1H ⁇ (121.5 MHz) spectra. Chemical shifts ( 31 P) were referenced to external H 3 PO 4 (85% w/w; 0 ppm).
  • a Crison Micro-pH meter Model 2002 equipped with Crison microcombination electrodes (5 and 3 mm diameter) and calibrated with Crison standard buffer solution at pH 4.01, 7.02, and 10.00, was used for pH measurements. The pH readings from the pH meter for D2O solutions are indicated as pD values and are uncorrected for the effect of deuterium on glass electrodes.
  • the suspension was cooled down for approximately 1 h in an ice bath to facilitate the precipitation of BaS0 4 prior to filtration through a plug of Celite ® .
  • the volume of the filtrate, which contained the final product, was reduced using a rotary evaporator (at 40 °C) and the pH of the concentrated filtrate was brought to ⁇ 1 using H2SO4 (95-97%).
  • Addition of methanol induced the precipitation of the desired product as a white precipitate that was filtered and washed with methanol and diethyl ether, and subsequently dried under vacuum. Elemental analyses were carried out using a Hewlett Packard 185 C and N analyzer.
  • ESI-MS was carried out to measure the molecular weight of the obtained Pt-BP using an electrospray interface and ion trap mass spectrometer.
  • Anal. Calc for [ ⁇ R ⁇ (bh)> 2 (m-AHBR- H 2 )](HS0 4 )-3H 2 0 (C 6 H29N 5 Oi4P2Pt2S, M w 879.4 g-mo ): C, 8.19%; N, 7.96%. Found: C, 7.99%; N, 7.45%.
  • Spectroscopic characterization of the Pt-BP was carried out using 1 H and 13 P Nuclear Magnetic Resonance (NMR) spectroscopy and ATR-FTIR. Fig. 1.
  • the synthesis procedure was followed as described above for the cold platinum- bisphosphonate complex.
  • the 195m Pt(N0 3 ) 2 (en) solution was received from NRG (Petten, the Netherlands).
  • the pH of 195m Pt(N0 3 ) 2 (en) solution was neutralized to pH 7 using 1M NaOH and reconstituted in sterile saline solution.
  • This Pt(NC>3)2(en) facilitates the synthesis of radioactive Pt-BP complexes using 195m pt radioisotopes for future applications as a theranostic agent (Fig 6 ).
  • Fig 6 described the Synthesis and Characterization of Pt-BP complex.
  • A Chemical structures of platinum complexes.
  • the doublet centered at 3.34 ppm is assigned to the protons of the methylene group of the bisphosphonate.
  • AHBP 2-amino-1-hydroxyethane-1 ,1-diyl-bisphosphonic acid
  • Fig. 4 In vivo phenotypic effects of Pt-BP in zebrafish embryos. Representative images of embryos treated with different concentrations of Pt-BP. Until 2 days post treatment (dpt), Pt- BP-treated embryos did not show any phenotypic abnormality in comparison to untreated and cisplatin-treated embryos. Scale bar: 50 pm.
  • the lateral line neuromast hair cells in embryos were stained with a vital dye to analyse the loss of hair cells after Pt-BP treatment.
  • Cisplatin was used as a control, as it was known to affect hair cells in humans.
  • the fluorescent dye 2-[4-(dimethylamino)styryl]-N-ethylpyridinium iodide (DASPEI) [Molecular Probes, Eugene, OR] was used to stain hair cells within neuromasts as described previously (75).
  • Embryos were treated with Pt-BP (5, 10, and 50 pM) and cisplatin (positive control, 30 pM) and lateral line neuromasts were stained using DASPEI.
  • B Quantification of the lateral line neuromast cells stained by DASPEI after 48 h Pt-BP and Cisplatin treatments. ***P ⁇ 0.001; ****p ⁇ 0.0001 by one-way ANOVA, followed by Dunnett’s method for multiple comparisons. Scale bar: 50 pm.
  • Example 9 Pt release from Pt-BP at physiological and acidic, tumor-mimicking pH
  • Example 10 In vivo biodistribution of cold Pt-species and quantification of Pt accumulation
  • Sterile saline solution (0.9% NaCI) was used to dissolve platinum complexes.
  • the concentration of injected Pt-BP or Pt(NC>3)2(en) solutions was 2.5 mM platinum, calculated based on the maximum tolerated dose (MTD) for cisplatin of 6 mg per kg body weight of the mice (52).
  • MTD maximum tolerated dose
  • mice were euthanized with CO224 h after injection, after which blood (approximately 600 mg per mouse), liver, spleen, kidneys, heart, lungs, and bones (femur, humerus, tibia, and spine) were harvested. Approximately half of the tissues were prepared for inductively coupled plasma-mass spectrometry (ICP-MS) analysis by digestion in 65% (v/v) nitric acid at 75 °C for approximately three days until the tissues were digested completely. Each tissue was cut into three samples and the samples were weighed prior to digestion in nitric acid.
  • ICP-MS inductively coupled plasma-mass spectrometry
  • the digested solutions were diluted with up to 6 ml of Milli-Q water to obtain 2% (v/v) nitric acid in order to measure platinum concentrations by ICP-MS (X series I, Thermo Electron Corporation).
  • the detection limit for determining platinum concentration with ICP-MS was 1 ppb.
  • the standard solutions were prepared from 1000 mgT 1 platinum ICP standard Certipur ( 1.70341.0100, Merck) ranging from 1 ppb to 2500 ppb.
  • the measured isotopes for platinum were 194 Pt, 195 Pt, 196 Pt, and 198 Pt.
  • Example 11 Pt-DNA adducts quantification using High Resolution ICP-MS The remaining half of the tissues from all mice were dissected and weighed for DNA extraction. DNA was isolated using DNeasy Blood & Tissue Kit (Qiagen, USA) for soft tissue and ChargeSwitch® gDNA Plant Kit (Thermofisher, USA) for bone samples. The DNA was digested with DNase I Solution (Thermofisher, USA) and filtered using 0.2 pm acrodisc GHP before analysis for Pt content using high resolution-ICP-MS (Element2, Thermo Finnigan).
  • the detection limit for determining the platinum concentration was 2 ng/l.
  • the standard solutions were prepared from 1000 mg ⁇ ! 1 platinum ICP standard Certipur ( 1.70341.0100, Merck) ranging from 5 ppt to 10 ppb.
  • the measured isotopes for platinum were 194 Pt and 195 Pt.
  • thallium (Tl) was added as an internal standard and measured at a molecular mass of 205 Da, which was prepared using a 1000 mg ⁇ ! 1 thallium standard (CGTL- 1 , Inorganic Ventures) to correct for matrix effects and long-term fluctuations of the measurement signal.
  • the Pt-DNA adduct concentration is represented as percentage of Pt involved in adduct formation to the total amount of Pt accumulated in the specific tissue.
  • Example 12 In vivo biodistribution of radioactive Pt-species and micro-SPECT quantification of 195m pt biodistribution
  • mice were scanned under general anesthesia (isoflurane/02) for 15 to 60 minutes using the 1.0-mm diameter pinhole mouse high sensitivity collimator tube, followed by a CT scan (spatial resolution 160 mm, 65 kV, 615 mA) for anatomical reference.
  • Scans were reconstructed with Ml Labs reconstruction software using an ordered-subset expectation maximization algorithm, with a voxel size of 0.4 mm.
  • SPECT/CT scans were analyzed and maximum intensity projections (MIP) were created using the Inveon Research Workplace software (IRW, version 4.1).
  • a 3D volume of interest was drawn using CT threshold to differentiate soft tissue from skeletal tissue and uptake was quantified as the percentage injected dose per gram (%l D/g), assuming a tissue density of 1 g/cm 3 .
  • the hot spot in the skeletal tissue region of interest (ROI) was chosen with the location of the edge of the ROI contour representing 75% of maximum intensity.
  • the mice from i95m pt(N0 3 )2(en) group were euthanized with CO2 after 3 days due to excessive loss of body weight, whereas mice from treated with 195m pt-BP were sacrificed at the end of experiments.
  • Fig. 3 195m Pt radioactivity in mice. Percentage of injected dose (%ID) of 195m pt-BP and i95m pt(N0 3 ) 2 (en) in mice, measured using an ionization chamber. ** P ⁇ 0.01; ****P ⁇ 0.0001 as determined by two-way ANOVA with a Bonferroni (multiple comparisons) post-hoc test.
  • Example 13 Laser ablation ICP MS imaging of 195m pt biodistribution in mice tibia
  • the tibias of mouse were incubated in neutral buffered formaldehyde for 36 h.
  • Tibias were dehydrated in ascending grades of 70% to 100% ethanol and embedded in poly(methyl methacrylate) (pMMA) resin, freshly prepared by mixing 600 ml_ of methyl methacrylate monomer (Acros Organics BVBA, Geel, Belgium), 60 ml dibutyl phthalate (Merck KGaA, Darmstadt, Germany) and 1.25 g perkadox ® 16 (Aldrich, Netherlands).
  • pMMA poly(methyl methacrylate)
  • the polymerization was followed by cutting serial horizontal sections (perpendicular to the tibia sample) of 5 pm thickness within the trabecular region of interest using an RM2155 microtome with a TC 65 blade (Leica Microsystems GmbH, Wetzlar, Germany). Microscopic images were obtained using an inverted fluorescence/ bright field microscope (BZ-9000, Keyence Deutschland GmbH, Neu-lsenburg, Germany). For image recording and processing, the software BZ-II Viewer and BZ-II Analyzer were used, respectively. To calculate the percentage of platinum co-localized with calcium, the background of the image and all pixels without hard bone tissue were excluded from the calculations. A pixel is considered to be background if its calcium intensity is below 15%. The platinum concentrations of the remaining pixels were then added up and divided by the sum of the entire platinum image to yield the percentage of platinum co-localized with calcium.
  • Example 14 Pt-BP favors bone-specific delivery of Ptwith reduced Pt-DNA adduct formation
  • the bone-seeking properties of Pt-BP and its bisphosphonate-free precursor Pt(N0 3 Men) were evaluated by quantitatively analyzing Pt biodistribution using Inductively Coupled Plasma-Mass Spectrometry (ICP-MS) in different tissues (e.g. tibia, femur, humerus, spine, blood, heart, lung, kidney, liver, and spleen) as shown in Fig. 7A.
  • ICP-MS Inductively Coupled Plasma-Mass Spectrometry
  • sterile saline solutions containing Pt-BP or Pt(N0 3 Men) with identical Pt concentrations were , intravenously injected into the tail vein of mice, which were sacrificed 24 h after injection.
  • the harvested tissues were weighed and digested in acid for subsequent ICP-MS analysis of Pt content.
  • Fig 7B shows the Pt concentrations in different tissues 24 h after injection, normalized for specific tissue weight.
  • Pt-BP clearly showed bone-seeking properties as evidenced by higher amounts of Pt accumulation ( ⁇ 3 ng Pt/mg tissue) in hard tissue (bone) compared to BP-free control Pt(NC>3)2(en) complexes ( ⁇ 1 ng Pt/mg tissue).
  • Fig. 7. shows the biodistribution profile of Pt-BP and Pt(NC>3)2(en) in vivo.
  • A Schematic representation of Pt biodistribution study in C57BI/6N mice. Pt-BP or Pt(NC>3)2(en) compounds were administered intravenously in mice (2.5 mM Pt concentration) followed by sacrifice after 24h. Hard tissues (tibia, femur, humerus, spine), soft tissues (heart, lungs, kidney, liver, spleen) and blood were collected. Collected tissues were subjected to nitric acid digestion and genomic DNA extraction for Pt quantification using ICP-MS and High-resolution ICP-MS, respectively.
  • the specificity of the two different Pt-species towards bone tissue relative to other soft tissues is depicted as the percentage of injected dose per gram of tissue (%l D/g). Higher uptake of the Pt-BP was observed in hard tissue (12.18 ⁇ 0.56 %l D/g) compared to excretory organs such as the kidney (5.70 ⁇ 0.15 %ID/g), liver (2.34 ⁇ 0.17 %ID/g) and spleen (1.22 ⁇ 0.12 %l D/g).
  • Pt(N0 3 ) 2 (en) showed higher uptake in kidney (3.38 ⁇ 0.28 %l D/g) compared to hard tissue (2.69 ⁇ 0.26 %ID/g), liver (1.54 ⁇ 0.33 %l D/g) and spleen (0.38 ⁇ 0.04 %l D/g).
  • Pt-BP exhibit a 4.5-fold higher affinity for bone compared to Pt(N0 3 ) 2 (en)).
  • the efficacy of Pt-based drugs for cancer treatment relates to the formation of Pt-DNA adducts, which hinder mitotic processes and halt cell division.
  • Fig. 7D shows the relative Pt uptake within specific tissues leading to Pt-DNA adduct formation 24h after injection.
  • Pt-BP formed a low amount of Pt-DNA adducts in all tissues ( ⁇ 0.5%) except for the kidney (2.8%) and spleen (1.4%).
  • the bisphosphonate-free Pt complexes showed a much higher extent of Pt-DNA adduct formation, especially in the kidneys (4.8%) and spleen (9.8%).
  • Example 15 195m Pt-BP accumulates specifically in metabolicallv active bone Radioactive 195m pt-BP was synthesized using 195m Pt(NC>3)2(en) as the precursor for 195m pt as reported above. To compare the biodistribution of 195m pt-BP with the precursor i95m pt(N0 3 ) 2 (en), a dose of approximately 10MBq 195m Pt was administered intravenously via the tail vein in C57BL/6N mice.
  • Micro-SPECT/CT was used to visualize 195m Pt-BP uptake upon intravenous administration in a time window between 1 h to 7 days (Fig. 8A).
  • the micro-SPECT/CT scans clearly demonstrated effective targeting of 195m pt-BP to growth plates in long bones, whereas i95m pt(N0 3 ) 2 (en) showed specific accumulation in soft tissues.
  • growth plates are metabolically active regions in bones of young mice since they are responsible for longitudinal bone growth.
  • a gamma counter to quantify uptake of radioactive 195m pt-BP complexes (Fig. 8A).
  • Bone-specific uptake of 195m pt-BP was highest in the femur (3.1 ⁇ 0.37%ID/g) followed by the tibia (2.86 ⁇ 0.46%ID/g) and humerus (2.53 ⁇ 0.33%ID/g), whereas 19m Pt(NC>3)2(en) showed limited uptake in these bones (1.4 ⁇
  • 195m Pt uptake was highest in soft tissue for 195m Pt(NC>3)2(en) with significantly higher uptake compared to 195m Pt-BP in kidneys (3.95 ⁇ 0.24%ID/g), liver (3.22 ⁇ 0.28%ID/g), spleen (2.76 ⁇ 0.67%ID/g), and lungs (1.08 ⁇ 0.16%ID/g).
  • 195m pt-BP showed relatively low uptake in soft tissues ( ⁇ 0.11 % I D/g) , except for kidneys (0.43 ⁇ 0.16%l D/g).
  • Fig. 8 shows a biodistribution profile of 195m pt-BP and 195m Pt(N03)2(en) in vivo.
  • 195m pt-BP showed rapid and strong uptake in bone (1.8 ⁇ 0.25%I.D/g) at 1 h, which remained constant (1.0 ⁇ 0.12%l. D/g) from 24h until day 7.
  • 195m pt-BP uptake was significantly lower in soft tissue compared to hard tissue (0.93 ⁇ 0.27%I.D/g at 1 h and 0.18 ⁇ 0.03%I.D/g at 24h).
  • 195m Pt(NC>3)2(en) showed equal uptake in both hard (1.5 ⁇ 0.1 %l .
  • the quantification of the hot spots in bone represents a twofold increased uptake of 195m pt for 195m pt-BP compared to i95m pt(N0 3 ) 2 (en) for all time points (Fig. 9C).
  • the hard-to-soft tissue uptake ratio of 195m pt-BP increased periodically from 3.3 at 1h, 6 at 24h and 6.7 after 72h.
  • the hard- to-soft tissue uptake ratio of 195m Pt(NC>3)2(en) remained almost constant at 1 at 1 h, 1.2 at 24h and 1.2 at 72h (Fig. 9D).
  • Fig. 9 Quantification of 195m pt-BP and 195m Pt(N03)2(en) biodistribution in vivo.
  • mice (after 3 days) in mice measured using gamma counting.
  • B Percentage of injected dose (%ID/g) of 195m pt-BP and 195m Pt(N0 3 ) 2 (en) in mice as quantified from the micro-SPECT/CT images in soft and hard tissues
  • C Percentage of injected dose (%l D/g) of 195m pt-BP and i95m pt(N0 3 ) 2 (en) in mice as quantified from the micro-SPECT/CT images in the hard tissue region of interest (ROI) with the location of the edge of the ROI contour representing 75% of maximum intensity.
  • D 195m pt hard-to-soft tissue uptake ratio excluding bladder uptake at 1h.
  • Fig. 10 Spatial distribution of Pt in metabolically active bone.
  • A Representative elemental mapping of calcium (Ca), phosphorus (P) and Pt in the proximal tibia of mice upon systemic administration of 195m pt-BP and 195m Pt(N03)2en. The bottom pictures shown an overlay of calcium (red) and platinum (green) mapping where co-localization of platinum and calcium is indicated in yellow.
  • B Percentage of platinum co-localized with calcium in 195m pt-BP and i95m pt(N0 3 ) 2 (en) treated mice. ****P ⁇ 0.0001 , two-tailed student’s test.
  • Fig. 10A The calcium and phosphorus distribution (Fig. 10A) clearly conformed to the structure of trabecular bone as observed in the dark-colored features in the microscopic image (Fig. 10A).
  • the overlay of Ca and Pt distinctly differentiates co-localization of Pt with Ca (yellow) from Pt surrounding the trabecular structure (green).
  • 195m pt-BP showed predominant Pt uptake along the trabecular bone and inner region of the cortical bone, as reflected by an increased density of Pt co localization with calcium.
  • 195m Pt(N0 3 ) 2 (en) showed the highest Pt density in the soft tissue surrounding the cortical bone.
  • the total amount of Pt not co-localized with Ca refers to Pt in soft tissue of the proximal tibia where 10% and 20% of Pt was detected in soft tissue for 195m Pt(NC>3)2(en) and 195m pt-BP, respectively.
  • 195m pt-BP showed almost a fourfold increased accumulation of Pt in bone compared to 195m Pt(NC>3)2(en) as shown in Fig 10C.
  • the inventors synthesized a Pt-BP compound comprising two 195m pt moieties and a bone seeking bisphosphonate group to target the compound specifically to bone.
  • This synthesis of Pt-BP (40, 42) was modified compared to previously reported synthesis strategies to facilitate introduction of radioactive 195m pt by using 195m Pt(NC>3)2(en) as Pt precursor.
  • 195m Pt(NC>3)2(en) is obtained from H 2 [ 195m PtCl 6 ]-6H 2 0, which is the Pt precursor used for synthesis of radioactive cisplatin, thereby allowing for future upscaling and clinical translation of 195m pt-BP (30).
  • Example 17 195m Pt-BP accumulates specifically in metastatic intratibial bone tumors in mice
  • mice bearing metastatic tibial bone tumors were randomly distributed for different treatments, namely intravenous administration of 195m pt-BP, 195m Pt-Cisplatin or a placebo/negative control (PBS).
  • a dose of 9 ⁇ 0.5 MBq 195m pt-BP and a dose of 5 ⁇ 0.3 MBq of 195m Pt-Cisplatin was administered intravenously via the tail vein in C57BL/6N mice bearing metastatic tibial tumors.
  • the administered Pt dose for 195m Pt-Cisplatin was below the Pt toxicity dose of 6 mg/kg for mice, in order to prevent a significant body weight loss within the first 3 days post injection (p.i.).
  • Pt toxicity dose 6 mg/kg for mice, in order to prevent a significant body weight loss within the first 3 days post injection (p.i.).
  • no behavioral or body changes were observed for 195m pt-BP treated mice.
  • Micro-SPECT/CT images were acquired 1 h - 7 days post intravenous administration of 195m pt. (FIG 11)
  • the micro-SPECT/CT images were quantitatively analyzed to determine the uptake of radioactive 195m pt complexes in the metastatic tibial bone tumors(volume of interest, VOI) (Fig. 12).
  • 195m pt-BP showed rapid and strong uptake in the VOI (8.2 ⁇ 1.7%I.D/g) at 1 h p.i., which reduced to 6.2 ⁇ 1.5%I.D/g at 24 h and remained almost constant until day 7 (5.9 ⁇ 1.1 %I.D/g).
  • 195m Pt-Cisplatin exhibited reduced uptake in the VOI at all time points, with the highest value (3.7 ⁇ 0.8%I.D/g) obtained at 1 h.
  • 195m pt-BP uptake was significantly higher in tumor-bearing tibias compared to control tibias as shown in Fig. 12B.
  • 195m pt uptake (%I.D/g) in VOI was normalized to 195m pt uptake (%l . D/g) in control tibia within individual mice to determine bone tumor-selective uptake of 195m pt complexes.
  • 195m pt-BP uptake in VOI was increased by factor of 2.8 and 2.3 at 1 h and 24 h, respectively.
  • 195m Pt-Cisplatin showed equal uptake in both tibia at 1 h and 24 h.
  • A Percentage of injected dose (%ID/g) of 195m pt-BP and 195m Pt-Cisplatin in mice as quantified from the micro-SPECT/CT images in metastatic tibial (volume of interest, VOI).
  • B 195m Pt tumor tibia-to-control tibia uptake ratio. Data from 3-5 mice per group are presented. ***P ⁇ 0.001 as determined by two-way ANOVA with a Bonferroni (multiple comparisons) post-hoc test. For the ratios, paired t-test was used to determine the differences among the two groups where *P ⁇ 0.01 was considered as significantly different.
  • Example 18 Therapeutic effects of 195m pt accumulation in metastatic tibial bone tumors in mice
  • the entire tibia sections were stained with Elastine van Gieson (EvG) to distinguish hard and soft tissue region in tibia.
  • EvG Elastine van Gieson
  • the effect of 195m pt on inducing DNA double-strand breaks was evaluated by immunohistochemical staining of g-H2AC molecules.
  • FragEL DNA fragmentation detection kit was employed to detect apoptosis. Counterstaining with methyl green was performed for immunohistochemical staining of g-H2AC and FragEL DNA fragmentation detection to aid in the morphological evaluation.
  • the g-H2AC positive tumor cells and apoptotic tumor cells were observed as dark brown.
  • Fig. 13 Representative images of tumor region in bone metastases mice model.
  • Fig. 12 Based on immunohistochemical staining of g-H2AC molecules, therapeutic effects of 195m pt-BP on tumor tissue are visualized in Fig. 12 represented by high number of g-H2AC positive tumor cells confirming double-strand breaks in DNA for 195m pt-BP treated group. Similar results were also observed regarding detection of apoptotic cells for the 195m pt-BP treated group, which confirms the radiotherapeutic potential of 195m pt-BP. The amount of Y-H2AX-positive tumor cells and apoptotic cells was lower for mice treated with 195m Pt-Cisplatin.
  • Example 19 Targeted 195m pt accumulation in tibial lesion promotes radiation-induced double strand DNA breaks and induces apoptosis in metastatic tumor cells
  • tibia sections treated with various types of Pt-based drugs were stained with hematoxylin and eosin (H&E) to differentiate between bone marrow (dark purple) and tumor regions (light purple or purplish-pink) (Fig. 14A-H).
  • H&E hematoxylin and eosin
  • Fig. 14A-H This histological analysis confirmed the presence of tumor cell mass within the bone marrow and surrounding tibial lesions.
  • One specific lesion treated with 195m Pt-BP showed the presence of a necrotic tumor region (Fig. 14D).
  • the y-H2AX- positive tumor cell area within the tumor region for mice treated with 195m pt-BP was 4.6-fold higher than 195m Pt-cisplatin (0.3 ⁇ 0.1%), 11-fold higher than radio-inactive Pt-BP (0.2 ⁇ 0.1%) and 32-fold higher than saline control (0.05 ⁇ 0.04%) (Fig. 14U).
  • the apoptotic tumor cell area within the tumor for mice treated with 195m pt-BP was 3- fold higher than treatment of mice with 195m Pt-cisplatin (0.3 ⁇ 0.1%), 3-fold higher than radio inactive Pt-BP (0.3 ⁇ 0.2%) and higher than saline control (0.2 ⁇ 0.02%).
  • 195m Pt-BP treatment caused DNA damage and apoptosis in tumor cells more efficiently than all other treatment groups.
  • FIG. 14 Representative histochemical and immunohistochemical images of tibial lesions in a prostate cancer cell-induced bone metastasis model after treatment.
  • A-D Representative overview of H&E stained tibial lesions. The rectangular box within each group (A-D) is magnified in (E-H).
  • E-H bone marrow stained as dark purple
  • T tumor stained as light purple/purplish-pink
  • NR necrotic region
  • B bone stained as light pink
  • M-P Immunostaining of y-H2AX-positive tumor cells (dark brown) in the tibial lesions correspond to double-strand DNA breaks in tumor cells.

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Abstract

L'invention concerne un composé comprenant un agent de ciblage osseux capable de cibler des os d'une activité métabolique élevée (un pyrophosphate ou un bisphosphonate) et un élément radiotoxique (un isotope du Pt, de préférence 195mPt ou 193mPt, plus préférentiellement l'isotope 195mPt) s'est avéré efficace dans le traitement synergique du cancer des os. L'invention concerne également l'utilisation du composé en tant que produit pharmaceutique dans le traitement (en ciblant des dommages à courte portée induits par une émission d'électrons Auger) et/ou le diagnostic (par imagerie SPECT de l'émission gamma) de cancers des os malins primaires et/ou métastasés.
PCT/EP2020/073212 2019-08-19 2020-08-19 Isotope du platine combiné à des agents de ciblage osseux destinés à être utilisés dans des médicaments anticancéreux Ceased WO2021032784A1 (fr)

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