WO2022242438A1 - Conjugué de texaphyrine-folate et son procédé de préparation et son application - Google Patents

Conjugué de texaphyrine-folate et son procédé de préparation et son application Download PDF

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WO2022242438A1
WO2022242438A1 PCT/CN2022/089478 CN2022089478W WO2022242438A1 WO 2022242438 A1 WO2022242438 A1 WO 2022242438A1 CN 2022089478 W CN2022089478 W CN 2022089478W WO 2022242438 A1 WO2022242438 A1 WO 2022242438A1
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texaphyrin
folate
chelate
derivative
folic acid
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Chinese (zh)
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弗兰克·杰瑞·拉罗德
乔瑟夫·米歇尔·凯卡
顾梵
陈汉杰
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弗兰克·杰瑞·拉罗德
乔瑟夫·米歇尔·凯卡
顾梵
陈汉杰
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Publication of WO2022242438A1 publication Critical patent/WO2022242438A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
    • A61K49/0052—Small organic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
    • A61K49/221—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by the targeting agent or modifying agent linked to the acoustically-active agent
    • 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
    • A61K51/041—Heterocyclic compounds
    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K51/0446—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K51/0451—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. phorphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the technical field of chemical synthesis, and relates to a texaphyrin-folate chelate and a preparation method and application thereof.
  • the folate receptor is a prominent target that has been shown to be overexpressed in a variety of cancer cell lines. [1] Based on this, a variety of imaging and therapeutic agents have been developed targeting multiple cancer types in a single chemotherapy or imaging agent. [2] Although a worthy target, the FDA has not approved the use of folic acid as a targeted cancer therapy or imaging agent.
  • Texaphyrin is capable of binding metals in the "expanded" 5-coordination pocket. Its ability to form 24 different stable 1:1 complexes with metal cations has been demonstrated and has applications in cancer therapy and imaging. Texaphyrins absorb strongly in the near-infrared range (700-900 nm), so they can uniquely provide in vivo excitation. Additionally, Texaphyrins exhibit tumor selectivity and tolerable human toxicity in human subjects. In addition, changing the central coordination metal in the Texaphyrin core can tune the function of Texaphyrin.
  • Texaphyrins into nanoparticles, for example, a texaphyrin-phospholipid conjugate disclosed in Chinese invention patent CN107735402B on April 14, 2016, comprising lipids with phospholipids Texaporphyrin, texaporphyrin derivatives, or texaporphyrin analogs covalently linked to the plastid side chain; another example is for-texaphyrin (GdTx) encapsulated in nanoparticles for in vivo MRI and hyperthermia in the dose. So far, there is no report of Texaphyrin-folate conjugate.
  • Texaphyrin-folate conjugate which comprises a chelate of Texaphyrin, a Texaphyrin derivative, or a Texaphyrin homolog covalently bound to an O-(alkylamino)diaminophenol derivative of folic acid or a folic acid derivative.
  • a nanoparticle comprising the above-mentioned Texaphyrin-folate chelate.
  • the present invention particularly provides a method for preparing Texaphyrin-folate chelate, especially a method for preparing catechol folic acid and a 1:1 stable metal complex.
  • metals include: manganese, iron, cobalt, zinc, yttrium, technetium, cadmium, indium, bismuth, samarium, europium, gadolinium, terbium, dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.
  • the Texaphyrin-folate chelate or nanoparticle of the present invention is provided for therapeutic applications, including radiosensitization, radiotherapy, and photothermal therapy. Also used in medical imaging including MRI, two-photon, SPECT, PET, CT, fluorescence and ultrasound.
  • the present invention presents for the first time the design and synthesis of this compound in cancer imaging and therapy.
  • texaphyrin-folate chelate provides a Tumor-specific drugs.
  • R1-R6 are each independently selected from hydrogen and alkyl, where alkyl is alkyl substituted by OH, SH, heteroalkyl, aryl, ketoaryl or heterocyclyl.
  • Fig. 1 Synthetic reaction scheme of Texaphyrin folate complex synthesized from compound 7.
  • Figure 2 shows the synthetic reaction scheme for the formation of gadolinium-Texaphyrin folate complex.
  • Figure 3 shows a possible Texaphyrin-folate conjugate chelation library. Elements shown to have stable 1:1 chelation are in bold.
  • the present invention describes novel tumor-targeting molecular bodies, Texaphyrin-folate homologues (Texaphyrin-folate analogue) preparation. Although many molecules have previously been used to decorate Texaphyrin, the present invention demonstrates a novel class of compounds utilizing rational synthetic design.
  • diaminophenols provide an efficient way to obtain functionalized Texaphyrin structures.
  • Texaphyrins are a subclass of heterocyclic molecules called porphyrins and have a core moiety as shown below.
  • "Texaphyrin, a Texaphyrin derivative, or a Texaphyrin homologue” refers to a molecule having a core moiety represented by Formula 1 below.
  • Example Texaphyrins, Texaphyrin derivatives or Texaphyrin homologues are described in 6,375,930 and 10,729,7925.
  • the general scheme for the synthesis of catechol-folate conjugates is based on the combination of phenylenediamine and spacer folic acid. After the combination, when reacted with tripyran, phenylenediamine is easy to form free base phthalate- Folic acid conjugates. Its core may form known stable 1:1 complexes with a variety of metals including: manganese, iron, cobalt, zinc, yttrium, technetium, cadmium, indium, bismuth, samarium, europium, gadolinium, terbium , dysprosium, holmium, erbium, thulium, ytterbium, and lutetium.
  • the molecules can be fine-tuned for specific biomedical applications.
  • the invention includes all Texaphyrin-folate structures, as well as their metal coordination equivalents.
  • a Texaphyrin-folate chelate wherein the Texaphyrin-folate comprises Texaphyrin, a Texaphyrin derivative or a Texaphyrin homolog covalently linked to folic acid.
  • a Texaphyrin-folate chelate wherein the Texaphyrin-folate comprises Texaphyrin, a Texaphyrin derivative or a Texaphyrin homologue covalently linked to a folic acid spacer.
  • said Texaphyrin, Texaphyrin derivative or Texaphyrin homologue is covalently linked to folic acid.
  • Texaphyrin, a Texaphyrin derivative, or a Texaphyrin homologue is sequestered on a carbon chain linker with 0 to 20 carbons covalently linked to folic acid.
  • the core part of Texaphyrins has the potential to form known stable complexes with a variety of metals.
  • Exemplary metals with which the Texaphyrin-folate chelate complexes include, but are not limited to, manganese, manganese, iron, cobalt, zinc, yttrium, technetium, cadmium, indium, bismuth, samarium, europium, gadolinium, terbium, dysprosium, Holmium, Erbium, Thulium, Ytterbium, and Lutetium.
  • Texaphyrin-folate complex can be used as a diagnostic agent.
  • a "diagnostic” or “diagnostic agent” is any chemical moiety that can be used for diagnosis.
  • diagnostic agents include imaging agents such as those containing radioactive isotopes such as indium-111 and technetium-99m (indium-111 and technetium-99m); contrast agents containing iodine or gadolinium; horseradish peroxidase peroxidase), GFP, alkaline phosphatase or ⁇ -galactosidase and other enzymes; fluorescent substances, such as europium derivatives; luminescent substances, such as N-methacrylic acid derivatives, etc.
  • imaging agents such as those containing radioactive isotopes such as indium-111 and technetium-99m (indium-111 and technetium-99m); contrast agents containing iodine or gadolinium; horseradish peroxidase peroxidase), GFP, alka
  • a method for preparing the Texaphyrin-folate conjugate as described above which comprises reacting diaminophenoxybutylfolate 7 with tripyran 8 under suitable reaction conditions to Generate Texaphyrin-folate complex (Texaphyrin-folate complex) (Scheme 1).
  • Compounds 7, 8 and 9 can be substituted as needed.
  • Compounds 7 and 8 can optionally be exchanged to produce compound 9 or a Texaphyrin-folate conjugate with the desired Texaphyrin, a Texaphyrin derivative or a Texaphyrin homologue, as covered in U.S. Pat. Nos. 5, 162,509; 6,207,660; 4,935,498 and 6,375,930.
  • compounds 7, 8 and 9 can be represented by the following general formula:
  • R7-R10 will contain folate conjugation as exemplified for compound 7 in the above scheme.
  • the rest of R7-R10 can be independently selected from hydrogen, alkyl, heteroalkyl, cycloalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl and Acyl.
  • R7 A -R10 group is specified to contain 1-10 carbons.
  • R1-R6 are each independently selected from hydrogen and alkyl, where alkyl is alkyl substituted by OH, SH, heteroalkyl, aryl, ketoaryl or heterocyclyl.
  • R1-R6 can be selected for improved water solubility or favorable packing interactions.
  • the alkyl group is preferably an alkyl group lower than C 1-6.
  • group means a linked collection of atoms or single atoms in a molecular entity, where a molecular entity is any structurally or isotopically distinct atom, molecule, ion pair, radical, radical ion, complex, conformation Isomers and the like can be identified as individually distinguishable entities. Describing a group as being “formed” by a particular chemical transformation does not imply that the chemical transformation involves the formation of a molecular entity comprising the group.
  • alkyl refers to a group formed by removing hydrogen from a carbon of an alkane, where an alkane is an acyclic or cyclic compound consisting entirely of hydrogen atoms and saturated carbon atoms.
  • An alkyl group may include one or more substituents.
  • heteroalkyl means a group formed by removing hydrogen from a carbon of a heteroalkane, where a heteroalkane is an acyclic or cyclic compound consisting entirely of hydrogen atoms, saturated carbon atoms, and one or more heteroatoms .
  • a heteroalkyl group may include one or more substituents.
  • alkenyl refers to a group formed by removing hydrogen from a carbon of an alkene, where an alkene is an acyclic or cyclic compound consisting entirely of hydrogen and carbon atoms and including at least one carbon-carbon double bond.
  • An alkenyl group may include one or more substituents.
  • alkynyl refers to a group formed by removing hydrogen from a carbon of an alkyne, where an alkyne is an acyclic or cyclic compound consisting entirely of hydrogen and carbon atoms and including at least one carbon-carbon triple bond .
  • An alkynyl group may include one or more substituents.
  • heteroalkynyl refers to a group formed by removing hydrogen from a carbon of a heteroalkyne, wherein the heteroalkyne is composed entirely of hydrogen atoms, carbon atoms and one or more heteroatoms and includes at least one carbon- Acyclic or cyclic compounds with carbon triple bonds.
  • a heteroalkynyl group may include one or more substituents.
  • aryl refers to a group formed by removing a hydrogen from a ring carbon atom of an aromatic hydrocarbon.
  • Aryl groups can be monocyclic or polycyclic, and can include one or more substituents.
  • a heteroaryl group can be monocyclic or polycyclic and include one or one substituent.
  • substituted refers to a group that replaces one or more hydrogen atoms in a molecular entity.
  • heterocyclyl refers to a group that replaces one or more hydrogen atoms from a cyclic compound having at least two atoms of different elements as its ring members.
  • acyl refers to a group formed by removing a hydroxyl group from an oxyacid, ie RCO-.
  • Either of compounds 6 and 7 can be exchanged as desired to yield compound 8 or a Texaphyrin-folate conjugate with the desired Texaphyrin, Texaphyrin derivative or Texaphyrin homologue, prepared as described above
  • Texaphyrin-folate conjugates see US Patent Nos. 5,162,509; 6,207,660; 4,935,498, 6,375,930 and 10,729,792.
  • compound 6 may have the following general formula.
  • R7-R10 will have a folate conjugate as exemplified above.
  • the remainder of R7-R10 can be independently derived from hydrogen, alkyl, heteroalkyl, cycloalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, aryl, heteroaryl, heterocyclyl, and an acyl group .
  • Compound 5 can be transposed as desired to yield Compound 9 or a Texaphyrin-folate conjugate with the desired Texaphyrin, Texaphyrin derivative or Texaphyrin homologue, including those described in the US patents. See US Patent Nos. 5,162,509; 6,207,660; 4,935,498, 6,375,930, and 10,729,792 when additionally performing the above operations.
  • compound 4 may have the following general formula.
  • R7-R10 will contain a linker that binds folic acid.
  • the rest of R7-R10 can be as above.
  • Another aspect of the present invention provides a method for preparing compound 5 from compound 4 by the classic Gabriel synthesis method under suitable conditions.
  • a method for synthesizing Texaphyrin, Texaphyrin derivatives or Texaphyrin homologues comprising cleaving Texaphyrin, Texaphyrin derivatives or Texaphyrin homologues from the above-mentioned Texaphyrin-folate conjugate.
  • enzymes are used for cleavage. Lyase is best used in WO2012 Lyase described in /167350.
  • Texaphyrins-folate chelate in positron emission spectroscopy, photodynamic therapy, photothermal therapy or fluorescence imaging.
  • Texaphyrin-folate chelate in magnetic resonance imaging, such as MRI, two-photon, SPECT, PET, CT, fluorescence or ultrasound medical imaging.
  • the synthetic route was designed to avoid possible alternatives, excluding the necessity to form a central phenylenediamine conjugated to folic acid. Trying to form Texaphyrin with an exocyclic carboxylate, trying to conjugate the conjugate with folic acid using different conditions and synthetic strategies.
  • reaction vessel was then heated to 50°C for 30 minutes while protected from light. Upon completion, the solvent was completely removed under reduced pressure. The residue was then washed with hexane (5 x 10 mL) to remove hydrophobic colored impurities to obtain 8 as a dark red solid.
  • gadolinium(III) complex 10 Add 8 (34.02 02 mol), acetic acid g(III) hydrate (35.73 ⁇ mol) and triethylamine (47.43 ⁇ L, 340.25 ⁇ mol) to a reaction vessel, in Add methanol to 4 mL and stir in air at 60 °C for 2 h. Upon completion, the solvent was completely removed and hexane (3 x 10 mL) was added to the residue to remove the light pink impurity to give 9 (75%, 25.5 ⁇ mol) as a dark green solid.
  • Lutetium(III) complex Add 8 mL (23 ⁇ mol), 5 mL methanol solution of lutetium(III) acetate hydrate (24.14 ⁇ mol) and triethylamine (229 ⁇ mol) to the reaction vessel, stir until ventilated at 52 °C for 1.5 Hour. Upon completion, the solvent was completely removed and hexane (3 x 10 mL) was added to the residue to remove the light pink impurity to give lutetium(II)-complexed Texaphyrin-folate as a green solid: 14.5 ⁇ mol , yield 63%.
  • Iron(II) complex In 5 mL of methanol, add 8 (15.63 ⁇ mol), iron(II) acetate (16.41 ⁇ mol), and triethylamine (156.33 ⁇ mol) to the reaction vessel, and stir to air at 52 °C for 1.25 hours. Upon completion, the solvent was completely removed and hexane (3 x 10 mL) was added to the residue to remove the light pink impurity to give iron(II) complexed grass-green Texaphyrin-folate as a dark green solid : 10.8 ⁇ mol, yield 69%.
  • Cobalt(II) complex Add 8 (13.79 ⁇ mol), cobalt(II) acetate (14.48 ⁇ mol), and triethylamine (137.94 ⁇ mol) in 5 mL of methanol to a reaction vessel and stir until air is dissolved at 52 °C for 45 minutes. Upon completion, the solvent was completely removed and hexane (3 x 10 mL) was added to the residue to remove the light pink impurities to give cobalt(II) complexed Texaphyrin-folate in the form of a dark green solid: 11.2 ⁇ mol, 81% yield.
  • Manganese(II) complex Add 8 (15.81 ⁇ mol), manganese(II) acetate (16.60 ⁇ mol), and triethylamine (158.13 ⁇ mol) in 5 mL of methanol to a reaction vessel and stir in open air at 52 °C for 1.5 hours. Upon completion, the solvent was completely removed and hexane (3 x 10 mL) was added to the residue to remove the light pink impurity to give cobalt(II) complexed Texaphyrin-folate as a dark green solid: 12.1 ⁇ mol, Yield 76%.
  • Gallium(III) complex Add 8 (15.81 ⁇ mol), gallium(III) acetate (16.60 ⁇ mol) and triethylamine (158.13 ⁇ mol) to the reaction vessel in 5 mL of methanol and stir to air at 52 °C 1.5 hours. Upon completion, the solvent was completely removed and hexane (3 x 10 mL) was added to the residue to remove the light pink impurity to give gallium(III)-complexed grass-green Texaphyrin-folate as a dark green solid : 11.4 ⁇ mol, yield 72%.
  • Manganese(II) complexes can be subjected to dual PET analysis.
  • uncomplexed carbon 11, nitrogen 13, oxygen 15 and fluorine 18 derivatives can be subjected to dual PET analysis.
  • Texaphyrins have a unique and powerful chelating ability and can form stable 1:1 complexes with a variety of metal ions. With this capability, the ability of Texaphyrin metal chelates in magnetic resonance imaging (MRI) has been evaluated.
  • the unique and favorable intrinsic properties of Gd-texaphyrin have led to its entry into phase III clinical trials in patients with non-small cell lung cancer-derived brain metastases.
  • Gd-texaphyrin is not FDA-approved, although neurological progression was delayed in patients treated with Gd-texaphyrin and whole-brain radiation compared with radiation alone.
  • Another paramagnetic Texaphyrin used in MRI contrast enhancement assessment is Mn-nanotexaphyrin. Novel self-assembled amphiphilic Texaphyrin-phospholipid conjugates yielded an organic-based multifunctional nanoparticle. 4 The authors chose to study a paramagnetic Mn-texaphyrin-based reagent because of its ability to simultaneously reduce T1 and T2 and the T2 relaxation constant in tissue. Mn–nanotexaphyrin was then evaluated in VX-2 head and neck tumor rabbits with cervical lymph node metastases.
  • Mn–nanotexaphyrin was injected subcutaneously at the proximal site of the tumor, followed by 2-hour T1- and T2-weighted imaging aimed at enhancing the visualization of lymphatic drainage from the tumor site to metastases Disease lymph nodes. Imaging results showed greatly enhanced visualization of lymphatic drainage from the tumor site to adjacent metastatic lymph nodes.
  • SSNs sentinel lymph node
  • In vivo MRI All animals received human care in accordance with policies established by the organizational animal care committees, the Ontario Research Animals Act and the Canadian Council for Animal Care. All animal studies were approved by protocol of the ORGANIZAION Animal Health Committee. Male New Zealand white rabbits (Charles River, Wilmington, MA, USA) weighing 2.0 to 3.5 kg were injected with 300 ⁇ L of LVX-2 tumor cell suspension (5 x 106 cfu /mL) to induce tumor entry into the bullas muscle. Two weeks after inoculation, tumors formed at the site of VX2 cell injection, and all rabbits developed at least one cervical lymph node metastasis.
  • One rabbit with lymph node metastases confirmed by CT imaging was injected subcutaneously with 1.5 mL of 8 mg/mL Ga-texaphyrin-folate subcutaneously surrounding the tumor area (similar to the sentinel lymph node biopsy (SLNB) procedure using tech 99).
  • MRI was performed on a 7 Tesla preclinical MR imaging system (Biospec, Inc., Ettlingen, Germany).
  • imaging was performed using a B-GA20S gradient coil and an orthogonal cylindrical RF volume coil manufactured by Bruker with an inner diameter of 15.5 cm. Orient the rabbit in the abdominal recumbent position within the plexiglass holder and insert it first into the hole. Anesthesia is delivered directly to the nose cone using an MR compatible system.
  • Coronal and axial T2-weighted imaging was performed at baseline, and coronal and axial T2-weighted and T1-weighted imaging were performed 2 hours after subcutaneous contrast injection. All acquisitions share a spatial resolution of 1x1x1.5 mm. Coronary acquisition has a 110x80 mm field of view, 110x80 matrix size and 36 slice coverage. Axial acquisition has a 96x72 mm field of view, 96x72 mm matrix size and 55 slice coverage. All T2-weighted image sets were acquired with an effective echo time of 66.5 msec (echo time 9.5 msec; rarity factor 14) and a repetition time of 6000 msec.
  • T1-weighted image sets were acquired with an effective echo time of 9.5 msec (echo time 9.5 msec; rarity factor 2) and a repetition time of 1000 msec. Acquisition times varied from 4 min 24 s for coronal 72-weighted imaging to 7 min 30 s for axial R2-weighted imaging.
  • MRI with Mn-texaphyrin folic acid-enabled T1- and T2-weighted imaging showed marked signal enhancement following contrast agent administration.
  • T1- and T2-weighted images at 30 minutes post-injection showed improved signal, clear borders, and visualization of tumor histology.
  • T1 and T2 maps were also acquired. The figure shows that at 45 minutes T1 and T2 values decreased in the peripheral region of the tumor and the contrast agent was retained.
  • MR imaging was performed using a B-GA12 gradient coil and an orthogonal cylindrical radiofrequency (RF) volume coil manufactured by Bruker with an inner diameter of 35 mm.
  • the mouse was placed prone inside the plastic stand with the head inserted into the hole first.
  • Anesthesia (1.8% isoflurane) is delivered directly into the nose cone.
  • Imaging included baseline, 15, 45, 90, and 120 minute post-injection sessions. Each session provided axial T2-weighted and T1-weighted image sets and axial quantitative T2 and T1 mapping acquisitions and took 4 min, 4 min 36 s, 14 min 57 s, and 16 min 40 s, respectively.
  • T2- and T1-weighted image sets were acquired with effective echo times of 48 and 10 msec (RARE factors of 12 and 2, respectively, at a common echo time of 8 msec) and repetition times of 4000 and 1000 msec, respectively.
  • Quantitative T2 mapping used the multiple spin echo technique (32 echoes from 12–384 ms; 12 ms refocusing interval).
  • Quantitative T1 mapping was performed using the variable repetition time method (RARE factor 2; seven repetition times 400, 800, 1200, 1600, 2000, 3500, 5000 ms).
  • T2 and T1 map generation uses online Bruker processing.
  • Orthotopic PC3 prostate tumor model Athymic nude male mice were purchased from Harlan Laboratories. A 5 mm long incision into the peritoneum was made in the abdomen; the bladder and seminal vesicles were partially excised from the abdominal cavity to expose the dorsal lobe of the prostate. Inject 5 ⁇ 105 PC-3M-luc-C6 cells (cell line expressing Lucifer, Caliper)

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Abstract

La présente invention concerne le domaine technique de la synthèse chimique, et concerne un conjugué de texaphyrine-folate et son procédé de préparation et son application. Le conjugué de texaphyrine-folate contient un conjugué formé par la liaison de texaphyrine, d'un dérivé texaphyrine ou d'un homologue de texaphyrine à un folate ou un dérivé de O-(alkyl amino)diaminophénol d'un dérivé folate à l'aide d'une liaison covalente. Le conjugué ou les nano-particules de texaphyrine-folate décrit·es dans la présente invention présente·nt des applications dans le traitement comprenant la radiosensibilisation, la radiothérapie et la thérapie photothermique, et peut·peuvent également être utilisé·es pour l'imagerie médicale comprenant l'IRM, la fluorescence excitée à deux photons, SPECT, PET, CT, la fluorescence et les ultrasons.
PCT/CN2022/089478 2021-05-21 2022-04-27 Conjugué de texaphyrine-folate et son procédé de préparation et son application WO2022242438A1 (fr)

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