EP4351650A1 - Composition and method for dual targeting in treatment of neuroendocrine tumors - Google Patents

Composition and method for dual targeting in treatment of neuroendocrine tumors

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Publication number
EP4351650A1
EP4351650A1 EP22820793.2A EP22820793A EP4351650A1 EP 4351650 A1 EP4351650 A1 EP 4351650A1 EP 22820793 A EP22820793 A EP 22820793A EP 4351650 A1 EP4351650 A1 EP 4351650A1
Authority
EP
European Patent Office
Prior art keywords
composition
group
compound
tumor
thyrointegrin
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.)
Pending
Application number
EP22820793.2A
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German (de)
English (en)
French (fr)
Inventor
Shaker Mousa
Mehdi Rajabi
Ozlem O. Karakus
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NanoPharmaceuticals LLC
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NanoPharmaceuticals LLC
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Priority claimed from US17/340,843 external-priority patent/US11351137B2/en
Application filed by NanoPharmaceuticals LLC filed Critical NanoPharmaceuticals LLC
Publication of EP4351650A1 publication Critical patent/EP4351650A1/en
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active 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
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • 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

Definitions

  • compositions for targeting and treating neuroendocrine tumors may include thyroid hormone DvE3 integrin receptor antagonists (referred to as “thyrointegrin antagonists”) and compounds that are targets of the norepinephrine transporter (NET) or the catecholamine transporter (such as benzyl guanidine (“BG”) or its derivatives).
  • thyrointegrin antagonists thyroid hormone DvE3 integrin receptor antagonists
  • NET norepinephrine transporter
  • BG catecholamine transporter
  • norepinephrine/catecholamine transporter (“norepinephrine transporter”) is essential for norepinephrine uptake at the synaptic terminals and adrenal chromaffin cells. In neuroendocrine tumors, the norepinephrine transporter is highly active and can be targeted for imaging and/or therapy with localized radiotherapy.
  • MIBG meta-iodobenzylguanidine
  • a guanidine analog of norepinephrine.123I/131I-MIBG theranostics have been applied in the clinical evaluation and management of neuroendocrine tumors, especially in neuroblastoma, paraganglioma, and pheochromocytoma.123I-MIBG imaging has been used in the evaluation of neuroblastoma, and 131I-MIBG for the treatment of relapsed high-risk neuroblastoma, however, the outcome remains sub-optimal.
  • PAT Positron Emission Tomography
  • Integrins are a super-family of cell surface adhesion receptors, which control the attachment of cells with the solid extracellular environment, both to the extracellular matrix (ECM), and to other cells. Adhesion is of fundamental importance to a cell; it provides anchorage, cues for migration, and signals for growth and differentiation. Integrins are directly involved in numerous normal and pathological conditions, and as such are primary targets for therapeutic intervention.
  • Integrins are integral transmembrane proteins, heterodimers, whose binding specificity depends on which of the 14 ⁇ -chains are combined with which of the 8 ⁇ -chains.
  • the integrins are classified in four overlapping subfamilies, containing the ⁇ 1, ⁇ 2, ⁇ 3 or ⁇ v chains.
  • a cell may express several different integrins from each subfamily. In the last several decades, it has been shown that integrins are major receptors involved in cell adhesion, and so may be a suitable target for therapeutic intervention. Integrin ⁇ v ⁇ 3 regulates cell growth and survival, since ligation of this receptor can, under some circumstances, induce apoptosis in tumor cells.
  • Thyrointegrin antagonists have been shown to effect tumor angiogenesis by interaction with integrin ⁇ v ⁇ 3.
  • the effect of thyrointegrin antagonists is described in U.S. Pat. Pub. No.2017/0348425 titled Non-Cleavable Polymer Conjugated with Alpha V Beta 3 ( ⁇ v ⁇ 3) Integrin Thyroid Antagonists, the contents of which are incorporated by reference.
  • a composition comprises a compound of a general formula: or a salt thereof; wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group; wherein R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, iodine, and an alkane group; and n 1 ⁇ 0; n 2 ⁇ 1; and Y includes an amine.
  • a method for dual targeting of tumor cells comprises administering a composition comprising: a compound of a general formula: or a salt thereof; wherein R1, R2, R3, and R4 are each independently selected from the group consisting of hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group; wherein R5, R6, R7, and R8 are each independently selected from the group consisting of hydrogen, iodine, and an alkane group; and n 1 ⁇ 0; n 2 ⁇ 1; and Y includes an amine.
  • a composition comprises N-benzyl guanidine; and a thyrointegrin ⁇ v ⁇ 3 receptor antagonist; wherein the N-benzyl guanidine and the thyrointegrin ⁇ v ⁇ 3 receptor antagonist are connected by a linker.
  • Figure 1 depicts a general formula of an exemplary composition for use in dual targeting of neuroendocrine tumors
  • Figure 2a depicts another general formula of an exemplary composition having a linker with a monoamine
  • Figure 2b depicts another general formula of an exemplary composition having a linker with a diamine
  • Figure 2c depicts another general formula of an exemplary composition having a linker with a triazole
  • Figure 3 depicts one exemplary composition for use in dual targeting of neuroendocrine tumors, referred to as Composition 300, BG-PEG-TAT, or BG-P-TAT
  • Figure 4a depicts an overview of a synthetic pathway for Composition 300 from Figure 3
  • Figure 4b depicts a detailed schematic of the synthetic pathway of Figure 4a
  • Figure 4c depict
  • compositions disclosed and described herein may be directed toward anti- angiogenic agents, particularly thyrointegrin antagonists, which may be capable of interacting with one or more cell surface receptors of the integrin ⁇ v ⁇ 3 receptor family.
  • compositions disclosed and described herein may also be directed toward targets of the norepinephrine transporter (also known as the catecholamine transporter).
  • Targets of the norepinephrine transporter may act as neuroendocrine tumor cell targeting agents.
  • the compositions disclosed and described herein may be directed toward a composition containing both a thyrointegrin antagonist and a norepinephrine transporter target. Further, the composition may use a polymer or other linker to link the thyrointegrin antagonist and the norepinephrine transporter target.
  • the norepinephrine transporter is a regulator of catecholamine uptake in normal physiology and is highly expressed and over-active in neuroendocrine tumors like neuroblastoma.
  • MIBG meta-iodobenzylguanidine
  • MIBG meta-iodobenzylguanidine
  • analogs such as (123)I / (131)I- MIBG or analogs having Fluoride (F18) instead of Iodide (radioactive) may also be used for diagnostic imaging of neuroblastoma and other neuroendocrine tumors.
  • F18 Fluoride
  • Iodide radioactive
  • benzyl guanidine and its derivatives demonstrated limited anti-cancer efficacy of neuroblastoma despite its maximal (90-100%) uptake into neuroblastoma and other neuroendocrine tumors.
  • treatment combinations of norepinephrine transporter targets such as benzyl guanidine or its derivatives together with thyrointegrin antagonists such as triazole tetraiodothyroacetic acid derivatives did not exceed 50% suppression of neuroblastoma growth and viability.
  • norepinephrine transporter targets such as benzyl guanidine derivatives and thyrointegrin antagonists such as triazole tetraiodothryoacetic acid derivatives via different polymer linker such as Polyethylene Glycol (PEG)
  • PEG Polyethylene Glycol
  • a thyrointegrin antagonist conjugated via a linker with a norepinephrine / catecholamine transporter target compound may provide a composition that has a dual targeting effect for neuroendocrine tumor targeting.
  • the composition may comprise an alpha-V-beta-3 ( ⁇ v ⁇ 3) integrin-thyroid hormone receptor antagonist linked to benzyl guanidine (or a benzyl guanidine derivative) according to one embodiment of the invention.
  • the compositions described herein may be comprised of compounds, for example a thyrointegrin antagonist or derivative thereof covalently linked to a target of the norepinephrine transporter to form a single chemical entity.
  • the thyrointegrin antagonist and the norepinephrine target may be joined via a linker.
  • Figure 1 depicts an embodiment of a general formula 100 comprising a thyrointegrin antagonist 110 joined to a norepinephrine transporter target 120 via a linker 130.
  • the composition may be referred to as a thyrointegrin antagonist derivative conjugated to a benzyl guanidine derivative via the linker 130, or a thyrointegrin antagonist derivative conjugated to a benzyl guanidine derivative modified with the linker 130.
  • Figure 1 depicts a carboxylic acid form of the general formula 100.
  • a salt e.g. a sodium salt
  • the linker 130 comprises a spacer 132 and a polymer 131. The linker 130 resists biodegradation such that the linker remains uncleaved under physiological conditions.
  • the spacer 132 comprises a CH 2 unit and an adjacent repeating linkage of methylene (CH 2 ) units which may be defined by n1 repeats wherein n1 is an integer that is ⁇ 0. In other embodiments, n1 may be ⁇ 1, ⁇ 2 or ⁇ 3.
  • the linker 130 further comprises a moiety “Y.” Embodiments of the moiety “Y”, may in some instances be may be an amine.
  • the moiety Y of the general formula may be a divalent alkane having one amine group or a divalent alkane having two amine groups as shown by the examples of general formula 200a and 200b of Figures 2a and 2b.
  • the moiety Y may be a triazole as shown by the example of general formula 200c shown in Figure 2c.
  • the polymer 131 may comprise a polyether such as polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • Other polymers may be used, including chitosan, alginic acid, hyaluronic acid, and other polymers.
  • the polymer may have a molecular weight between 200 and 4,000g per mole.
  • the term thyroid antagonist describes a compound that has the ability to inhibit or antagonize one or more thyroid hormone receptors known by a person skilled in the art, for example the integrin family of thyroid hormone receptors, such as the thyroid hormone cell surface receptor ⁇ v ⁇ 3.
  • the thyrointegrin antagonist 110 may be an anti-angiogenic thyroid hormone or a thyroid hormone receptor antagonist.
  • the thyrointegrin antagonist 110 may be an alpha-V-beta-3 ( ⁇ v ⁇ 3) integrin- thyroid hormone receptor antagonist.
  • Specific embodiments of the thyrointegrin antagonist 110 may include tetraiodothyroacetic acid (tetrac), triiodothyroacetic acid (triac), derivatives thereof and variations thereof.
  • Examples of one or more variations of the thyrointegrin antagonist comprising tetrac and triac may include, in some embodiments Diaminotetrac (DAT) or Diaminotriac (DATri) (hereinafter may be referred to interchangeably as “DAT”), Monoaminotetrac (MAT) or Monoaminotriac (MATri) (hereinafter referred to interchangeable as “MAT”), Triazoletetrac (TAT) or Triazoletriac (TATri) (hereinafter referred to interchangeable as “TAT”), derivatives thereof or other thyroid antagonist known by those skilled in the art.
  • DAT Diaminotetrac
  • DATri Diaminotriac
  • MAT Monoaminotetrac
  • MATri Monoaminotriac
  • TAT Triazoletetrac
  • TTri Triazoletriac
  • derivatives thereof or other thyroid antagonist known by those skilled in the art may be of the type described in U.S. Pat. Pub.
  • thyrointegrin antagonists based on the general structure 100 from Figure 1 are shown below in Table 1.
  • Table 1 [0062]
  • the variables depicted as R5, R6, R7, and R8 may each independently be substituted for molecules such as hydrogen, iodine, and alkanes.
  • the alkanes have four or fewer carbons.
  • the variables depicted as R5, R6, R7, and R8 may each independently be substituted for molecules of hydrogen, iodine, or alkane groups such as isopropyl or isobutyl. In the embodiments of Table 1, the alkanes have four or fewer carbons.
  • the norepinephrine transporter target 120 may be a neuroendocrine tumor cell targeting agent. As an example, the norepinephrine transporter target 120 may be benzyl guanidine or a benzyl guanidine derivative.
  • the norepinephrine transporter target 120 may be N-benzyl guanidine or a derivative thereof.
  • Exemplary norepinephrine transporter targets 120 based on the general formula 100 from Figure 1 are shown below in Table 2.
  • Table 2 [0066]
  • the variables depicted as R1, R2, R3, and R4 may be each independently be substituted for molecules such as hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group.
  • the variables depicted as R1, R2, R3, and R4 may be each independently be substituted for molecules of hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group as described above in Table 2. Additional embodiments and substitutions may also be used.
  • at least one of R1, R2, R3 and R4 is a radiolabel. Examples of suitable radiolabels include I(123), I(131) and F(18). The compound may be administered to humans or animals.
  • any of the exemplary thyrointegrin antagonists 110 may be joined via the linker 130 to any of the exemplary norepinephrine transporter targets 120 (along with any of the other norepinephrine transporter target embodiments taught herein) to form a composition.
  • the exemplary norepinephrine transporter targets 120 (along with any of the other norepinephrine transporter target embodiments taught herein) to form a composition.
  • Table 1 and Table 2 there are a large number of compounds that may be used as the thyrointegrin antagonist 110 and a large number of compounds that may be used as the norepinephrine transporter target 120 in the composition.
  • each of the compositions described herein may have multiple types of utility for treating a plurality of different diseases modulated by angiogenesis or the inhibition thereof.
  • Each of the compositions described in the present disclosure in view of presence of the thyrointegrin antagonist 110 present in the described compositions, may have an affinity for targeting the integrin receptor ⁇ v ⁇ 3 located on numerous types of cells found throughout the human body and various animal bodies.
  • each of the compositions described in the current application may have utility for treating a plurality of different diseases characterized by activity of the norepinephrine transporter.
  • Each of the compositions described in the present disclosure in view of presence of the norepinephrine transporter target 120 present in the described compositions, may each have an affinity for targeting numerous types of cells found throughout the human body and various animal bodies that utilize the norepinephrine transporter.
  • Each of the compositions described in the present disclosure may have increased affinity for targeting cells demonstrating increased or above average activity of the norepinephrine transporter, such as neuroendocrine tumor cells.
  • the composition may have increased affinity for targeting neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumor, and carcinoid tumor cells.
  • the composition may have increased utility and efficacy against certain diseases and/or conditions.
  • neuroendocrine tumors are susceptible to treatment with thyrointegrin antagonists while also demonstrating increased activity of the norepinephrine transporter.
  • the compositions described herein make use of both compounds for a dual targeting effect in treatment of neuroendocrine tumor cells.
  • embodiments of the chemical structure may include one or more variables defining the additional features of the thyrointegrin antagonist 110 of the general formula 100.
  • the variables depicted as R5, R6, R7, and R8 may be each independently be hydrogen, iodine, and alkanes as described above in Table 1.
  • the thyrointegrin antagonist 110 of the general formula 100 may comprise a substitution of iodine for R5–R8, resulting in the formation of a tetraiodothyroacetic acid (tetrac) derivative having a three-carbon linker and a monoamine as the Y moiety.
  • tetrac tetraiodothyroacetic acid
  • General formula 200a may be referred to as monoamine-tetrac (MAT) conjugated via PEG to benzyl guanidine or a benzyl guanidine derivative.
  • the tetrac molecule further comprises a diamino Y moiety connected to the carbon linker.
  • This general formula 200b may be referred to as diamino tetrac (DAT) conjugated via PEG to benzyl guanidine or a benzyl guanidine derivative.
  • the general formula 200c may comprise a triazole moiety connected to the single carbon of the carbon linker.
  • This general formula 200c may be referred to as triazole tetrac (TAT) conjugated via PEG to benzyl guanidine or a benzyl guanidine derivative.
  • thyrointegrin antagonist compounds may also be used in forming the compositions described herein.
  • the general structure of the thyrointegrin antagonists 110a, 110b, and 110c may be used wherein only R5–R7 include iodine, thereby giving similar triac derivatives.
  • R5–R7 include iodine
  • similar structures may be used in which the thyrointegrin antagonist comprises a substitution of other elements or functional groups for any and/or all of R5–R8.
  • the norepinephrine transporter target 120 may comprise benzyl guanidine or a benzyl guanidine derivative.
  • Embodiments of the chemical structure of the norepinephrine transporter target 120 may include one or more variables defining the additional features of the norepinephrine transporter target 120 of the general formula 100 shown in Figure 1.
  • the variables depicted as R1, R2, R3, and R4 may be each independently be substituted for molecules of hydrogen, iodine, fluorine, bromine, a methoxy group, a nitro group, an amine group, and a nitrile group as described above in Table 2.
  • Figure 3 depicts an exemplary Composition 300 of the general formula 100.
  • Composition 300 comprises triazole tetrac conjugated to benzyl guanidine modified PEG.
  • Composition 300 may also be referred to as BG-PEG-TAT or BG-P-TAT.
  • Synthesis of the compositions described herein is demonstrated below, primarily with reference to the exemplary composition shown in Figure 3, namely Composition 300. Synthesis of similar compositions, namely Composition 201 and Composition 202 (see Figure 4c–4f) are also provided as examples and without limiting the disclosure to such compositions.
  • Example 1a Synthesis of Exemplary Composition 300 [0079] This example provides a sample method for preparing Composition 300 shown in Figure 3.
  • Composition 300 is referred to as BG-PEG-TAT or BG-P-TAT.
  • Composition 300 has the chemical name of 2-(4-(4-((1-(20-(4-(guanidinomethyl)phenoxy)-3,6,9,12,15,18-hexaoxaicosyl)-1H-1,2,3-triazol-4- yl)methoxy)-3,5-diiodophenoxy)-3,5-diiodophenyl)acetic acid, or [4-(4- ⁇ 1-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[2-(4- Guanidinomethyl-phenoxy)-ethoxy]-ethoxy ⁇ -ethoxy)-ethoxy]-ethoxy ⁇ -ethoxy)-ethyl]-1H-[1, 2,3]triazol- 4-ylmethoxy ⁇ -3,5-diiodo-phenoxy)-3,5-diiodo-phenyl]
  • the molecular weight of Composition 300 is 1284.44g/mol.
  • All commercially available chemicals were used without further purification. All solvents were dried and anhydrous solvents were obtained using activated molecular sieves (0.3 or 0.4 nm depending on the type of solvent). All reactions (if not specifically containing water as reactant, solvent or co-solvent) were performed under Ar or 2 atmosphere, in oven-dried glassware. All new compounds gave satisfactory 1 H NMR and mass spectrometry results. Melting points were determined on an Electrothermal MEL-TEMP® melting point apparatus and then on a Thomas HOOVER Uni-mel capillary melting point apparatus.
  • Infrared spectra were recorded on a Thermo Electron Nicolet Avatar 330 FT-IR apparatus. UV spectra were obtained from a SHIMADZU UV-1650PC UV-vis spectrophotometer.
  • the solution-state NMR experiments were all performed a Bruker Advance II 800 MHz spectrometer equipped with a cryogenically cooled probe (TCI) with z-axis gradients (Bruker BioSpin, Billerica, MA) at the Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute (RPI, Troy, NY). All tubes used were 5 mm outside diameter.
  • Figure 4a depicts an overview of a synthetic pathway for Composition 300.
  • Figure 4b depicts a detailed schematic of the synthetic pathway from Figure 4a.
  • Figure 4a shows the scheme of synthesis of Composition 300 as an example of conjugation of tetrac analogs to benzyl guanine modified PEG via click chemistry. Other synthetic pathways may be used.
  • the individual steps of the scheme of synthesis of Composition 300 shown in Figure 4b will be described in more detail below in which the intermediary products are referred to by the number shown in the click chemistry scheme.
  • Synthesis of heterobifunctional PEG is a synthetic pathway for Composition 300.
  • heterobifunctional linker is commercial available, for the purposes of this example the following synthetic route for preparation is used: Langmuir 2014, 30, 11301 ⁇ 11306 Langmuir 2014, 30, 11301 ⁇ 11306 [0086] Synthesis of Product 2 tert-butyl [(4-hydroxyphenyl)methyl]carbamate 2. [0087] Tert-butyl [(4-hydroxyphenyl)methyl]carbamate was synthesized according to the protecting method previously published ⁇ 1) ACS Medicinal Chemistry Letters, 8(10), 1025-1030; 2017.2) European Journal of Medicinal Chemistry, 126, 384-407; 2017.3) Tetrahedron Letters, 47(46), 8039- 8042; 3006 ⁇ the contents of which are hereby incorporated by reference.
  • FIG. 3 depict overviews of synthetic pathway for other exemplary compositions, for example Composition 201 following the general formula 200a and Composition 202 following the general formula 200b, using either a tosylate group or an aldehyde.
  • Composition 201 may be referred to as BG-P-MAT, BG-PEG-MAT, or benzyl guanidine conjugated to monoaminotetrac via PEG.
  • Composition 202 may be referred to as BG-P-DAT, BG-PEG- DAT, or benzyl guanidine conjugated to diaminotetrac via PEG.
  • Benzyl guanidine derivatives or other norepinephrine transport targets may be used as described herein.
  • Tetrac derivatives or other thyrointegrin antagonists may also be used as described herein, including but not limited to triac and triac derivatives.
  • Figures 4e and 4f depict detailed schematics of the synthetic pathway from Figures 4c and 4d.
  • Figures 4e and 4f shows the scheme of synthesis of Compositions 201 and 202 as further examples of conjugation of tetrac analogs to benzyl guanine modified PEG via click chemistry. Again, other synthetic pathways may be used.
  • METHODS OF USE [0103]
  • the compositions disclosed herein demonstrate novel dual targeting in treatment of cancer cells and tumors, particularly in treatment of neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors.
  • compositions show increased efficacy against neuroendocrine tumor cells when compared with thyrointegrin antagonist or norepinephrine transporter targets used or administered separately, i.e., not conjugated into a single composition.
  • the compositions may also be used for imaging of cancer cell/tumors.
  • the compositions described herein may be used to image neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors. Imaging may be desirable for diagnosis and/or for treatment monitoring.
  • the compositions may be used for simultaneous treatment and imaging.
  • the compositions may demonstrate increased retention in the targeted cancer cells/tumors, allowing for enhanced treatment and more effective imaging.
  • Example 2 Effect on Subcutaneously Implanted Tumor in Female Nude Mice
  • BG-P-TAT neuroblastoma SKNF2 cells implanted into nude female mice.
  • FIG. 1 shows the effect of the control and Composition 300 (BG-PEG-TAT) treatment on body weight of mice implanted with SKNF2 cell lines. As is shown, the body weight was consistent across all groups. Data demonstrate that daily treatment with Composition 300 (BG-PEG-TAT) at different doses 1, 3 and 10 mg/kg daily for 15 days have no effect on animal body weight versus control animals.
  • Composition 300 BG-PEG-TAT
  • Figure 6 shows the effect of Composition 300 (BG-PEG-TAT) treatment versus control on tumor volumes of mice implanted with SKNF2 cell lines.
  • the control group showed an increase in tumor volume from approximately 825mm 3 to 1050mm 3 over the 15 days of treatment.
  • All groups receiving treatment with Composition 300 (BG-PEG-TAT) showed decreased tumor size.
  • the groups receiving treatment with Composition 300 (BG-PEG-TAT) showed dose-dependent decreases in tumor size, with the 10 mg/kg Group showing a tumor size reduction from approximately 825mm 3 to 100mm 3 .
  • Figures 7a–7b comprise photographs of mice from each treatment group in which subcutaneous tumors 70 can be visually compared.
  • the control group shows large, clearly visible tumors 70. Control animals also showed abnormal circling (head rotation) 79, which was absent in all treatment arms. The abnormal circling is believed to be an effect of the tumor on the central nervous system.
  • the treatment groups show clear dose dependent reductions in the size of the tumors 70 to complete absence at the 10 mg/kg dose. As shown, in the 10 mg/kg treatment group there is an absence of any visible tumor at the tumor location 70’.
  • Figure 8 shows the effect of the control and Composition 300 (BG-PEG-TAT) treatment on tumor weight of mice implanted with SKNF2 cell lines.
  • FIG. 9a and Figure 9b shows the effect of the control and Composition 300 (BG-PEG-TAT) treatment on vasculature and tumor size of mice implanted with SKNF2 cell lines.
  • the control group demonstrated significant increases in size of the tumors 70 as increased vascularization.
  • Vascularized areas 90 of the control group tumors 70 are clearly visible.
  • the treatment groups show a dose-dependent reduction in size of the tumors 70, including tumor shrinkage at the 10 mg/kg dose. Tumor vasculature was also clearly diminished as shown.
  • FIG. 10 shows the effect of the control and Composition 300 (BG-PEG-TAT) treatment on tumor cell viability of mice implanted with SKNF2 cell lines.
  • the treatment groups show a dose-dependent reduction in tumor cell viability. 70-75% cell viability was shown in control with 20- 30% necrosis in the center of the tumor.
  • FIG. 11 shows the effect of the control and Composition 300 (BG-PEG-TAT) treatment on tumor cell necrosis of mice implanted with SKNF2 cell lines. As can be seen, the treatment groups show a dose-dependent increase in tumor cell necrosis.
  • FIG. 12a and 12b shown the effect of the control and treatment with BG, BG derivatives, thyrointegrin antagonists such as TAT derivatives, and combinations (co-administration) thereof, versus Composition 300 (BG-P-TAT) on tumor cell necrosis of mice implanted with SKNF2 cell lines.
  • BG-P-TAT Composition 300
  • triazole tetrac derivatives delivered subcutaneously daily for three (3) weeks at 3mg/kg has been shown to reduce tumor growth by approximately 40-50% and reduce tumor viability by approximately 40-50%.
  • triazole tetrac derivatives have also been shown to reduce tumor growth by approximately 40-50% and reduce tumor viability by approximately 40-50%.
  • even a combination treatment of two triazole tetrac derivatives in combination delivered subcutaneously daily for three (3) weeks at 3mg/kg only achieves a reduction of 40-50% for tumor growth and tumor viability.
  • Comparative Example 3a Effect of TAT Derivative on Tumor Weight: [0123] The ⁇ v ⁇ 3 integrin receptor antagonists (thyrointegrin antagonists) showed limited (40-50%) efficacy in term of tumor growth rate and cancer viability inhibition in the case of neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors.
  • the graph of Figure 12b includes the effect of a triazole tetrac derivative (referred to as TAT) on tumor weight when compared with a control group (phosphate-buffered saline “PBS”). The specific derivative tested was beta cyclodextrin triazole tetrac.
  • Comparative Example 3b Effect of Benzyl Guanidine and Derivatives on Tumor Weight: [0125] Similarly, benzyl guanidine and its derivatives demonstrate limited (40-50%) efficacy in term of tumor growth rate and cancer viability inhibition in the case of neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors.
  • neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors.
  • the graph in Figure 12a includes the effect of benzyl guanidine (BG) and benzyl guanidine derivatives (such as MIBG and a polymer conjugated benzyl guanidine (specifically PLGA-PEG-BG, referred to as polymer-BG) on tumor weight when compared with a control group (PBS).
  • BG benzyl guanidine
  • polymer-BG polymer conjugated benzyl guanidine
  • the treatment compounds demonstrated limited anti-cancer efficacy of neuroblastoma despite its maximal (90-100%) uptake into neuroblastoma and other neuroendocrine tumors.
  • Comparative Example 3c Effect of Co-Administration of Separate Norepinephrine Transporter Target and Thyrointegrin Antagonist: [0127] Furthermore, treatment combinations comprising co-administration of norepinephrine transporter targets such as benzyl guanidine or derivatives together with thyrointegrin antagonists such as triazole tetraiodothyroacetic acid derivatives did not exceed 40-50% suppression of neuroblastoma growth and viability. For example, benzyl guanidine co-administered with a tetrac derivative (BG+TAT) did not surpass the 40–50% efficacy demonstrated by individual treatment with either compound as shown in Figure 12b (BG+TAT).
  • BG+TAT tetrac derivative
  • Example 4 Imaging of Subcutaneously Implanted Tumor in Athymic Female Mice.
  • Athymic female mice were implanted twice each with 10 6 cells/implant.
  • the SKNF1 cell line was used with subcutaneous xenografts.
  • Group 1 consisted of three mice and were treated with PEG-TAT-dye (Cy5).
  • Group 2 consisted of three mice and were treated with PEG-BG-dye (Cy5).
  • Group 3 consisted of three mice and were treated with TAT-PEG-BG-dye (Cy5) wherein the TAT and BG were covalently linked with a PEG linker as compound 300.
  • the treatment groups are shown below: [0135] Fluorescence imaging (Cy5) was conducted 1 hour, 2 hours, 4 hours, 6 hours, and 24 hours post-administration. Imaging results are shown in Figures 13a and 13b, in which the tumor location is circled in yellow and the Cy5 dye appears as red.
  • composition 300 showed marked improvement in both uptake into the SKNF1 neuroblastoma tumors and retention time within the tumor when compared with either a triazole tetrac derivative alone or a benzyl guanidine derivative alone.
  • Neuroblastoma tumor cells were used in the treatment example discussed. Those skilled in the art would appreciate these examples are valid models for treatment of other tumor types, particularly other neuroendocrine tumors. Further, any tumor or disease state demonstrating increased activity of the norepinephrine transporter in which thyrointegrin moderated antiangiogenic activity would be desired may be treated by the disclosed compositions.
  • compositions described herein show increased efficacy against tumor cells, particularly neuroendocrine tumors. These compositions may be used to treat neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors, for example by injectable, topical, sublingual, oral, and other routes of administration.
  • neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors
  • ADDITIONAL EXEMPLARY COMPOUNDS [0138]
  • compositions based on the general structure 100 may include variations at R1 through R8 and/or variations in the linker 130, for example, variations in the spacer 132, the polymer 131, and/or the moiety Y. Exemplary embodiments including such variations are discussed in more detail below.
  • FIG 14 depicts an exemplary Composition 7a of the general formula 100.
  • Composition 7a comprises triazole tetrac conjugated to benzyl guanidine modified PEG wherein iodo groups have been chosen as substituents on the benzyl guanidine aromatic ring.
  • Composition 7a may also be referred to as dI-BG-PEG-TAT or dI-BG-P-TAT.
  • Figure 15 depicts an exemplary Composition 7b of the general formula 100.
  • Composition 7b comprises triazole tetrac conjugated to benzyl guanidine modified PEG wherein methoxy groups have been chosen as substituents on the benzyl guanidine aromatic ring.
  • Composition 7b may also be referred to as dM-BG-PEG-TAT or dM-BG-P-TAT.
  • Figure 16 depicts an exemplary Composition 15 of the general formula 100.
  • Composition 15 comprises tetrac conjugated to benzyl guanidine modified PEG wherein the amine of the moiety Y is piperazine.
  • Composition 15 may also be referred to as BG-PEG-PAT or BG-P-PAT wherein PAT refers to piperazine tetrac.
  • PAT refers to piperazine tetrac.
  • Scheme 3 Synthesis diagram of compound 19. a) SOCl 2 , MeOH; b) 17, ACN, Cs 2 CO 3 , 60°C, 18 h; c) 4 N HCl in dioxane, 2 h. Scheme 3 is shown in Figure 19. [0152] Compound 19 was introduced (Scheme 2) to a PEG unit after the tosylation reaction of PEG- OH 10 in the presence of K 2 CO 3 and ACN to give compound 12. The 1 H-NMR spectrum of 12 ( Figure S40) confirmed the structure by observing tetrac and N-Boc benzylamine aromatic proton peaks at 7.18- 7.79 and 6.88-7.20, respectively.
  • Compounds dI-BG-P-TAT (7a), dM-BG-P-TAT (7b), and BG-P-PAT showed relatively higher binding affinity towards purified integrin ⁇ v ⁇ 3 receptor with lower IC 50 values 1.1 nM, 0.5 nM, and 0.3 nM, respectively, compared to 10.3 nM for BG-P-TAT.
  • Compound 15 BG-P-PAT shows approximately a 30-fold increase in binding affinity relative to BG-P-TAT.
  • Figure 20 shows the respective binding percentage towards purified integrin ⁇ v ⁇ 3 receptor.
  • the 30- fold higher ⁇ v ⁇ 3 binding affinity of 15 versus the close analog BG-P-TAT may be due to additional hydrogen bonds of the BG portion of 15 in with Asp-127 and Asp-126, which may be a result of the longer linker chain in BG-P-PAT, allowing the BG portion easier access to this domain than the BG in BG-P-TAT, as well as additional hydrogen bonding of the piperazine nitrogen.
  • Example 7 Effect on Subcutaneously Implanted Tumor in Female Nude Mice
  • the efficacy of Compositions 7a (dI-BG-P-TAT), 7b (dM-BG-P-TAT), and 15 (BG-P-PAT) were tested using neuroblastoma SKNF1 cells implanted into nude female mice similar to the examples discussed above for Composition 300 (BG-P-TAT).
  • FIG. 22 shows the effect of Compositions 7a (dI-BG-P-TAT), 7b (dM-BG-P-TAT), and 15 (BG-P-PAT) versus control on tumor volumes of mice implanted with SKNF1 cell lines. As shown, both completed treatment groups (Compositions 7b (dM-BG-P-TAT) and 15 (BG-P-PAT)) showed decreased tumor volume compared with the control.
  • FIG. 23 shows the effect of Compositions 7a (dI-BG-P-TAT), 7b (dM-BG-P-TAT), and 15 (BG-P-PAT) versus control on tumor weight of mice implanted with SKNF1 cell lines.
  • the completed treatment groups show a reduction of tumor weight in comparison with the control group.
  • Data showed a 90% decrease in tumor weight for Composition 15 (BG-P-PAT) and an 86% decrease in tumor weight for Composition 7b (dM-BG-P-TAT).
  • compositions described herein show increased efficacy against tumor cells, particularly neuroendocrine tumors. These compositions may be used to treat neuroendocrine tumors such as neuroblastoma, pheochromocytoma, pancreatic neuroendocrine tumors, and carcinoid tumors, for example by injectable, topical, sublingual, oral, and other routes of administration.

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