WO2015008195A1 - Dérivés de dendrimère pamam pour la thérapie antithrombotique - Google Patents

Dérivés de dendrimère pamam pour la thérapie antithrombotique Download PDF

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Publication number
WO2015008195A1
WO2015008195A1 PCT/IB2014/062979 IB2014062979W WO2015008195A1 WO 2015008195 A1 WO2015008195 A1 WO 2015008195A1 IB 2014062979 W IB2014062979 W IB 2014062979W WO 2015008195 A1 WO2015008195 A1 WO 2015008195A1
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Prior art keywords
pamam
derivatized
dendrimers
blood
circulatory system
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PCT/IB2014/062979
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English (en)
Inventor
Esteban DURAN LARA
Luis Guzman
John Amalraj
Leonardo Silva Santos
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Fundacion Fraunhofer Chile Research
Universidad De Talca
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Publication of WO2015008195A1 publication Critical patent/WO2015008195A1/fr

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    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/785—Polymers containing nitrogen
    • 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
    • A61K47/56—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/595—Polyamides, e.g. nylon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

  • the present invention is related to novel compounds for antithrombotic therapy or novel compounds with anticoagulant activity.
  • Cardiovascular disease is the leading cause of mortality worldwide. In the USA, nearly 800,000 strokes occur annually with almost one in four being a recurrent event. In Europe, stroke is the third leading cause of death, and stroke complications now account for approximately 5% of the UK's National Health Service budget.
  • Cardioembolic stroke in which the thrombus forms in the heart, occurs primarily in patients with atrial fibrillation and is prevented with anticoagulation. Pooling of blood in the fibrillating atria allows formation of a clot that initially adheres to the atrial wall but may later dislodge and produce an embolism.
  • Noncardioembolic ischaemic stroke in which the thrombus results from arterial plaque rupture, is best managed with antiplatelet therapy. Platelets are anucleate blood cells that retain cytoplasmic mRNA and maintain functionally intact protein translational capabilities, playing an important role both in the pathogenesis of atherosclerosis and subsequent thrombosis. Following fibrous cap's rupture of the atherosclerotic plaque, prothrombotic materials are exposed to the circulating blood leading to the development of a platelet-rich thrombus over the disrupted lesion.
  • Dendrimers have attracted great interest in biomedical applications because of their unique dendritic structures and multiple surface properties. Because of the presence of a large number of terminal groups, drug molecules can be attached to the dendrimer surface through covalent bonds, whereas internal cavities are capable of encapsulating small molecules. Nevertheless, their interactions with cell compounds and compartments are nonselective, so they also have the potential to cause cytotoxicity and hemotoxicity.
  • platelets have not received significant research attention regarding possible mechanisms of nanoparticle toxicity.
  • platelet activation by injected drug delivery nanoconstructs could readily result in unintended consequences in host circulation.
  • PAMAM polyamidoamine
  • Platelets comprise a major metabolically active blood component, circulating constantly at 2.5 ⁇ 108 platelets/mL of blood, are highly responsive to diverse physical and biochemical stimuli with potent coagulation and growth factors, and are responsible primarily for hemostasis.
  • Platelets are anucleated blood cells that play an important role both in the pathogenesis of atherosclerosis and subsequent thrombosis.
  • Dendrimers have attracted great interest in biomedical applications because of their unique dendritic structures and multiple surface properties, nevertheless, their interactions with cell compounds and compartments are nonselective, so they also have the potential to cause cytotoxicity and hemotoxicity because of their terminal cationic groups.
  • US patent application US20100028402 describes, among other nanomolecules, PAMAM dendrimers of generation 4.5 that has carboxy-terminated dendritic branches. It is specifically described the use as anticoagulant, and the examples describe different advantages, showing that no cytotoxicity is produced with said molecule.
  • the nanomolecule described in US20100028402 can further be used for coating a medical device, such as a stent, in which case, the nanomolecule coating avoids producing blood clotting when inserting the device in the circulatory system.
  • US patent application US20100069608 describes the functionalization of a biomaterial using dendrimers or semi-dendrimers.
  • the biomaterial intended use is for biomedical implants, and the dendrimer coating is directed to help to the integration of the biomedical device with the surrounding tissue.
  • the present invention corresponds to different PAMAM derivatives, which were tested in order to prove their interaction with serum metabolites, and its effect on the viability of red blood cells and their antithrombotic or anticoagulant properties.
  • FIG. 1 MALDI-TOF spectra.
  • Figure 6 Effect of G4-Arg-Tos on collagen-induced platelet thrombus formation under arterial flow at a shear rate of 1000 s ⁇ 1 .
  • A) shows the intensity (CTCF) over a time lapse
  • C) bar diagram (values are mean ⁇ SD; n 3). * p ⁇ 0.05.
  • the present invention is directed to nanoparticles with antithrombotic activity, more particularly, the nanoparticles are PAMAM dendrimers derivatives, which present low toxicity and high anticoagulant or antithrombotic activity.
  • the invention also considers methods for treating a condition wherein anticoagulation activities are needed.
  • Dendrimer A unimolecular assembly comprising three elements: (i) an initiator core, (ii) interior layers (which correspond to the generation G) consisting of repeating units, radially attached to the initiator core and (iii) an exterior surface.
  • PAMAM dendrimer a polyamidoamine dendrimer, wherein the initiator core is an ehtylenediamine core, and the branched units (layers) are constructed based on methyl acrylate and ethylendiamine.
  • Gn or Gn PAMAM A polyamidoamine dendrimer of n th generation.
  • G4 PAMAM is a 4 th generation polyamidoamine dendrimer.
  • Anticoagulant a substance that prevents blood clotting.
  • Thrombosis a condition wherein a blood clot is formed in vivo, inside a blood vessel, obstructing normal blood flow.
  • Antithrombotic a substance for treating a thrombotic condition (i.e., existence of thrombosis or thrombus).
  • the present invention corresponds to different derivatized nanomolecules with proven effectiveness in producing an antithrombotic or anticoagulant effect.
  • the derivatized nanomolecules of the present invention correspond to derivatized polyamidoamine (PAMAM) dendrimers of different generations.
  • PAMAM polyamidoamine
  • the derivatized PAMAM dendrimers are of generations 2 nd , 3 rd , 4 th , 5 th , or 6 th .
  • the derivatized nanomolecules are half-generation polyamidoamine (PAMAM) dendrimers, i.e. 0.5, 1 .5, 2.5, 3.5, 4.5 generation dendrimers.
  • the derivatized nanomolecules of the invention are polyamidoamine (PAMAM) dendrimers of generations 4 and 5.
  • PAMAM polyamidoamine
  • the derivatization of the nanomolecules comprises a derivatization group.
  • the derivatization group corresponds to an amino acid conjugated with a terminal functional group.
  • the amino acid is a basic amino acid, such as histidine, lysine, or arginine.
  • the terminal functional group conjugated to the amino acid is a carbamate or a tosyl group.
  • the carbamate group is a carboxybenzyl group.
  • the present invention comprises pharmaceutical compositions comprising at least one of the dendrimers considered in the present invention, a suitable solvate, suitable salts, and or excipients.
  • the molecules of the invention can be included in different dosage forms, such as for example, and with no intention of limiting the scope of the invention, oral dosage forms, such as pills, films, tablets, capsules, dragees, pastes, powders, liquid solutions or suspensions; parenteral dosage forms, suitable for intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, or intrathecal administration; topical dosage forms such as creams, gels, liniments, balms, lotions, ointments, skin patches.
  • oral dosage forms such as pills, films, tablets, capsules, dragees, pastes, powders, liquid solutions or suspensions
  • parenteral dosage forms suitable for intradermal, intramuscular, intraosseous, intraperitoneal, intravenous, subcutaneous, or intrathecal administration
  • topical dosage forms such as creams, gels, liniments, balms, lotions, ointments, skin patches.
  • the molecules of the invention or active ingredient are present in such an amount, that the concentration reached in the zone where the antithrombotic or anti-platelet effect is required is at least 1 ⁇ , more preferentially at least 3 ⁇ , and even more preferentially at least 5 ⁇ .
  • Other higher concentrations are also considered to be in the scope of the present invention, such as up to 10 ⁇ , or up to 15 ⁇ .
  • the molecules of the invention are used for coating of medical devices. More particularly, the molecules of the invention are used for coating stents or tube meshes that are used for treating narrow or weak blood vessels. In a further embodiment of the invention, the molecules of the invention can also be used for coating medical devices used in surgery, more particularly for coating devices for circulatory system related surgeries.
  • the molecules of the invention are used for coating synthetic blood vessels used for example in bypass surgery.
  • the present invention further encompasses the use of the molecules described herein in the treatment or alleviation of thrombotic conditions or as anticoagulant.
  • a solution of the molecules of the invention is used as an alternative to heparin for blood collection in laboratory environments, for example in blood sample collector devices.
  • the invention considers a tube for blood sample collection containing a solution of a pharmaceutical composition of the molecules of the present invention, which is useful in avoiding clotting of blood samples.
  • a pharmaceutical composition comprising the molecules of the invention is injected in a patient in need thereof.
  • the injection or application of the molecules of the invention for providing an anti-platelet or antithrombotic effect in a patient in need thereof is achieved when reaching a concentration of at least 1 ⁇ , more preferentially at least 3 ⁇ , and even more preferentially at least 5 ⁇ .
  • concentrations are also considered to be in the scope of the present invention, such as up to 10 ⁇ , or up to 15 ⁇ .
  • Lys-Cbz and Arg-Tos were coupled to the amine terminals of the PAMAM G4 dendrimers by EDC and HOBt coupling reaction.
  • a higher molar ratio of 1 :70 was used to get all the 64- amine groups of the PAMAM G4 dendrimer conjugated.
  • 16 Arg-Tos and 39 Lys-Cbz molecules were found to be covalently attached to the PAMAM G4 dendrimers, respectively.
  • the modification of the dendrimers surface was characterized by MALDI-TOF- MS spectrometry analysis ( Figure 2a and 2b). The spectra analyses of PAMAM G4 dendrimers showed that 16 Arg-Tos and 39 Lys-Cbz were attached to the derivatives, respectively.
  • the circulatory system seems to be the most convenient way of drug administration because an active compound within a relatively short time is able to reach distant tissues, which are unavailable directly.
  • blood constituents can be the first and unwanted targets of drug action. Binding to plasma proteins, erythrocytes, leukocytes, platelets, and blood vessel walls, may lead to serious problems, or at least dramatically lower the amount of drug available for therapy.
  • PAMAM G4, G5 and G5-Cou derivative afforded more interaction with serum metabolites, producing variations in three blood metabolites each one, both with Gl, TCh, and Ur (G4 and G5-Cou), and TCh, Gl and Cr (G5) (Table 1 ).
  • the variations found in the different metabolites are not enough to cause physiological changes in the human body.
  • TCh Total Cholesterol
  • Gl Glycemia
  • Trg Triglycerides
  • Ca Calcium
  • TB Total Bilirubin
  • UrA Uric Acid
  • Ur Urea
  • Cr Creatinine
  • Figure 3 shows the hemolysis of RBCs expressed as percentage of released hemoglobin compared to the positive control Triton X-100 (0.2%, V/V).
  • the PAMAM G4 dendrimer produced the highest percentage of hemolysis compared to the positive control (100% hemolysis).
  • the PAMAM dendrimer derivatives of the invention showed a reduction in the percentage of hemolysis with a 4.7% (Cou) and 5.3% (FA), respectively, of hemolysis compared with the 6.6% of hemolysis for the net PAMAM G5.
  • results obtained related to the hemolysis and agglutination may be due to the partial incorporation of the dendrimers into the lipid bilayer, or by removing the outer monolayer.
  • the interaction of each of the PAMAM dendrimer derivatives synthesized indicates that these nanoparticles do not cause significant hemolytic reactions at the concentration used (0.25 mg/mL). According to previous studies, less than 10% of hemolysis compared to positive control (Triton X-100 at 0.2%) is not considered as cytotoxic.
  • G4-Arg-Tos act as potent inhibitors of platelet aggregation induced by ADP.
  • G4-Arg-Tos 100 ⁇ g mL
  • G4-Arg-Tos presented inhibition of platelet secretion, indicating that G4-Arg-Tos increases the cyclic-nucleotide concentration (cAMP) of human platelet.
  • cAMP cyclic-nucleotide concentration
  • Platelets are exposed to a broad range of hemodynamic conditions in vivo, ranging from relatively low flow situations in veins to stenosed arteries with high shear rates. Platelets have the unique capacity to form stable adhesion contacts over all shear conditions operating in vivo, and show to be indispensable for hemostatic plug formation and thrombosis at elevated shear rates.
  • Kits for biochemical analyses were obtained from Valtek (Valtek, Nunoa, Chile), the biochemical analyses were recorded on a Spectrophotometer (Clima Plus, RAL S.A, Barcelona), the counts of platelets and red blood cells were obtained in an hematologic counter (Bayer Advia 60 Hematology System, Tarrytown, NY, USA).
  • the reaction mixture was vigorously stirred for 72 h.
  • the functionalized dendrimer was purified through dialysis membranes with a cut-off of 500 Da to remove the excess of the amino acid. Then, the product was lyophilized and the amount of the PAMAM G4-Boc-Arginine (Tos)-OH obtained was 55 mg.
  • a solution of HCI/dioxane (4.0 mL, 4.0 M) in a 25 mL round-bottom flask equipped with a magnetic stirrer was cooled by an ice-water bath under nitrogen.
  • PAMAM G4-Boc-Arginine (Tos)-OH (0.2 mmol) was added in one portion with stirring.
  • the functionalized dendrimer was purified through dialysis membranes with a cut-off of 500 Da to remove the excess of the amino acid. After the lyophilization, the amount of the PAMAM G4-Boc-Lysine-Cbz-OH obtained was 42 mg. Finally, a solution of HCI/dioxane (4.0 mL, 4.0 M) in a 25 mL round-bottom flask equipped with a magnetic stirrer, was cooled by an ice-water bath under nitrogen, and PAMAM G4-Boc-Lysine-Cbz-OH (0.2 mmol) added in one portion with stirring. The ice-bath was removed and the mixture was kept under stirred for 1 h.
  • mass spectrometric analysis of the dendrimers was performed on a MALDI-TOF (matrix assisted laser desorption/ionization-time of flight) with a pulsed nitrogen laser (337 nm), operating in positive ion reflector mode, using 19 kV acceleration voltage and the matrix 2,5 dihydroxybenzoic acid (DHB).
  • MALDI-TOF matrix assisted laser desorption/ionization-time of flight
  • the blood samples were obtained from healthy donors. For this, to each donor were extracted 10 mL of whole blood, then was centrifuged at 2000 rpm for 15 min., to separate the serum from the rest of the blood. All the serum samples were mixed, aliquoted and frozen at -80 °C until use. To perform the Assay of Red Blood Cells Lysis, blood from healthy donors was extracted and anticoagulated with 3.2% citrate tubes.
  • Erythrocytes were separated from the plasma and leucocytes by centrifugation (1500 rpm, 5 min) at 4 e C and washed three times with phosphate-buffered saline (PBS: 150 mM NaCI, 1 .9 mM NaH2P04, 8.1 mM Na2HP04, pH 7.4).
  • PBS phosphate-buffered saline
  • the hemolysis assay was performed according to the method of Duncan et al., 2005. Briefly, washed (RBCs) at 2% were incubated at 30 °C with a final concentration of 0.25 mg/mL of the selected dendrimer. After 2 h of incubation, the samples were centrifuged at 2000 rpm for 10 min and the absorbance of the supernatant was measured at 550 nm. Hemolysis was expressed as percentage of released hemoglobin. It was used as control (100% of hemoglobin released) a solution of RBCs incubated with Triton X-100 (0.2% V/V). Additionally, morphological changes in the RBCs were determined by optical microscopy.
  • PRP platelet-rich plasma
  • Platelet aggregation was monitored by light transmission turbidimetric method according to Born and Cross, using a lumi-aggregometer. Briefly, 480 ⁇ _ of PRP in the reaction vessel were pre-incubated with 20 ⁇ _ of PAMAM (all samples at 100 ⁇ g/mL, 0.2% DMSO V/V, final concentration of 5 ⁇ ), negative control of inhibition (0.2% DMSO in saline, final concentration) or positive control (acetylsalicylic acid 110 ⁇ , final concentration). After 5 min of incubation, 20 ⁇ _ of agonist were added to initiate platelet aggregation, which was measured for 6 min. ADP, collagen, TRAP-6 and arachidonic acid, were used as agonists. All measurements were performed in triplicate. The results of platelet aggregation were determined by the software AGGRO/LINK, and the relative inhibition of the maximum platelet aggregation was calculated as:
  • Platelet Aggregation 100 - (%AgDendrimer x 100) / %AgNeg. Control)
  • %AgDendrimer percentage of aggregation of the dendrimer under study
  • %AgNeg percentage of aggregation of negative control
  • Platelet secretion was determined by measuring the release of ATP using luciferin/luciferase reagent. Luciferin/luciferase (26 ⁇ _) was added to 480 ⁇ _ of platelet suspension (PRP adjusted to 2x105 platelets/ ⁇ -) within 2 min before stimulation. Platelet secretion was recorded in real time in a lumi-aggregometer at 37 °C with stirring (1000 rpm) and luminescence (x0.2). To determine the effects on platelet secretion, platelets were pre- incubated with PAMAM 100 ⁇ g/mL for 2 min prior to the addition of ADP.
  • BioFlux 200-flow system with high shear plates 48 wells, up to 20 dyne/cm2 was used.
  • the microfluidic chambers were coated for 1 h with 50 ⁇ _ of collagen 200 ⁇ g/mL at a wall shear rate of 200 s ⁇ 1 .
  • the plaque coating was allowed to dry at room temperature for 1 h.
  • the channels were perfused with PBS for 10 min at a wall shear rate of 200 s ⁇ 1 .
  • the channels were blocked with bovine serum albumin (BSA) 0.5% for 10 min at a wall shear rate of 200 s _1 .
  • BSA bovine serum albumin
  • the plaque-coated microfluidic high shear plates were mounted on the stage of an inverted fluorescence microscope.
  • Control blood and blood with the different dendrimers 100 ⁇ g mL, final concentration
  • the mixture was added to the inlet well, and chambers were perfused for 10 min at a wall shear rate of 1000 s 1 . All the experiments were performed at room temperature.
  • Platelet deposition was observed and recorded in real-time (30 frames per min) with a CCD camera.
  • perfused surface fields of the size of 237,900 ⁇ 2 located in the middle of the channels of the viewing window) were recorded, and fluorescence images were later analyzed off-stage by quantifying the area covered by platelets with the ImageJ software. In each field, the areas covered by platelets were quantified.
  • results were analyzed statistically, comparing the results of each dendrimer under study with the respective control.
  • the results were expressed as mean ⁇ SE.
  • t test was used with the software SPSS 15.0 (Statistical Product and Service Solutions). P values ⁇ 0.05 were considered statistically significant.
  • the molecules of the present invention have wide applicability in health and laboratory environments, as anticoagulant pharmaceutical compositions, as coatings for medical devices, as diagnostic laboratory compositions, among many other uses.

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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Materials For Medical Uses (AREA)

Abstract

La présente invention se rapporte à des nanoparticules présentant une activité antithrombotique, les nanoparticules étant plus particulièrement des dérivés de dendrimères PAMAM, qui présentent une faible toxicité et une grande activité anticoagulante ou antithrombotique. L'invention considère également des méthodes de traitement d'un état dans lequel des activités d'anticoagulation sont nécessaires.
PCT/IB2014/062979 2013-07-19 2014-07-09 Dérivés de dendrimère pamam pour la thérapie antithrombotique WO2015008195A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111714445A (zh) * 2020-07-22 2020-09-29 桂林医学院 癸酸修饰的树枝状大分子衍生物的用途
WO2022258005A1 (fr) * 2021-06-10 2022-12-15 The University Of Hong Kong Système d'administration photosensible basé sur une pamam modifiée et procédés associés

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100028402A1 (en) * 2006-10-25 2010-02-04 Marina Dobrovolskaia Nanoparticle-based anticoagulant
US7981444B2 (en) * 2004-04-20 2011-07-19 Dendritic Nanotechnologies, Inc. Dendritic polymers with enhanced amplification and interior functionality
US8445528B2 (en) * 2008-03-12 2013-05-21 The Regents Of The University Of Michigan Dendrimer conjugates

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7981444B2 (en) * 2004-04-20 2011-07-19 Dendritic Nanotechnologies, Inc. Dendritic polymers with enhanced amplification and interior functionality
US20100028402A1 (en) * 2006-10-25 2010-02-04 Marina Dobrovolskaia Nanoparticle-based anticoagulant
US8445528B2 (en) * 2008-03-12 2013-05-21 The Regents Of The University Of Michigan Dendrimer conjugates

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111714445A (zh) * 2020-07-22 2020-09-29 桂林医学院 癸酸修饰的树枝状大分子衍生物的用途
WO2022258005A1 (fr) * 2021-06-10 2022-12-15 The University Of Hong Kong Système d'administration photosensible basé sur une pamam modifiée et procédés associés

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