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WO2018142007A1 - Nanoconjugués constitués de molécules dendritiques et de peptides utilisés comme agents antitumoraux contre le cancer - Google Patents

Nanoconjugués constitués de molécules dendritiques et de peptides utilisés comme agents antitumoraux contre le cancer Download PDF

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Publication number
WO2018142007A1
WO2018142007A1 PCT/ES2018/070062 ES2018070062W WO2018142007A1 WO 2018142007 A1 WO2018142007 A1 WO 2018142007A1 ES 2018070062 W ES2018070062 W ES 2018070062W WO 2018142007 A1 WO2018142007 A1 WO 2018142007A1
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WIPO (PCT)
Prior art keywords
dendritic
nanoconjugates
peptide
nanoconjugate
cells
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Ceased
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PCT/ES2018/070062
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English (en)
Spanish (es)
Inventor
F.Javier DE LA MATA DE LA MATA
Mª José CARMENA SIERRA
Rafael GÓMEZ RAMÍREZ
Javier SÁNCHEZ-NIEVES FERNÁNDEZ
Laura MUÑOZ MORENO
María SANCHEZ MILLA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universidad de Alcala de Henares UAH
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Universidad de Alcala de Henares UAH
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Publication of WO2018142007A1 publication Critical patent/WO2018142007A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers

Definitions

  • Nanoconjugates that exhibit antitumor activity, mainly against advanced prostate cancer.
  • Nanoconjugates are composed of dendritic systems (dendrimers and dendrons) and neuropeptides.
  • the dendritic molecules are mainly of carbosilane structure and with ammonium functions in the periphery and the peptides are preferably of the glucagon / secretin family (eg, VIP, GHRH, PACAP).
  • PC Prostate cancer
  • this type of cancer has a tendency to metastasize to bone (90%) and lung (46%) (Bubendorf, et ai, Hum Pathol, 2000, 31, 578), which are of the metastases with a lower prognosis of cure.
  • Neuropeptides such as vasoactive intestinal peptide (VIP), growth hormone releasing hormone (GHRH), or pituitary adenylate cyclase activating peptide (PACAP), belonging to the glucagon / secretin family (Cardoso, et al., BMC Evol. Biol., 2010, 10, 13), have a wide biological activity in the organism and are very involved in the etiopathogenesis of PC.
  • VIP has a protumoral effect on prostate tumors, increasing proliferation, protecting it from apoptosis (Gutiérrez-Ca ⁇ as, et al., Br. J. Pharmacol., 2003, 139, 1050), increasing angiogenesis (Collado, et al. ., Peptides (Amsterdam, Neth.), 2007, 28, 1896), metastasis (Fernández-Mart ⁇ nez, et al., Prostate, 2009, 69, 774) and helping the progression of cancer towards more aggressive stages (Fernández- Mart ⁇ nez, et al., Cancer Lett., 2010, 299, 11).
  • GPCR type receptors PACi, VPACi, VPAC 2 and FPRL-1 (Garcia-Fernandez, etal., Peptides, 2003, 24, 893, El Zein, et al., 2008, 83, 972 ).
  • GHRH also acts through GPCR receptors, in this case hGHRH and its different variants of "spiicing" (SVs). Its function is to regulate the secretion of growth hormone (GH) (Martinez-Moreno, et al., Gen. Comp. Endocrinol., 2014, 199, 38), which in turn induces the activation of the IGF-1 factor ( Gan, et al., Mol.
  • GH growth hormone
  • the dendritic systems are hyperbranched macromolecules of perfectly defined structure and polyfunctionalized.
  • the dendrimers are of spherical morphology with a multivalent surface and the dendrons are of wedge type topology, also with a multivalent surface and an additional active position at the apex of this wedge called focal point.
  • Dendrons can be considered fragments of dendrimers, and in fact, one of the synthetic procedures of dendrimers uses precisely dendrons as a building block (Sánchez-Nieves, et al., Tetrahedron, 2010, 9203).
  • Dendritic systems have been used as transporters of drugs or antitumor nucleic acids because of their ability to absorb "in vivo" in tumor areas and internalize the treatment in cancer cells due to the EPR (Enhanced Permeability and Retention) effect (Chen, et ai, World J. Surg. Oncol., 2012, 10, 3, Jain, et ai, Eur. J. Pharm. Biopharm., 2014, 87, 500, Huang, et ai, Biomacromolecules, 2014, 15, 915).
  • EPR Enhanced Permeability and Retention
  • cationic systems are generally employed, such as cationic dendritic molecules, which by electrostatic interaction with them, allow these acids to be protected from degradation by nucleases (Svenson, et ai, Advanced Drug Delivery Reviews, 2012 , 64, 102). Similar strategies have been used for studies of peptide therapies, such as against human immunodeficiency virus (HIV) (lonov, et ai, Biochimica et Biophysica Acta, 2015, 1848, 907). Also in these nanoconjugates the electrostatic interaction between the dendritic system and peptide is used to stabilize the peptides and transport them to the cells, where their release facilitates their activity. DESCRIPTION OF THE INVENTION
  • the present invention provides the preparation of active nanoconjugates against advanced prostate cancer.
  • These systems are made up of dendritic molecules (dendrimers and dendrons) and neuropeptides.
  • the dendritic macromolecules are of carbosilane structure, mainly with cationic functions in the periphery
  • the neuropeptides are of the glucagon / secretin family, mainly VIP, GHRH and PACAP.
  • These nanoconjugates are formed by combining the dendritic molecule and the corresponding peptide in the necessary proportion. The formation of the nanoconjugate allows to create a system that presents anticancer properties in advanced prostate cancer and avoid metastasis.
  • a first aspect of this invention relates to a combination of peptide and dendritic molecule comprising:
  • a neuropeptide preferably from the glucagon / secretin family.
  • This peptide is preferably the vasoactive intestinal peptide (VIP), the growth hormone releasing hormone (GHRH) or the pituitary adenylate cyclase activating peptide (PACAP), without ruling out others having a similar activity.
  • VIP vasoactive intestinal peptide
  • GHRH growth hormone releasing hormone
  • PACAP pituitary adenylate cyclase activating peptide
  • a dendritic compound which refers in the present invention to a highly branched macromolecule where the growth units, branches or branches have carbosilane skeleton.
  • This dendritic compound is preferably a dendrimer, spherical in shape that has a growth nucleus of the polyfunctional molecule.
  • the growth units, branches or branches have carbosilane skeleton and the outer layer, surface or periphery of the dendrimer incorporates preferably cationic groups.
  • the skeleton and structure of these carbosilane dendrimers with different nuclei have been previously described (see for example ES-2444490).
  • the dendritic compound can also be dendritic or dendron wedge type, which refers to a highly branched cone-shaped macromolecule and is defined by a focal point, the units, branches or branches of growth, which start from said focal point and the outer layer, surface or periphery of said branches that incorporates functional groups.
  • dendritic or dendron wedge type refers to a highly branched cone-shaped macromolecule and is defined by a focal point, the units, branches or branches of growth, which start from said focal point and the outer layer, surface or periphery of said branches that incorporates functional groups.
  • the skeleton and structure of these dendrons carbosilanes with different focal points have been previously described (see for example ES-2444490).
  • the dendritic compound further comprises, in the outer layer of the dendrimer or dendron or at the focal point of the dendron, at least one functional group of different nature to the rest of the functional groups, and which can be selected from a molecule etiquette, a steering group or an active substance.
  • tag molecule refers in this description to any biorecognizable substance, chromophore, fluorophore or any other group detectable by spectrophotometric, fluorometric, optical microscopy, fluorescence or confocal, antibody and / or NMR techniques, and which easily allows detection of another molecule that alone is difficult to detect and / or quantify.
  • fluoroforo is selected from a list comprising cytochrome, fluorescein, rhodamine and dansyl.
  • directory group is meant a molecule or functional group capable of directing the dendritic compound specifically to a type of cells or to a specific area of a cell, such as folic acid, a signal peptide or an antibody, among other known by any subject matter expert.
  • Said lead group can be previously functionalized to bind the dendritic compound.
  • active ingredient or “drug” is meant in the present invention any purified chemical substance used in the prevention, diagnosis, treatment, mitigation or cure of a disease; to avoid the appearance of an unwanted physiological process; or to modify physiological conditions for specific purposes.
  • Said active principle is able to bind directly to the dendritic compound or with a previous modification of its structure for it.
  • the present invention also relates to the uses in biomedicine of the peptide / dendritic molecule combinations.
  • this invention is for the development of drugs for the treatment of prostate cancer.
  • other types of cancers are not excluded.
  • the present invention focuses on the treatment of advanced prostate cancer.
  • Another aspect of the present invention relates to the use of the nanoconjugates of the invention for the manufacture of a medicament. More preferably, the medicament is used for the prevention and / or treatment of prostate cancer.
  • a pharmaceutical composition comprising at least one dendritic molecule and a neuropeptide, as described above, and a pharmaceutically acceptable carrier.
  • this pharmaceutical composition may comprise another active ingredient, preferably with antitumor properties.
  • the antitumor may be doxorubicin, methotrexate or platinum compounds or others with antitumor properties.
  • compositions that can be used in said compositions are the vehicles known to a person skilled in the art.
  • pharmaceutical preparations include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (gels, solutions, suspensions or emulsions) for oral, nasal, topical or parenteral administration.
  • the term "therapeutically effective amount” refers to the amount of the composition calculated to produce the desired effect and, in general, will be determined, among other causes, by the characteristics of the composition itself, the age, condition and history of the patient, the severity of the disease, and the route and frequency of administration.
  • Figure 2 Example of third generation cationic carbosilane dendron.
  • X OH, NH 2 , SH, or others of interest.
  • Figure 4 Results of adhesion assays on PC3 cell lines of dendrimer 1 alone or bound to peptide VI P or GHRH. Mean values ⁇ E.S.M. , of 6 experiments, ** p ⁇ 0.01 and *** p ⁇ 0.001 versus control values; # p ⁇ 0.05 and ## p ⁇ 0.01 with respect to the dendrimer.
  • Figure 5 Migration of PC3 cells at time 0, 6 and 24 hours with the different treatments.
  • Figure 6. Migration of PC3 cells at 6 h. of treatment. Mean values ⁇ E.S.M. , of 1 experiment, with 6 duplicates. * p ⁇ 0.05 versus control values.
  • FIG. 7 Flow cytometry test in PC3 cells 24 hours after treatment. Mean values ⁇ E.S.M., of 2 experiments, * p ⁇ 0.05 versus control values are shown.
  • Dendrimers and dendrons are dendrimers and dendrons.
  • the formation of the nanoconjugates was carried out by mixing in solution, preferably aqueous in the presence or absence of buffer, the dendritic molecules and the corresponding peptides, in the proportion of interest.
  • the mixtures were made directly on the tumor cells.
  • 445 ⁇ _ of RPMI-1640 medium with 10% fetal bovine serum (FBS) with 1% antibiotic and antifungal (penicillin / streptomycin / amphotericin) were added.
  • FBS fetal bovine serum
  • antibiotic and antifungal penicillin / streptomycin / amphotericin
  • nanoconjugates may also be formed prior to their addition on the well containing the cells.
  • a solution is prepared containing 45 ⁇ _ of RPMI-1640 medium with 10% fetal bovine serum (FBS) with 1% antibiotic and antifungal (penicillin / streptomycin / amphotericin).
  • FBS fetal bovine serum
  • antibiotic and antifungal penicillin / streptomycin / amphotericin
  • 50 ⁇ _ of a 10 "8 M solution of the dendritic system made in the same medium mentioned above are added.
  • 5 ⁇ _ of peptide VIP stock 10 " 4 M or GHRH stock 10 "5 M
  • the cells are maintained in RPMI-1640 medium with 10% serum Fetal bovine (FBS) with 1% antibiotic and antifungal (penicillin / streptomycin / amphotericin).
  • FBS serum Fetal bovine
  • antibiotic and antifungal penicillin / streptomycin / amphotericin
  • the cells are stored at 37 ° C in a humid environment and with 5% C0 2 . Toxicity test by reduction of tetrazolium salts.
  • This technique is a colorimetric assay based on the selective ability of living cells to reduce 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyl tetrazolium bromide in formazan insoluble crystals.
  • This method makes it possible to determine the lethal effect of the compounds under study on cell metabolism, since cellular damage results in a decrease in the mitochondrial activity of the cell and the cytotoxicity of these molecules can be measured.
  • This test was carried out according to the manufacturer's instructions (MTT, Sigma-Aldrich, St Louis, USA) - PC-3 cells (15 x 10 4 cells / ml) are plated in 24-well plates. After 24 hours the culture medium is removed and treated.
  • the supernatant containing the treatment is removed at 24 hours and replaced by 500 ⁇ of a culture medium to which 25 ⁇ of MTT in PBS of a concentration of 1 mg / ml is added. After 1.5 hours of incubation under culture conditions, the supernatant is removed with the excess of unreacted MTT. Formazan crystals are subsequently dissolved with 100 ⁇ of isopropanol. The absorbance is read at 570 nm by subtracting the background measured at 620 nm. The relative cell viability (%) with respect to the control (untreated cells) is calculated based on the formula: [A] test / [A] control x 100.
  • the suspension of PC3 cells (25 x 10 4 cells / ml) is separated into several fractions that will depend on the number of treatments to be performed and are kept in suspension for 1 hour, at 37 ° C, with agitation every 10 minutes.
  • the plates with the collagen that acts as matrix are prepared with 100 ⁇ of type I collagen (8 ⁇ g / cm 2 ) diluted in 10 mM acetic acid / well, in P-96 plates, for 1 hour, at 37 ° C, in a dry atmosphere to achieve a complete fixation to the well. After that time, the collagen is aspirated and the plate is washed four times with PBS. 100 ⁇ of the previously treated cell suspension is added to each well and the medium is aspirated at 40 minutes.
  • PC3 cells (20 x 10 4 cells / ml) are seeded in 24-well plates. Cells are treated with the dendrimer and peptides 24 hours. After removing the medium, a wound is made in each well and the progression of its closure at different times is followed by photographs taken with the inverted microscope coupled to the Motic camera. The results are processed by measuring the size of the wound and the% of the progress of the wound is plotted against that of zero time.
  • PC3 cells (7.5 x 10 4 cells / ml) are seeded on P-6 plates and held for 24 h to achieve adhesion, at which time they are deprived with serum-free medium for 24 h. After this time, the different treatments are performed and at 24 hours, the cells are washed with PBS, raised with trypsin and centrifuged. The cell precipitate is fixed and permeabilized with 70% cold ethanol, for 5 days, at 4 o C. Then, the cells are centrifuged to remove the ethanol and washed with PBS.
  • the studied dendrimer / peptide combination (1 / VIP, 1 / GHRH) slows tumor growth and causes cancer cells to die at low concentrations, leading to anticancer behavior (Fig. 3, dendrimer results 1).
  • these peptides studied (VIP / GHRH) have protumoral activity and that although the dendritic systems used (1 and 2) They showed some anti-tumor activity, the combination with VIP and GHRH is much more effective.
  • Subsequent trials showed that these nanoconjugates favored cell adhesion and avoided tumor cell migration processes (Fig. 4, 5, 6, results of dendrimer 1). This effect was contrasted with that which only the dendrimer (1) would have and their inefficiency in preventing adhesion and migration was observed.

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Abstract

La présente invention concerne la formation de nanoconjugués qui présentent une activité antitumorale, principalement contre le cancer avancé de la prostate, mais sans s'y limiter. Les nanoconjugués sont constitués de systèmes dendritiques 8dendrimères ou dendrones) et de neuropeptides. Les molécules dendritiques sont principalement de structure carbosylane à fonctions ammonium en périphérie. Les peptides sont de préférence de la famille du glucagon/de la sécrétine (par ex. : VIP, GHRH, PACAP). La combinaison de ces deux systèmes donne un nanoconjugué aux propriétés anticancérigènes différentes de celles de ses précurseurs séparément. L'activité antitumorale se reflète dans l'inhibition de croissance et mort de cellules tumorales du cancer avancé de la prostate (PC3) et en outre ces nanoconjugués favorisent l'adhésion cellulaire et évitent les processus de migration des cellules tumorales, c'est-à-dire, les processus de métastase.
PCT/ES2018/070062 2017-01-31 2018-01-26 Nanoconjugués constitués de molécules dendritiques et de peptides utilisés comme agents antitumoraux contre le cancer Ceased WO2018142007A1 (fr)

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ES201700069A ES2677242B1 (es) 2017-01-31 2017-01-31 Nanoconjugados formados por moléculas dendríticas y péptidos como agentes antitumorales frente al cáncer
ESP201700069 2017-01-31

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WO2018142007A1 true WO2018142007A1 (fr) 2018-08-09

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060078535A1 (en) * 2004-10-13 2006-04-13 The Regents Of The University Of Michigan Anticancer compounds and methods
US20110268789A1 (en) * 2008-09-25 2011-11-03 Min Li Use of pituitary adenylate cyclase-activating polypeptide (pacap) and pacap analogs as adjunctive treatments with anticancer agents
ES2444490A1 (es) * 2012-07-25 2014-02-25 Universidad De Alcalá Compuestos dendríticos carbosilanos homo y hetero-funcionalizados
US20160015823A1 (en) * 2012-08-14 2016-01-21 Angiochem Inc. Peptide-dendrimer conjugates and uses thereof
US20160122406A1 (en) * 2013-06-07 2016-05-05 The Administrators Of The Tulane Educational Fund Analogs of pituitary adenylate cyclase-activating polypeptide (pacap) and methods for their use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060078535A1 (en) * 2004-10-13 2006-04-13 The Regents Of The University Of Michigan Anticancer compounds and methods
US20110268789A1 (en) * 2008-09-25 2011-11-03 Min Li Use of pituitary adenylate cyclase-activating polypeptide (pacap) and pacap analogs as adjunctive treatments with anticancer agents
ES2444490A1 (es) * 2012-07-25 2014-02-25 Universidad De Alcalá Compuestos dendríticos carbosilanos homo y hetero-funcionalizados
US20160015823A1 (en) * 2012-08-14 2016-01-21 Angiochem Inc. Peptide-dendrimer conjugates and uses thereof
US20160122406A1 (en) * 2013-06-07 2016-05-05 The Administrators Of The Tulane Educational Fund Analogs of pituitary adenylate cyclase-activating polypeptide (pacap) and methods for their use

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ES2677242B1 (es) 2019-03-27

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