WO2010014081A1 - Compositions de particules avec un mode d'internalisation de cellule présélectionné - Google Patents

Compositions de particules avec un mode d'internalisation de cellule présélectionné Download PDF

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Publication number
WO2010014081A1
WO2010014081A1 PCT/US2008/071470 US2008071470W WO2010014081A1 WO 2010014081 A1 WO2010014081 A1 WO 2010014081A1 US 2008071470 W US2008071470 W US 2008071470W WO 2010014081 A1 WO2010014081 A1 WO 2010014081A1
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Prior art keywords
particles
cell
particle
receptors
endocytosis
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PCT/US2008/071470
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English (en)
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Paolo Decuzzi
Mauro Ferrari
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Board Of Regents Of The University Of Texas System
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Application filed by Board Of Regents Of The University Of Texas System filed Critical Board Of Regents Of The University Of Texas System
Priority to PCT/US2008/071470 priority Critical patent/WO2010014081A1/fr
Priority to MX2011001121A priority patent/MX2011001121A/es
Priority to CA2732252A priority patent/CA2732252A1/fr
Priority to CN200880130677XA priority patent/CN102112117A/zh
Priority to KR1020117003851A priority patent/KR20110039466A/ko
Priority to EP08782489A priority patent/EP2326314A1/fr
Priority to AU2008360004A priority patent/AU2008360004A1/en
Priority to JP2011521073A priority patent/JP2011529491A/ja
Publication of WO2010014081A1 publication Critical patent/WO2010014081A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • 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
    • 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
    • A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the inventions relate generally to micro and nanosized particle compositions and their applications and, more particularly, to micro and nanosized particle compositions having a particular pre-selected cell internalization mode.
  • Endocytosis is a general term defining processes, by which a cell can import and/or export selected extracellular species, such as molecules, viruses, particles and microorganisms and target them to specific organelles within a cytoplasm. Endocytosis can occur through a variety of pathways including clathrin-mediated and caveole- mediated endocytosis; phagocytosis; clathrin- and caveole-independent endocytosis. A particular endocytosis pathway may depend on the size and nature of the extracellular cargo, see e.g. Conner S.D. and SX. Schmid. 2003. Nature 422: 37-44.
  • caveole -mediated endocytosis is assisted by the activation of caveole, plasma membrane invaginations, with a characteristic size of 50 - 60 nm; clathrin-mediated endocytosis requires the concentration of transmembrane receptors and their bound ligands on the plasma membrane leadingto the formation of vesicular cages with a characteristic size up to few hundreds microns (100-500 nm); phagocytosis involves specific cell-surface receptorsand signaling cascades with the formation of cell membrane protrusions that eventually envelope the external micrometer cargo (> 1 ⁇ m).
  • Clathrin- and caveole-independent endocytosis can be associated with the formation of invaginating vesicles smaller than 100 nm.
  • Particle endocytosis can be of fundamental importance in several fields, such as virology, drug and gene delivery and in nanotoxicology, see e.g. Marsh M. and A. Helenius. 2006. Cell 124:729-40; Vasir J.K., and V. Labhasetwar. 2006. Expert Opin. Drug Deliv. 3:325-344; Oberdorster G., E. Oberdorster, J. Oberdorster. 2005. 113:823- 39.
  • the most effective internalization mechanism can be a receptor-mediated endocytosis, in which molecules (ligands) distributed over the particle surface bind to countermolecules (receptors) expressed over the cell membrane, which can eventually bend to invaginate the foreign cargo, see e.g. Marsh M. and A. Helenius. 2006. Cell 124:729-40; Smith A.E., A. Helenius. 2004. Science 304:237-42.
  • These receptors can be collected at the site of invagination by surface diffusion, without which endocytosis would not occur or would occur over a much longer time scale.
  • One embodiment provides a method of formulating a particle composition having a pre-selected cell internalization mode, which comprises a) selecting a cell having surface receptors; and b) obtaining particles that have i) surface moieties, that have an affinity for or are capable of binding to the receptors, and ii) a shape, wherein a surface distribution of the surface moieties and the shape are effective for the preselected cell internalization mode for the selected cell.
  • Another embodiment is a method of treating or monitoring a physiological condition comprising administering to a subject in need thereof an effective amount of a particle composition having a pre-selected cell internalization mode.
  • Yet another embodiment is a particle composition having a pre-selected cell internalization mode.
  • FIG. 1 schematically depicts a particle that has an elliptical cross-section.
  • the particle has ligand molecules on its surface that can interact with receptor molecules on a surface of cell's membrane.
  • FIG. 2 illustrates evolution of the elliptical cylindrical particle presenting the half- wrapping time 0.5 ⁇ w and the wrapping length ratio X n ⁇ x /R 1 as a function of the aspect ratio F, ranging from 0.9 to 4, fori? 2 fixed at 50 nm.
  • FIG. 3 presents a graph of F min , which is a value of F for a fixed R 2 corresponding to the minimum for the half-wrapping time, as a function of R 2 .
  • FIG. 3 also presents a graph of the half- wrapping time for F min as a function of R 2 .
  • Endocytosis and endocytotic mean receptor mediated endocytosis and receptor mediated endocytotic respectively.
  • Mcroparticle refers to a particle having a maximum dimension from 1 micrometer to 1000 micrometers, or, in some embodiments from 1 micron to 100 microns as specified.
  • Nanoparticle refers to a particle having a maximum dimension of less than 1 micron.
  • Phagocytosis refers to an uptake of large (characteristic size of more than 2 microns) particles by specialized phagocyte cells, which include macrophages, monocytes and neutrophils. Phagocytosis involves the formation of protrusions in the cell membrane that eventually envelope the external particle.
  • Receptor mediated endocytosis refers to an internalization by a cell of a particle, which has moieties, such as ligands, distributed over its surface, which can bind to countermoieties (receptors) expressed over the cell's membrane.
  • RME involves bending of the cell's membrane, which results in a full wrapping of the particle by the membrane and eventual internalization of the particle by the cell.
  • Particles that are internalized via RME can have smaller characteristic size than particles that undergo internalization via phagocytosis.
  • RME is not limited to phagocyte cells.
  • Biodegradable refers to a material that can dissolve or degrade in a physiological medium or a biocompatible polymeric material that can be degraded under physiological conditions by physiological enzymes and/or chemical conditions.
  • the present inventors recognized an importance of a particle shape for a receptor mediated endocytosis. Accordingly, the present invention provides a method of formulating a particle composition with a pre-selected cell internalization mode, which can involve selecting a target cell and obtaining particles that have on their surfaces surface moieties, that have affinity for or are capable of binding to surface receptors of the surface of the target cell. The surface distribution of the surface moieties on the particles and a shape of the particles are such that they are effective for the pre-selected cell internalization mode for the selected cell.
  • the pre-selected cell internalization mode may be selected from an "endocytosis" or "no-endocytosis" mode.
  • Endocytosis refers to a mode, when a particle can be fully wrapped by the cell's membrane via a receptor mediated endocytosis and eventually internalized
  • no-endocytosis refers to a mode, when the particle can be at most partially wrapped by the cell's membrane.
  • the pre-selected cell internalization mode may a frustrated or partial endocytosis.
  • “Frustrated endocytosis” refers to a mode, when the particle gets only partially wrapped by the cell's membrane and does not get internalized by the cell.
  • the particles with a pre-selected cell internalization mode may be used for treating and/or monitoring a physiological condition.
  • a target site which is affected with the physiological condition and has cells of which have surface receptors on its surface, in a body of a subject, such as a mammal, preferably a human, and administering to the subject an effective amount of a composition that comprises particles with a pre-selected internalization mode for the cells of the target site.
  • the physiological condition can be for example a disease, such as cancer or an inflammation.
  • the selected cell may be any type of cell that has surface receptors on its surface.
  • the selected cells can be a mammal cell, such as a human cell.
  • a particular selected internalization mode may depend on the application intended for the particles.
  • the endocytosis mode may be preferred when the particle contains a cargo, such as an imaging or a therapeutic agent, which is desired to be delivered inside the cell.
  • no endocytosis or frustrated endocytosis modes may be preferred when the particle contains a cargo, which is not intended for delivery inside the cell.
  • One example of such situation can be a multistage delivery vehicle disclosed in PCT publication WO 2008/021908, where a first stage particle of the vehicle, which contains inside second stage particles, is intended to recognize and adhere to a target site in endothelium, without being internalized by the endothelial cells. After adherence, the first stage particle can release the second stage particles.
  • the selected cell can be a non-phagocyte cell, i.e. a cell that cannot perform phagocytosis.
  • phagocyte cells i.e. cells that perform phagocytosis include neutrophills, monocytes and macrophages.
  • the selected cell may be an endothelial cell, such as an endothelial vasculature cell, and the target site may be a vasculature site, such as a coopted vasculature, an angiotensic vasculature or a renormalized vasculature.
  • the surface receptors may be angiopoietin 2 receptors; for cells of angiogenic vasculature, the surface receptors may be vascular endothelial growth factors (VEGF), basic fibroblast growth factors or endothelial markers such as O v ⁇ 3 integrins; for cells of renormalized vasculature, the surface receptors may be carcinoembionic-related cell adhesion molecules 1 (CEACAMl), endothelin-B receptor (ET-B), vascular endothelial growth factor inhibitors gravin/AKAP12, scaffolding proteins for protein kinase A and protein kinase C.
  • VEGF vascular endothelial growth factors
  • CEACAMl carcinoembionic-related cell adhesion molecules 1
  • ET-B endothelin-B receptor
  • vascular endothelial growth factor inhibitors gravin/AKAP12
  • the surface moieties of the particle's surface can be complimentary to the receptors on the selected cell's surface.
  • the surface moieties may be, for example, antibodies, aptamers or ligands with affinity for or capable of binding to the receptors on the selected cell's membrane surface.
  • the surface moieties may include specific moieties to the receptors on the selected cell's membrane surface.
  • the surface moieties may include non-specific moieties to the receptors on the selected cell's membrane surface. Yet in other embodiments, the surface moieties may include both specific and non-specific moieties.
  • Particles with a pre-selected internalization mode may be a part of a composition that can also include particles without the pre-selected internalization mode.
  • the particles with the pre-selected internalization mode may constitute at least 10 % or at least 25 % or at least 50 % or at least 75 % or at least 90 % by number of the total number of particles in the composition.
  • the particle can be a non-spherical particle.
  • the particle can be a particle with a circular cross section.
  • the particle can be an ellipsoidal particle.
  • the particle can be a cylindrical particle with an elliptical cross section in a direction perpendicular to the axis of the cylinder.
  • the particle's largest characteristic size can be less than 2 microns, or less than 1 micron or less than 800 nm or from 5 nm to 500 nm or from 5 nm to 800 nm from 5 nm to 1 micron or from 10 nm to 1 micron or from 10 nm to 800 nm or from 10 nm to 500 nm or from 20 nm to 1 micron or from 20 nm to 800 nm or from 20 nm to 500 nm or from 50 nm to 1 micron or from 50 nm to 800 nm or from 50 nm to 500 nm.
  • the particle's largest characteristic size is substantially smaller than a characteristic size of the selected cell.
  • the particle's largest characteristic size can be at least 3 times smaller or at least 5 times smaller or at least 10 times smaller or at least 20 times smaller or at least 30 times smaller or at least 50 times smaller or at least 100 times smaller or at least 200 times smaller or at least 300 times smaller or at least 500 times smaller or at least 100 times smaller than the characteristic size of the selected cell.
  • a characteristic size of the selected cell may vary from about 5 microns to about 40 microns or from about 10 microns to about 30 microns.
  • the obtained particles may be particles that have a convex subsurface with a local curvature and a local surface density of the moieties, such as ligands, that are effective for internalization of the particles via a receptor mediated endocytosis, which means that the local curvature K is smaller than a maximum endocytosis curvature /r max for the local surface density of the moieties.
  • Maximum endocytosis curvature can depend on a binding energy between moieties on the surface of the particle and receptors on the surface of the selected cell's membrane, a bending energy factor of the selected cell's membrane and surface densities of the moieties of the particle and of the receptors on the selected cell's membrane. Methods of evaluating maximum endocytosis curvature are disclosed below. [0035] In some embodiments, the local surface density of the moieties at the convex surface may be greater than a surface density of the moieties at other parts of the surface of the particle, thus, making a surface distribution of the surface moieties on the surface of the particle non-uniform.
  • obtaining particles with a preselected cell internalization mode may involve obtaining particles that have an aspect ratio corresponding to the selected mode.
  • Figure 1 illustrates a elliptical cross section of an elliptical cylindrical particle that interacts with a membrane via specific ligand receptor bonds.
  • a surface density of the ligands on the surface of the particle is mi, while the surface density of the receptors on a surface of the cell's membrane is m r .
  • the elliptical cross section can be characterized ⁇ 1 and i? 2 , which are semi- lengths of the axes of the ellipse.
  • R s is a radius of a particle with a circular cross-section that has the same are as the elliptical particle.
  • the geometry of the particle can be fully defined by a number of pairs of parameters such ⁇ 1 and i? 2 ; T and R ⁇ ; T and i? 2 , T and R s or T and V, where V is the volume of the particle.
  • a shape parameter determining a pre-selected internalization mode can be an aspect ratio r for a particular i? 2 .
  • the particle can be in an endocytosis mode if the aspect ratio of the particle for a particular semilength of its minor axis is greater than the first critical value, T' , and less than the second critical value, T" .
  • the maximum endocytosis curvature K n ⁇ x can be defined as an inverse minimum endocytotic radius calculated for the selected cell for a spherical particle or a particle with a circular cross section that has the same ligands on its surface as the non- spherical particle.
  • K d D K d l h , where K d is an equilibrium dissociation constant for the same ligand-receptor pair determined, for example, experimentally in solution and h is a thickness of a confinement region, to which the ligand-receptor sites are restricted. In many cases, h can be equal approximately to 10 nm.
  • B is a bending energy factor of the cell's membrane, which can be determined as detailed in Hochmuth, R.M., J. Biomech., 33:15-22, 2000.
  • m r which is an average surface density on the receptors, when the particle is not interacting with the cell, can be determined using methods known to those of ordinary skill in the art. For example, one can determine m r in vivo by using radiolabeled monoclonal antibodies complimentary to the receptors as detailed for intercellular adhesion molecule 1 receptors in Panes J., et al. Am. J. Physiol. 1995; 269(6Pt2):H1955-64. Alternatively, m r can be determined using fluorescently labeled monoclonal antibodies complementary to the receptors. Such fluorescently labeled monoclonal antibodies can be antibodies labeled with phycoerythrin disclosed in US patent No. 4,520,110.
  • mi is a local surface density of ligands mi, which can be varied by controlling surface functionalization conditions for the particle and/or by varying a size of the ligand molecule.
  • the actual surface density of ligands on the particle can be verified experimentally using citofluometry or radiolabeled countermolecules in radioassays.
  • the local surface density and the average surface density can be the same.
  • the minimum endocytotic radius and thus the maximum endocytotic curvature can be evaluated as disclosed in US patent application no. 12/034,259 "Endocytotic particles" filed February 20, 2008, which is incorporated herein by reference in its entirety.
  • Figure 3 presents a graph of F min , which is a value of F for a fixed R 2 corresponding to the minimum for the half- wrapping time, as a function of R 2 .
  • Figure 3 also presents a graph of the half- wrapping time for F min as a function of R 2 .
  • Table 1 The same date is presented in Table 1 , together with F' r and T" r . TABLE 1
  • the two parameters describing the geometry of the elliptical cylindrical particle may be F and R s .
  • a shape parameter determining a pre-selected cell internalization mode can be an aspect ratio F for a particular value of R s .
  • the particle can be in an endocytosis mode if the aspect ratio of the particle for a particular semilength of its minor axis is greater than the first critical value, F 1 ' , and less than the second critical value, F 1 * .
  • a type of a particle with a pre-selected internalization mode is not particularly limiting.
  • the particle may be a liposome, a polymer-based particle, a silicon-and silica based particle, a quantum dot, a gold nanoshell, a dendrimer or a viral particle.
  • particles may be fabricated with a shape effective for a pre-selected internalization mode.
  • particles having a shape effective for a pre-selected internalization mode may be selected from a pool of particles, which may have a broad distribution of shapes and/or sizes. The selection from the pool of particles may be performed, for example, using ZetasizerTM Nano series instrument from Malvern Instruments, Worcestershire, United Kingdom, which allows measuring geometrical dimensions of the particles.
  • Particles may be fabricated using a number of methods. In general, fabrication methods that provide a control of the size and shape of the particles may be preferred.
  • the particles may be fabricated by top-down microfabrication or nanofabrication methods, such as photolithography, electron beam lithography, X-ray lithography, deep UV lithography or nanoprint lithography.
  • the advantage of using the top-down fabrication methods can be that such methods may provide for a scaled up production of particles that are uniform in dimensions.
  • the particles may have on their surfaces targeting moieties, such as ligands, aptamers or antibodies.
  • ligands may be chemically linked to appropriate reactive groups on the surface of the particles.
  • Protein ligands may be linked to amino- and thiol-reactive groups under conditions effective to form thioether or amide bonds respectively.
  • Non-uniform surface distribution of surface moieties can be achieved, for example, when making particles by top-down microfabrication or nanofabrication methods.
  • a substrate, from which the particles are made may be patterned using a coating that resists ligands deposition, so that the particle has at least two different surface areas: one that is resistant to ligand deposition and one that is not. Subsequent exposure of the substrate to a solution containing a ligand may result in particles having non-uniform distribution of ligands upon their release from the substrate.
  • the particle may have one or more channels connecting a reservoir with the surface.
  • the reservoir and the channels may be pores in the body of the particle.
  • the particle may comprise a porous or nanoporous material.
  • the pores of the porous or nanoporous material may be controlled to achieve a desired load of the active agent and/or a desired release rate.
  • the nanoporous material with controllable pore size may be an oxide material, such as SiO 2 , Al 2 O 3 , or TiO 2 . Fabrication of nanoporous oxide particles, also known as sol gel particles, is detailed, for example, in Paik J. A. et. al. J. Mater. Res., Vol. 17, Aug 2002.
  • the nanoporous material with controllable pore size may be also nanoporous silicon.
  • nanoporous silicon particles see, for instance, Cohen M. H. et. ah Biomedical Microdevices 5:3, 253-259, 2003.
  • the particle may have no channels at all.
  • Such particle may comprise, for example, a biodegradable material.
  • the particle may be formed of metals, such as iron, titanium, gold, silver, platinum, copper, and alloys and oxides thereof.
  • the biodegradable material may be also a biodegradable polymer such as polyorthoesters, polyanhydrides, polyamides, polyalkylcyanoacrylates, polyphosphazenes, and polyesters. Exemplary biodegradable polymers are described, for example, in U.S. Pat. Nos. 4,933,185, 4,888,176, and 5,010,167.
  • biodegradable polymer materials include poly(lactic acid), polyglycolic acid, polycaprolactone, polyhydroxybutyrate, poly(N-palmitoyl-trans-4-hydroxy-L-proline ester) and poly(DTH carbonate).
  • the particle may be an active agent per se.
  • the active agent may be a therapeutic compound and/or an imaging agent. The selection of a particular active agent depends on the desired application.
  • the therapeutic agent may be a physiologically or pharmacologically active substance that can produce a desired biological effect in fenestrated vasculature of the subject, such as a mammal or a human.
  • the therapeutic agent may be an inorganic or organic compound, including peptides, proteins, nucleic acids, and small molecules.
  • the therapeutic agent may be in various forms, such as an unchanged molecule, molecular complex, pharmacologically acceptable salt, such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, salicylate, and the like.
  • pharmacologically acceptable salt such as hydrochloride, hydrobromide, sulfate, laurate, palmitate, phosphate, nitrite, nitrate, borate, acetate, maleate, tartrate, oleate, salicylate, and the like.
  • salts of metals, amines or organic cations for example, quaternary ammonium
  • Derivatives of drugs such as bases, esters and amides also may be used as a therapeutic agent.
  • a therapeutic agent that is water insoluble may be used in a form that is a water soluble derivative thereof, or as a base derivative thereof, which in either instance, or by its delivery, is converted by enzymes, hydrolyzed by the body pH, or by other metabolic processes to the original therapeutically active form.
  • the therapeutic agent may be a chemotherapeutic agent, an immunosuppressive agent, a cytokine, a cytotoxic agent, a nucleolytic compound, a radioactive isotope, a receptor, and a pro-drug activating enzyme, which may be naturally occurring or produced by synthetic or recombinant methods, or any combination thereof.
  • Drugs that are affected by classical multidrug resistance such as vinca alkaloids (e.g., vinblastine and vincristine), the anthracyclines (e.g., doxorubicin and daunorubicin), RNA transcription inhibitors (e.g., actinomycin-D) and microtubule stabilizing drugs (e.g., paclitaxel) may have a particular utility as the therapeutic agent.
  • vinca alkaloids e.g., vinblastine and vincristine
  • the anthracyclines e.g., doxorubicin and daunorubicin
  • RNA transcription inhibitors e.g., actinomycin-D
  • microtubule stabilizing drugs e.g., paclitaxel
  • a cancer chemotherapy agent can be also a preferred therapeutic agent.
  • Useful cancer chemotherapy drugs include nitrogen mustards, nitrosorueas, ethyleneimine, alkane sulfonates, tetrazine, platinum compounds, pyrimidine analogs, purine analogs, antimetabolites, folate analogs, anthracyclines, taxanes, vinca alkaloids, topoisomerase inhibitors and hormonal agents.
  • Exemplary chemotherapy drugs are Actinomycin-D, Alkeran, Ara-C, Anastrozole, Asparaginase, BiCNU, Bicalutamide, Bleomycin, Busulfan, Capecitabine, Carboplatin, Carboplatinum, Carmustine, CCNU, Chlorambucil, Cisplatin, Cladribine, CPT-I l, Cyclophosphamide, Cytarabine, Cytosine arabinoside, Cytoxan, dacarbazine, Dactinomycin, Daunorubicin, Dexrazoxane, Docetaxel, Doxorubicin, DTIC, Epirubicin, Ethyleneimine, Etoposide, Floxuridine, Fludarabine, Fluorouracil, Flutamide, Fotemustine, Gemcitabine, Herceptin, Hexamethylamine, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Mech
  • Useful cancer chemotherapy drugs also include alkylating agents, such as Thiotepa and cyclosphosphamide; alkyl sulfonates, such as Busulfan, Improsulfan and Piposulfan; aziridines, such as Benzodopa, Carboquone, Meturedopa, and Uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine; nitrogen mustards, such as Chlorambucil, Chlornaphazine, Cholophosphamide, Estramustine, Ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, Melphalan, Novembiehin, Phenesterine, Prednimustine, Trofosfamide, uracil mustard; nitroureas, such as Cannustine,
  • anti-hormonal agents that act to regulate or inhibit hormone action on tumors
  • anti-estrogens including for example Tamoxifen, Raloxifene, aromatase inhibiting 4(5)-imidazoles, 4 Hydroxytamoxifen, Trioxifene, Keoxifene, Onapristone, And Toremifene (Fareston); and anti-androgens such as Flutamide, Nilutamide, Bicalutamide, Leuprolide, and Goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • Cytokines may be also used as the therapeutic agent. Examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones.
  • growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones, such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor- ⁇ and - ⁇ ; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors, such as NGF- ⁇ ; platelet growth factor; transforming growth factors (TGFs), such as TGF- ⁇ and TGF- ⁇ ; insulin- like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors
  • FSH follicle stimulating
  • the imaging agent may be a substance, that can provide imaging information about a targeted site in a body of an animal, such as a mammal or a human being.
  • the imaging agent can comprise magnetic material, such as iron oxide, for magnetic resonance imaging.
  • the active agent can be, for example, a semiconductor nanocrystal or quantum dot.
  • the imaging agent can be a metal, e.g. gold or silver, nanocage particle.
  • the imaging agent can be also an ultrasound contrast agent, such as a micro or nanobubble or iron oxide micro or nanoparticle.
  • the particles having a pre-selected internalization cell mode for particular type of cells can be part of a composition, such as a pharmaceutical composition.
  • a composition may be a suspension comprising the particles described above for use in administering a therapeutic or imaging agent.
  • the particles may be suspended in an aqueous medium at a selected concentration.
  • concentration can depend on the characteristics (e.g., solubilization properties) of the particle, type of therapeutic application and mode of administration.
  • compositions for oral administration can be relatively viscous, and may therefore contain a higher concentration (e.g., >50%) of the particle.
  • Solutions for bolus injections preferably contain a relatively concentrated suspension of the particles (e.g., 10-50%), but not so concentrated that it has an appreciably higher viscosity than saline (to minimize need for large -bore needles).
  • the solution used for continuous intravenous infusion typically can contain a relatively low concentration (e.g., 2-10% suspension) of the particles, due to the relatively large volumes of fluid that are administered.
  • the particles may be suspended in a number of suitable aqueous carrier vehicles.
  • a suitable pharmaceutical carrier can be a carrier that is non-toxic to the recipient at the dosages and concentrations employed and is compatible with other ingredients in the formulation.
  • suitable carrier vehicles include but are not limited to water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin.
  • Suspensions for use in injectable formulations are preferably isotonic with the subject's blood.
  • the carrier can contain minor amounts of additives, such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives, as well as low molecular weight (less than about 10 residues) polypeptides, proteins, amino acids, carbohydrates including glucose or dextrans, chelating agents such as EDTA, or other excipients.
  • the suspension of particles Prior to administration to the subject, the suspension of particles may be sterilized by a suitable sterilization method. Particles fabricated from a heat-stable material may be heat-sterilized, e.g., using an autoclave. Particles fabricated from a not heat-stable material may be sterilized by passage through a commercially-available sterilization filter. Of course, filtration may be used only in cases where the particles is smaller than the pores of the sterilizing filter.
  • the particles may be administered to a subject in need of therapeutic intervention via a number of suitable administration methods.
  • the particular method employed for a specific application can be determined by the attending physician.
  • the particles may be administered by one of the following routes: topical, parenteral, inhalation, oral, vaginal and anal.
  • Intravascular administration which includes intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) injection, may be particularly preferred.
  • Intravascular administration may be either local or systemic.
  • Local intravascular delivery may be used to bring the particles in the vicinity of a body site having a known tumor or inflammation by use of guided catheter system, such as a CAT-scan guided catheter.
  • General injection such as a bolus i.v. injection or continuous/trickle-feed i.v. infusion are typically systemic.
  • the particles may be injected into the blood stream and allowed to circulate and localize to their target site. Preferably, the particles are injected to a vasculature of the target site.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Biotechnology (AREA)
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  • Medicinal Preparation (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention porte sur un procédé de formulation d'une composition de particules qui présente un mode d'internalisation de cellule présélectionné et qui entraîne la sélection d'une cellule cible ayant des récepteurs de surface et l'obtention de particules qui ont i) des fractions de surface, qui ont une affinité pour les récepteurs de surface de la cellule ou qui sont capables de s'y lier, et ii) une forme présélectionnée, la distribution de surface des fractions de surface sur les particules et la forme des particules étant efficaces pour le mode d'internalisation de cellule présélectionné.
PCT/US2008/071470 2008-07-29 2008-07-29 Compositions de particules avec un mode d'internalisation de cellule présélectionné WO2010014081A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PCT/US2008/071470 WO2010014081A1 (fr) 2008-07-29 2008-07-29 Compositions de particules avec un mode d'internalisation de cellule présélectionné
MX2011001121A MX2011001121A (es) 2008-07-29 2008-07-29 Composiciones de particulas con modo de incorporacion preseleccionado en la celula.
CA2732252A CA2732252A1 (fr) 2008-07-29 2008-07-29 Compositions de particules avec un mode d'internalisation de cellule preselectionne
CN200880130677XA CN102112117A (zh) 2008-07-29 2008-07-29 具有预先选择的细胞内化模式的颗粒组合物
KR1020117003851A KR20110039466A (ko) 2008-07-29 2008-07-29 미리 선택된 세포 내재화 방식을 갖는 입자 조성물
EP08782489A EP2326314A1 (fr) 2008-07-29 2008-07-29 Compositions de particules avec un mode d'internalisation de cellule présélectionné
AU2008360004A AU2008360004A1 (en) 2008-07-29 2008-07-29 Particle compositions with a pre-selected cell internalization mode
JP2011521073A JP2011529491A (ja) 2008-07-29 2008-07-29 あらかじめ選択された細胞内在化様式を有する粒子組成物

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/071470 WO2010014081A1 (fr) 2008-07-29 2008-07-29 Compositions de particules avec un mode d'internalisation de cellule présélectionné

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WO2010014081A1 true WO2010014081A1 (fr) 2010-02-04

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EP (1) EP2326314A1 (fr)
JP (1) JP2011529491A (fr)
KR (1) KR20110039466A (fr)
CN (1) CN102112117A (fr)
AU (1) AU2008360004A1 (fr)
CA (1) CA2732252A1 (fr)
MX (1) MX2011001121A (fr)
WO (1) WO2010014081A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10434070B2 (en) 2015-01-02 2019-10-08 Cellics Therapeutics, Inc. Use of nanoparticles coated with red blood cell membranes to enable blood transfusion
US11110127B2 (en) 2014-06-02 2021-09-07 Cellics Therapeutics, Inc. Use of nanoparticles coated with red blood cell membranes to treat hemolytic diseases and disorders
US11439698B2 (en) 2013-12-02 2022-09-13 Arytha Biosciences, Llc Toxoid preparation and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021908A2 (fr) * 2006-08-08 2008-02-21 Board Of Regents Of The University Of Texas Administration d'agents actifs à étapes multiples
US20080102030A1 (en) * 2006-10-11 2008-05-01 Decuzzi Paolo Particles for cell targeting

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008021908A2 (fr) * 2006-08-08 2008-02-21 Board Of Regents Of The University Of Texas Administration d'agents actifs à étapes multiples
US20080102030A1 (en) * 2006-10-11 2008-05-01 Decuzzi Paolo Particles for cell targeting
WO2008067049A2 (fr) * 2006-10-11 2008-06-05 Board Of Regents Of The University Of Texas System Particules pour le ciblage de cellule

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DECUZZI ET AL: "The role of specific and non-specific interactions in receptor-mediated endocytosis of nanoparticles", BIOMATERIALS, ELSEVIER SCIENCE PUBLISHERS BV., BARKING, GB, vol. 28, no. 18, 29 March 2007 (2007-03-29), pages 2915 - 2922, XP022004013, ISSN: 0142-9612 *
DECUZZI P ET AL: "The receptor-mediated endocytosis of nonspherical particles", BIOPHYSICAL JOURNAL, vol. 94, no. 10, May 2008 (2008-05-01), pages 3790 - 3797, XP002528094, ISSN: 0006-3495 *
FERRARI M: "CANCER NANOTECHNOLOGY: OPPORTUNITIES AND CHALLENGES", NATURE REVIEWS. CANCER, NATUR PUBLISHING GROUP, LONDON, GB, vol. 5, 1 March 2005 (2005-03-01), pages 161 - 171, XP009046171, ISSN: 1474-175X *
TASCIOTTI ENNIO ET AL: "Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications.", NATURE NANOTECHNOLOGY MAR 2008, vol. 3, no. 3, March 2008 (2008-03-01), pages 151 - 157, XP002528093, ISSN: 1748-3395 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11439698B2 (en) 2013-12-02 2022-09-13 Arytha Biosciences, Llc Toxoid preparation and uses thereof
US11110127B2 (en) 2014-06-02 2021-09-07 Cellics Therapeutics, Inc. Use of nanoparticles coated with red blood cell membranes to treat hemolytic diseases and disorders
US10434070B2 (en) 2015-01-02 2019-10-08 Cellics Therapeutics, Inc. Use of nanoparticles coated with red blood cell membranes to enable blood transfusion

Also Published As

Publication number Publication date
CN102112117A (zh) 2011-06-29
JP2011529491A (ja) 2011-12-08
EP2326314A1 (fr) 2011-06-01
AU2008360004A1 (en) 2010-02-04
KR20110039466A (ko) 2011-04-18
MX2011001121A (es) 2011-05-23
CA2732252A1 (fr) 2010-02-04

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