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WO2009038659A2 - Nanoparticules de silice organiquement modifiées avec des photosensibilisateurs incorporés par covalence pour l'administration de médicaments lors d'une thérapie photodynamique - Google Patents

Nanoparticules de silice organiquement modifiées avec des photosensibilisateurs incorporés par covalence pour l'administration de médicaments lors d'une thérapie photodynamique Download PDF

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Publication number
WO2009038659A2
WO2009038659A2 PCT/US2008/010608 US2008010608W WO2009038659A2 WO 2009038659 A2 WO2009038659 A2 WO 2009038659A2 US 2008010608 W US2008010608 W US 2008010608W WO 2009038659 A2 WO2009038659 A2 WO 2009038659A2
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photosensitizer
nanoparticles
nanoparticle
group
groups
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WO2009038659A3 (fr
Inventor
Ravindra Pandey
Lalit Goswami
Allan Oseroff
Janet Morgan
Paras Prasad
Earl Bergey
Tymish Ohulchanskyy
Indrajit Roy
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Health Research Inc
Research Foundation of the State University of New York
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Health Research Inc
Research Foundation of the State University of New York
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    • 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
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0089—Particulate, powder, adsorbate, bead, sphere
    • A61K49/0091—Microparticle, microcapsule, microbubble, microsphere, microbead, i.e. having a size or diameter higher or equal to 1 micrometer
    • A61K49/0093—Nanoparticle, nanocapsule, nanobubble, nanosphere, nanobead, i.e. having a size or diameter smaller than 1 micrometer, e.g. polymeric nanoparticle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • 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
    • A61K49/0036—Porphyrins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
    • A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
    • A61K49/1821—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles
    • A61K49/1824—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles coated or functionalised microparticles or nanoparticles coated or functionalised nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1241—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins
    • A61K51/1244—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules particles, powders, lyophilizates, adsorbates, e.g. polymers or resins for adsorption or ion-exchange resins microparticles or nanoparticles, e.g. polymeric nanoparticles
    • 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 present invention relates to the field of nanoparticle mediated drug delivery in photodynamic therapy.
  • Photodynamic therapy a light-activated treatment for cancer and other diseases
  • PS photosensitizers
  • the therapeutic effect is activated by the photoexcitation of the localized photosensitizers and the subsequent generation of cytotoxic species, such as singlet oxygen (1O2), free radicals or peroxides, which lead to selective and irreversible destruction of the diseased tissues without damaging adjacent healthy ones.
  • Photodynamic therapy is based on the concept that certain therapeutic molecules called photosensitizers (photosensitizer) can be preferentially localized in malignant tissues, and when these photosensitizers are activated with appropriate wavelength of light, they pass on their excess energy to surrounding molecular oxygen resulting in the generation of reactive oxygen species (ROS), such as free radicals and singlet oxygen ( 1 O 2 ), which are toxic to cells and tissues.
  • ROS reactive oxygen species
  • PDT is a non-invasive treatment and used for several types of cancers, and its advantage lies in the inherent dual selectivity.
  • selectivity is achieved by a preferential localization of the photosensitizer in target tissue (e.g. cancer)
  • second, the photoirradiation and subsequent photodynamic action can be limited to a specific area. Since the photosensitizer is non-toxic without light exposure, only the irradiated areas will be affected, even if the photosensitizer does infiltrate normal tissues.
  • colloidal carriers for photosensitizers such as oil- dispersions, liposomes, low-density lipoproteins, polymeric micelles, and recently ceramic nanoparticles are examples of delivery shuttles for photosensitizer molecules some of which may offer benefits from rendering aqueous stability and appropriate size for passive targeting to tumor tissues by the "enhanced permeability and retention" (EPR) effect, offering a possibility of bioconjugation approaches to enhance bioavailability as well as tumor targeting and offering a possibility of actively targeting tumor tissues by appropriate surface functionalization.
  • EPR enhanced permeability and retention
  • nanoparticles containing covalently linked photosensitizer molecules are provided to overcome the drawback of their premature release and thus enhance the outcome of PDT.
  • silica-based nanoparticles are provided containing at least one covalently linked photosensitizer.
  • the photosensitizer is preferably a tetrapyrrole-based compounds related to porphyrins, chlorins, bacteriochlorins, benzochlorins, benzoporphyrin derivatives, pheophorbides including pyropheophorbides, and phthalocyanines, naphthanocyanines with and without fused ring systems and derivatives of all the above.
  • the nanoparticle may also include covalently linked imaging agents, e.g. radionuclides, magnetic resonance (MR) and fluorescence imaging agents.
  • MR magnetic resonance
  • the imaging agents and photosensitizers may be at a periphery (surface) of the nanoparticles to increase efficiency.
  • Target-specific nanoparticles may be provided by incorporating biotargeting molecules such as specific antibodies at the surface that react with particular ligands to obtain target specificity. Diagnostic agents may be present in the antibody in addition to imaging agents and tumor specific photosensitizers as previously and subsequently discussed.
  • the nanoparticle of the invention has the structural formula:
  • the ring represents a silicone polymer matrix
  • R 4 is (Ri) n -R 2 -(Rs) n
  • Ri is a labeled photosensitizer (IP) or unlabeled photosensitizer (P), cyanine dye, SPECT imaging agent, PET imaging agent, MR imaging agent or fluorescent imaging agent at least partially available at a surface of the silicone polymer matrix
  • R 2 is -O-, -COO-, -NR 5 or -NH- connected to the silicone polymer matrix directly or through an intermediate group, n is 0 or 1; provided that at least one n is 1 and R3 is cyanine dye, SPECT, PET, MR or fluorescent imaging agent, linked targeting agent RGD, F3 peptide, carbohydrate or folic acid or labeled photosensitizer (IP) or unlabeled photosensitizer (P) embedded in the silicone polymer matrix
  • R5 is lower alkyl of from 1 to 5 carbon atoms where a plurality of
  • Figure IA shows graphic results of spin-filtration of various formulations of
  • the graph shows the relative optical densities (read at 663 nm, the long- wavelength absorbance peak for IP) of the 'filtrate' and 'retentate' fractions, as well as the non-filtered 'original' samples, for cell lines NY-362 through NY-365.
  • the non-silylated photosensitizer 3-iodobenzyl-pyro, or EP is used as the control, both dissolved in Tween-80 micelles as well as encaphotosensitizerulated in ORMOSIL nanoparticles.
  • Figure IB shows a TEM image of NY-363.
  • FIG. 1C shows a scheme 1 for synthesis of the precursor 3-iodobenzylpyro- silane (EPS) shown as compound II.
  • EPS 3-iodobenzylpyro- silane
  • IP compound I
  • Figure 2 shows emission of EP upon UV irradiation following TLC of EP- conjugated (lane 1) and encapsulated (lane 2) ORMOSlL nanoparticles.
  • Lane 3 shows the same for EP/1 % Tween-80.
  • Figure 3A shows absorption spectra of the "micelle free" nanoparticle samples (retentate collected after spin-filtration and resuspended), as well as non-filtered micellar suspensions of EP/Tween-80 and NY-362 (100% of EPS, no VTES). Fluorescence was obtained on exciting the molecule at 514 nm.
  • Figure 3B shows fluorescence spectra of the "micelle free” nanoparticle samples (retentate collected after spin-filtration and resuspended), as well as non-filtered micellar suspensions of EP/Tween-80 and NY-362 (100% of EPS, no VTES). Fluorescence was obtained on exciting the molecule at 514 nm.
  • Figure 4A shows results on singlet oxygen production by "micelle-free" suspensions of nanoparticles which were obtained by singlet oxygen phosphorescence spectroscopy, showing remarkable similarity to those obtained following the same trend: EP/Tween-80 micellar suspension demonstrated higher 1 O 2 generation than NY-363, NY-364, NY-365; whereas, intensitiy for NY-362 is lower.
  • FIG 4B shows results on singlet oxygen production by "micelle-free" suspensions of nanoparticles, obtained using an ADPA (anthracenedipropionic acid) bleaching method.
  • ADPA anthracenedipropionic acid
  • Non-spin-filtered micellar suspensions of EP/Tween-80 and NY-362 (100% of Iphotosensitizer, no VTES) were used as controls.
  • Rose Bengal (RB) in methanol was used as a reference standard for the 1 O 2 phosphorescence measurements. This means that singlet oxygen generated within nanoparticles is mostly deactivated outside nanoparticles, causing bleaching of ADPA. Irradiation with 514 nm, applied laser power was 5 times higher for the bleaching experiment than for spectra acquisition.
  • Figure 5 shows decays of the emission from Iphotosensitizer/VTES nanoparticle and IP Tween-80 suspensions at 1270 nm.
  • Figure 6 shows combined comparative photomicrographs Figure 6 of Colon-
  • Figure 7 shows a nonoparticle 10 having R4 groups where the ring represents a silicone polymer matrix.
  • R 4 is (Rt) n -R 2 -(Rs) n .
  • Ri is a labeled photosensitizer (IP) or unlabeled photosensitizer (P), cyanine dye, SPECT imaging agent, PET imaging agent, MR imaging agent or fluorescent imaging agent at least partially available at a surface of the silicone polymer matrix.
  • R 2 is -O-, -COO-, -NR5 or -NH- connected to the silicone polymer matrix directly or through an intermediate group, n is 0 or 1; provided that at least one n is 1.
  • R3 is cyanine dye, SPECT, PET, MR or fluorescent imaging agent, linked targeting agent RGD, F3 peptide, carbohydrate or folic acid or labeled photosensitizer (IP) or unlabeled photosensitizer (P) embedded in the silicone polymer matrix.
  • R 5 is lower alkyl of from 1 to 5 carbon atoms where a plurality of Ri groups, R 2 groups or mixtures thereof are photosensitizer and/or labeled photosensitizer.
  • IP I 124 -labeled photosensitizer
  • targetingents e.g. RGD, F3 peptides, carbohydrates and folic acid.
  • nanoparticles containing covalently linked photosensitizer molecules are provided to overcome the drawback of their premature release and thus enhance the outcome of PDT.
  • silica-based nanoparticles are provided containing at least one covalently linked photosensitizer.
  • the photosensitizer is preferably a tetrapyrrole-based compounds related to porphyrins, chlorins, bacteriochlorins, benzochlorins, benzoporphyrin derivatives, pheophorbides including pyropheophorbides.
  • Specific ezamples of such photosensitizers may, for example be found in U.S.
  • the nanoparticle may also include covalently linked imaging agents, e.g. radionuclides, magnetic resonance (MR) and fluorescence imaging agents.
  • the imaging agents and photosensitizers may be at a periphery (surface) of the nanoparticles to increase efficiency.
  • Target-specific nanoparticles may be provided by incorporating biotargeting molecules such as specific antibodies at the surface that react with particular ligands to obtain target specificity. Diagnostic agents may be present in the antibody in addition to imaging agents and tumor specific photosensitizers as previously and subsequently discussed.
  • the nanoparticle of the invention has the structural formula:
  • R 4 is (Ri) n -R 2 -(Rs) n where Ri is a labeled photosensitizer (IP) or unlabeled photosensitizer (P), cyanine dye, SPECT (single proton emission computed tomography) imaging agent, PET (positron emission tomography) imaging agent, MR imaging agent or fluorescent imaging agent at least partially available at a surface of the silicone polymer matrix.
  • IP labeled photosensitizer
  • P unlabeled photosensitizer
  • cyanine dye cyanine dye
  • SPECT single proton emission computed tomography
  • PET positron emission tomography
  • MR imaging agent positron emission tomography
  • At least one Ri or R 3 group may be a tetrapyrollic photosensitizer, e.g. porphyrins, chlorins, bacteriochlorins, benzochlorins, benzoporphyrins, pheophorbides including pyropheophorbides, and derivatives thereof.
  • R 2 is -O-, -COO-, -NR5 or -NH- connected to the silicone polymer matrix directly or through an intermediate group.
  • the intermediate group may, for example, be subtituted or unsubstituted alkylene or phenylene.
  • the alkylene or phenylene may be substituted with at least one hydroxy, carboxy, amino, sulfo, alkylester, alkylether, heterocyclo, or halo group.
  • n is 0 or 1 ; provided that at least one n is 1.
  • R3 is cyanine dye, SPECT, PET, MR or fluorescent imaging agent, linked targeting agent RGD, F3 peptide, carbohydrate or folic acid or labeled photosensitizer (IP) or unlabeled photosensitizer (P) embedded in the silicone polymer matrix.
  • RGD is a peptide that contains the Arg-Gly-Asp attachment site that recognizes v3 and v5 integrin receptors that play a role in angiogenesis, vascular intima thickening and proliferation of malignant tumors.
  • R 5 is lower alkyl of from 1 to 5 carbon atoms.
  • a plurality of Ri groups, R3 groups or mixtures thereof are photosensitizer and/or labeled photosensitizer.
  • the Ri or R 3 group may be phthalocyanine, naphthanocyanine and derivatives thereof and may also be a radionuclide or MR or fluorescencent imaging agent.
  • a plurality of Ri groups are preferably photosensitizers located at peripheral positions on the nanoparticle and a plurality of R 3 groups are imaging agents located at peripheral positions on the nanoparticle.
  • the nanoparticle are desirably provided with biotargeting molecules following suitable surface functionalization to obtain target-specific nanoparticles.
  • biotargeting molecules examples include antibodys and the suitable surface functionalization for the antibody is a ligand, e.g. RGD and F3 peptide..
  • the nanoparticle may further include at least one diagnostic agent.
  • Photosensitiers as used herein means any material that can enter or attach to a cell or portion thereof and be activated by eletromagnetic radiation, usually light, to destroy the cell or significantly alter its activity.
  • nanoparticles made of an organically modified silica refers to nanoparticles made from silica that has been organically modified to self organize into polysicone nanoparticles upon precipitation from solution.
  • Preferred organically modified silica nanoparticles are ORMOSIL nano particles usually made by inclusion of a vinyltriethoxysilane in a sufactant solution followed by precipitation with ammonia or other amine, e.g. 3 aminopropyltriethoxy silane. In the first case the nanoparticle has surface -OH groups and in the second case has surface amino groups.
  • the silane (silicone) matrix is formed by self reaction of hydroxy silanes by dehydration to form a polymeric silicone matrix of silcon atoms interconnected by oxygen atoms.
  • the starting silanes have the formula R 4 Si where R is independently at each occurrence an alkyl, alkylene, hydroxy or alkoxy group, provided that at least two of said R groups are hydroxy groups.
  • the other R groups are usually hydroxy, alkoxy or an alkyl group substituted with an alkoxy, carboxy, hydroxyl, amino or mercapto group.
  • the silanes and R groups are selected such that they will form nanoparticles having a size of less than 200nm, preferably less than 100 nm and most preferably less than 50 nm. Particles of a size less than 20 nm are most desirable in most circumstances.
  • the silanes are selected so that the nanoparticles will have hydroxyl, amino, mercapto and/or carboxy groups exposed at its surface.
  • the silane is desirably selected from the group consisting of vinyltrimethoxysilane, vinyltriethoxysilane, vinylytriacetosilane, ⁇ - glycidoxypropyltrimethoxysilane, ⁇ -methacryloxypropyltrimethoxysilane, ⁇ - aminopropyltrimethoxysilane, ⁇ -aminopropyltriethoxysilane, ⁇ - mercaptopropyltrimethoxysilane, ⁇ -3,4-epoxycyclohexyltrimethoxysilane and phenyltrimethoxysilane.
  • the invention further includes a method for forming nanoparticles having covalently bonded photosensitizer. This accomplished by providing reactive intermediate structures on the the nanoparticle, either by providing them on the nanoparticle precursor or by adding them subsequent to nanoparticle formation.
  • a specific method for forming such nanoparticles includes the steps of: a) forming a uniform medium comprising from about 70 to about 80 weight percent of a lower alcohol selected from isopropanol, n-butanol, isobutanol and n-pentanol, from about 20 to about 30 weight percent of DMSO, from about 2 to about 3 percent water and from about 0.05 to about 0.15 percent of sufficient surfactant to maintain a dispersion; b) uniformly incorporating one or more silanes, as above described wherein the amount of silane or mixtures of silanes is about the maximum permitted for stability; c) adding sufficient reactive basic compound to form nanoparticles having reactive hydroxyl, amino, mercapto and/or carboxy groups exposed at their surface; d) dialyzing the nanoparticles through a membrane having a pore size of from about 0.1 to about 0.3 ⁇ M; e) during step b) or prior to step d), reacting a photosensitizer
  • the surfactant used in the method is usually a polyoxyethylene sorbitan monooleate or sodium dioctyl sulfosucinate and the silane usually includes: vinyltrimethoxysilane, vinyltriethoxysilane, vinylytriacetosilane, ⁇ - glycidoxypropyltrimethoxysilane, ⁇ -methacryloxypropyltrimethoxysilane, ⁇ - aminopropyltrimethoxysilane, ⁇ -aminopropyltriethoxysilane, ⁇ - mercaptopropyltrimethoxysilane, ⁇ -3,4-epoxycyclohexyltrimethoxysilane and phenyltrimethoxysilane.
  • the silane is preferably vinyltriethoxysilane or phenyltrimethoxysilane and the basic compound is usually ammonia or 3-aminopropylethoxysilane. It should; however be understood that essentially any base may be used provided that it if it is a strong base, e.g. an alkali hydroxide, it is sufficiently diluted.
  • Preferred photosensitizers are preferentially absorbed or adsorbed by cells that require destruction or significant alteration, e.g. cells of hyperproliferative tissue such as tumor cells, hypervascularization such as found in macular degeneration and hyperepidermal debilitating skin diseases.
  • Selectivity can be further enhanced by incorporating with nanoparticles in accordance with the present invention, targeting agents such as an monoclonal antibodies, integrin-antagonists or carbohydrates which have high affinity for target tissue (mainly cancer).
  • Preferred photosensitizers are tetrapyrrole-based compounds related to porphyrins, chlorins, bacteriochlorins, benzochlorins, benzoporphyrin derivatives, pheophorbides including pyropheophorbides, and phthalocyanines and, naphthanocyanines with and without fused ring systems and derivatives of all the above.
  • a desirable photosensitizer for many applications is a tumor avid tetrapyrollic photosensitizer, that may be complexed with an element X where X is a metal selected from the group consisting of Zn, In, Ga, Al, or Cu or a radioisotope labeled moiety wherein the radioisotope is selected from the group consisting of 11 C, 18 F, 64 Cu, 124 I, 99 Tc, 111 In and GdIII that may be used in a method for diagnosing, imaging and/or treating hyperproliferative tissue such as tumors and other uncontrolled growth tissues such as found in macular degeneration.
  • the photosensitizer may have the generic formula:
  • R 9 -OR 1 0 where Ri 0 is lower alkyl of 1 through 8 carbon atoms, -(CH 2 -O) n CH 3 , -(CH 2 ) 2 CO 2 CH 3 , -(CH 2 ) 2 CONHphenyleneCH 2 DTPA,
  • R 2 , R 2a , R 3, R 33 , Ri, Rs, Rsa, R7, and R 7a are independently hydrogen, lower alkyl or substituted lower alkyl or two R 2 , R 2a , R 3 , R 3a , R5, Rsa, R7, and R 7a groups on adjacent carbon atoms may be taken together to form a covalent bond or two R 2 , R 2a , R 3 , R 3a , R 5 , R 5a , R 7 , and R 7a groups on the same carbon atom may form a double bond to a divalent pendant group; R 2 and R 3 may together form a 5 or 6 membered heterocyclic ring containing oxygen, nitrogen or sulfur; R 6 is -CH 2 - , -NRn- or a covalent bond; Rs is -(CH 2 ) 2 CO 2 CH 3 , -(CH 2 ) 2 CONHphenyleneCH 2 DTPA,
  • R n is -CH 2 CONH-RGD-Phe-Lys, -CH 2 NHCO-RGD-PhC-LyS, a fluorescent dye moiety, or -CH 2 CONHCH 2 CH 2 SO 2 NHCH(CO 2 )CH 2 NHCOPhenylOCH 2 CH 2 NHcycloCNH(CH 2 ) 3 N; and polynuclide complexes thereof; provided that the compound contains at least one integrin antagonist selected from the group consisting of -CH 2 CONH-RGD-Phe-Lys, -CH 2 NHCO- RGD-Phe-Lys and -CH 2 CONHCH 2 CH 2 SO 2 NHCH(CO 2 )CH 2 NHCOPhenylOCH 2 CH 2 NHcycloCNH(CH 2 ) 3 N, where X is a metal selected from the group consisting of Zn, In, Ga, Al, or Cu or a radioisotope labeled moiety wherein the radioisotope is
  • the complexes with X are readily made simply by heating the compound with a salt of X such as a chloride.
  • the complex will form as a chelate of a -DTPA moiety, when present, or within the tetrapyrollic structure between the nitrogen atoms of the amine structure or both. Examples of such structures are:
  • M In, Cu, Ga (with or without radioactive isotope)
  • a method for the synthesis of organically modified silica (ORMOSIL) nanoparticles with a covalently linked photosensitizer molecule is provided.
  • ORMOSIL organically modified silica
  • the nanoconjugated photosensitizer retained its spectral and therapeutic properties, was uptaken by tumor cells in culture and could elicit PDT effect upon photoirradiaion of the targeted cells.
  • nanoparticles with covalently incorporated photosensitizer eliminate the possibility of premature release of the photosensitizer molecules while being in circulation and ensure maximum delivery of the photosensitizer to the targeted site.
  • ORMOSIL nanoparticles where the photosensitizer molecule is covalently incorporated within the ORMOSIL nanoparticle matrix, have been synthesized and characterized. This has been achieved by the synthesis of iodobenzyl-pyro-silane (Iphotosensitizer), a precursor for ORMOSIL with the linked photosensitizer iodobenzylpyropheophorbide (IP).
  • Iphotosensitizer iodobenzyl-pyro-silane
  • IP linked photosensitizer iodobenzylpyropheophorbide
  • ORMOSIL nanoparticles were synthesized upon co-precipitation of Iphotosensitizer with the commonly used ORMOSIL precursor vinyltriethoxysilane (VTES). This synthesis is carried out in the non-polar core of Tween-80/water microemulsion media. In this microemulsion media, ORMOSIL nanoparticles can readily be synthesized with the combination of Iphotosensitizer and VTES. Photophysical study has demonstrated that the spectroscopic and functional (generation of cytotoxic singlet oxygen) properties of the photosensitizer are preserved in their 'nanoconjugated' state.
  • the surfaces of these nanoparticles may, however, be modified using bioconjugation approaches to improve their biocompatibility and biotargeting efficiency.
  • the conjugated IP may also be modified with radiolabeled probes (e.g. 1-124) in an effort to combine the feasibiliy of positron-emission tomographic (PET) imaging along with PDT for these nanoparticles.
  • PET positron-emission tomographic
  • VTES vinyltriethoxysilane
  • NANOSEP IOOK OMEGA Microfuge membrane-filters
  • N-Ethyl-N'-(3-dimethylaminopropyl) carbodiimide hydrochloride, 4- dimethylamino pyridine and 4-(triethoxysilyl)-aniline were purchased from Aldrich and used without further purification.
  • 9,10-Anthracenedipropionic acid, disodium salt (ADPA) was purchased from Invitrogen. Colon-26 cells were cultured according to manufacturer's instructions. Unless otherwise mentioned, all cell culture products were obtained from Invitrogen
  • the nanoparticles were synthesized by the alkaline hydrolysis and polycondensation of the organo-trialkoxysilane precursors within the non-polar core of Tween-80/water microemulsion. Briefly, to 10 ml of 2% aqueous Tween-80 solution, 300 ⁇ L of co-surfactant 1-butanol was dissolved. To this solution, 40 ⁇ L of a solution (10 mM in DMSO) of Iphotosensitizer (Compound II, Scheme 1) was dissolved by simple magnetic stirring.
  • VTES 0 or 40 or 80 or 160 ⁇ L of VTES was added dropwise and the resulting mixture was magnetically stirred for one hour. At this stage, 10DL of aqueous ammonia was added and the resulting solution was magnetically stirred overnight for the formation of the nanoparticles.
  • the dialysate containing the IP-conjugated ORMOSIL nanoparticles was sterile filtered (0.2 uM membrane) and was stored at 4 0 C for further use.
  • Table 1 represents the amounts of the Iphotosensitizer and VTES used in the various formulations.
  • the amount of photosensitizer associated with each fraction could be estimated by reading their optical density at 663 nm (the long wavelength absorption peak for IP/Iphotosensitizer). All subsequent studies with the nanoparticles were carried out with the micelle-free 'retentate' fraction, unless otherwise mentioned.
  • TLC Thin-layer chromatography
  • TEM Transmission electron microscopy
  • the treated cells were washed thoroughly with PBS and then directly imaged using a confocal laser scanning microscope (MRC- 1024, Bio-Rad, Richmond, CA).
  • a Ti:sapphire laser (Tsunami from Spectra-Physics) pumped by a diode- pumped solid state laser (Millenia, Spectra Physics) was used as a source of excitation.
  • the Ti:sapphire output tuned to 830 nm, was frequency doubled by second harmonic generation (SHG) in a ⁇ -barium borate ( ⁇ -BBO) crystal to obtain the 415-nm light, and was coupled into a single mode fiber for delivery into the confocal scan head.
  • SHG second harmonic generation
  • ⁇ -BBO ⁇ -barium borate
  • a long-pass filter, 585 LP (585 nm), and an additional band pass filter with transmission at 680 ⁇ 15 nm (Chroma 680/30) were used as emission filters for fluorescence imaging.
  • Figures IA and IB show the relative optical densities (read at 663 nm, the long-wavelength absorbance peak for IP) of the 'filtrate' and 'retentate' fractions, as well as the non-filtered 'original' samples, for NY-362 through NY-365.
  • the non-silylated photosensitizer 3-iodobenzyl-pyro, or EP is used as the control, both dissolved in Tween-80 micelles as well as encaphotosensitizerulated in ORMOSIL nanoparticles.
  • a formation of the rigid, spherical and monodisperse nanoparticles with size about 20 nm for NY-363 is shown by TEM (Fig.l,B). It is worth noting that while TEM of NY-362 showed no formation of nanoparticles, thus confirming inability of Iphotosensitizer alone to form nanoparticles, NY-364 and NY-365 both formed the same-sized nanoparticles as NY-363 (data not shown), showing that the size of the nanoparticles is unaffected by the amount of the precursor used.
  • Intensity of the singlet oxygen emission sensitized in all suspensions of nanoparticles / micelles correlates with fluorescence intensity (Figure 3B). Intensity of 1 O 2 emission as well as fluorescence intensity that was almost identical for NY-363, NY-364, NY-365. IP/Tween-80 micellar suspension shows slightly higher fluorescence and 1 O 2 emission intensities, whereas intensity for NY-362 (non-spin-filtered) is lower. [0073] Correlation of the fluorescence and 1 O 2 emission intensities confirms aggregation affecting singlet oxygen generation.
  • FIG. 4B results on singlet oxygen production, which were obtained with method of ADPA bleaching, showed remarkable similarity to those obtained by singlet oxygen phosphorescence spectroscopy ( Figure 4B), following the same trend: IP/Tween-80 micellar suspension demonstrated higher 1 O 2 generation then NY-363, NY-364, NY-365, whereas intensitiy for NY-362 is lower. This means that singlet oxygen generated within nanoparticles is mostly deactivated outside nanoparticles, causing bleaching of ADPA. In this case, lifetime of the singlet oxygen generated within nanoparticles should be determined by the water environment and be around 4 ⁇ s. 13 [0076]
  • Figure 5 is a graph showing decays of emission at 1270 nm. Signal obtained for the suspension of neat ORMOSIL nanoparticles (100% of VTES) was used as Instrument Response Function (IRF). Rose Bengal (RB) in methanol was used as a reference standard producing singlet oxygen. Figure 5 shows decays of the emission from
  • Iphotosensitizer/VTES are very close to that sensitized by IP/Tween-80 micellar suspension and have average lifetime ( ⁇ ) in the range of 4.5-5 ⁇ s.
  • ⁇ average lifetime
  • decay of 1 O 2 emisssion sensitized by RB in methanol is also shown, demonstrating monoexponential fitting with ⁇ wlO ⁇ s, which is characteristic lifetime for 1 O 2 in methanol. 13
  • Rise time of the 1 O 2 emission sensitized by the nanoparticle / micellar suspensions is noticeably higher then for RB molecular solution, including time of diffusion of the molecular oxygen to the incorporated photosensitizer chromophores.
  • FIG. 6 is a plurality of micrographs showing cellular uptake Colon-26 cells treated overnight with NY-363 (A), NY-364 (B), NY-365 (C). Transmission (above) and fluorescence (below) channels are shown. Confocal pinhole and PMT gain remained same during imaging.
  • FIG. 7 A structural representation of a nanoparticle in accordance with the invnetion is shown in Figure 7.
  • Ri labeled photosensitizer
  • P unlabeled
  • a modified formulation of the nanoparticles is provided with the photosensitizer molecule being covalently linked, instead of just being physically encaphotosensitizerulated.
  • the photosensitizer molecule being covalently linked, instead of just being physically encaphotosensitizerulated.
  • nanoparticle conjugated (covalently linked) photosensitizers have been demonstrated having simple preparation that eliminate the possibility of premature release of the photosensitizer to unwanted sites in vivo.
  • the invention permits ease of active targeting by attaching targeting grouphotosensitizer on the particle surface
  • the composite contains a covalently linked radioactive atoms for PET/SPECT imaging or magnetic resonance imaging contrast agents (i.e gadolinium).

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Abstract

L'invention concerne des nanoparticules contenant des photosensibilisateurs liés par covalence qui remédient au problème de la libération prématurée et améliorent donc le résultat de la PDT. L'invention concerne des nanoparticules à base de silice qui contiennent au moins un photosensibilisateur lié par covalence. Le photosensibilisateur est de préférence constitué de composés à base de tétrapyrrole de types porphyrines, chlorines, bactériochlorines, benzochlorines, dérivés de benzoporphyrine, phéophorbides, notamment pyrophéophorbides, et phthalocyanines, naphthanocyanines avec et sans systèmes de cycles condensés et dérivés de tous les composés ci-dessus. La nanoparticule peut également comprendre des agents d'imagerie liés par covalence, par exemple radionucléides, agents d'imagerie par résonance magnétique (RM) et fluorescence. Les agents d'imagerie et les photosensibilisateurs peuvent se trouver à la périphérie (surface) des nanoparticules pour augmenter leur efficacité. Des nanoparticules spécifiques d'une cible peuvent être obtenues en incorporant des molécules de ciblage biologique, comme des anticorps spécifiques sur la surface, qui réagissent avec des ligands particuliers pour obtenir une spécificité de cible. Des agents de diagnostic peuvent être présents dans l'anticorps en plus d'agents d'imagerie et de photosensibilisateurs spécifiques d'une tumeur.
PCT/US2008/010608 2007-09-14 2008-09-11 Nanoparticules de silice organiquement modifiées avec des photosensibilisateurs incorporés par covalence pour l'administration de médicaments lors d'une thérapie photodynamique Ceased WO2009038659A2 (fr)

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FR2956109A1 (fr) * 2010-02-11 2011-08-12 Commissariat Energie Atomique Procede de preparation par voie stober de particules de silice contenant un derive de phtalocyanine, lesdites particules et leurs utilisations.
EP2186862A3 (fr) * 2008-10-31 2011-09-21 Westfälische Wilhelms-Universität Münster Fabrication et produits associés de photosensibilisation de nanomatériaux et leur utilisation dans le traitement photodynamique
US20120184495A1 (en) * 2009-06-12 2012-07-19 Amrita Vishwa Vidyapeetham University Kerala Targeted nano-photomedicines for photodynamic therapy of cancer
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EP2591056A4 (fr) * 2010-07-06 2013-09-11 Health Research Inc Améliorations par métallisation de l'imagerie tumorale et de la thérapie pdt
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JPWO2013073243A1 (ja) * 2011-11-18 2015-04-02 株式会社Adeka 新規化合物及びこの新規化合物を担持した担持体
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WO2016094991A1 (fr) * 2014-12-16 2016-06-23 Universidade Estadual De Campinas - Unicamp Procédé d'obtention de nanoparticules de silice pégylées transporteuses d'agences pharmaceutiques hydrophobes, nanoparticules ainsi obtenues et leurs utilisations
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US10835495B2 (en) 2012-11-14 2020-11-17 W. R. Grace & Co.-Conn. Compositions containing a biologically active material and a non-ordered inorganic oxide material and methods of making and using the same
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US6540981B2 (en) * 1997-12-04 2003-04-01 Amersham Health As Light imaging contrast agents
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US20120184495A1 (en) * 2009-06-12 2012-07-19 Amrita Vishwa Vidyapeetham University Kerala Targeted nano-photomedicines for photodynamic therapy of cancer
WO2011098504A1 (fr) * 2010-02-11 2011-08-18 Commissariat à l'énergie atomique et aux énergies alternatives Procédé de préparation par voie stöber de particules de silice contenant un dérivé de phtalocyanine, lesdites particules et leurs utilisations
FR2956109A1 (fr) * 2010-02-11 2011-08-12 Commissariat Energie Atomique Procede de preparation par voie stober de particules de silice contenant un derive de phtalocyanine, lesdites particules et leurs utilisations.
EP2591056A4 (fr) * 2010-07-06 2013-09-11 Health Research Inc Améliorations par métallisation de l'imagerie tumorale et de la thérapie pdt
US9155791B2 (en) 2010-07-06 2015-10-13 Health Research, Inc. Metallation enhancements in tumor-imaging and PDT therapy
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WO2012104102A1 (fr) * 2011-02-05 2012-08-09 Marvis Technologies Gmbh Dispositif médical implantable ou insérable et détectable par irm, ayant un revêtement comprenant des ions paramagnétiques et procédé de préparation associé
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US9530571B2 (en) 2011-11-18 2016-12-27 Adeka Corporation Compound and support material supporting this novel compound
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