WO2009050696A2 - Composition et procédé pour l'activation cellulaire et la réparation tissulaire utilisant des nanoparticules et de la lumière - Google Patents

Composition et procédé pour l'activation cellulaire et la réparation tissulaire utilisant des nanoparticules et de la lumière Download PDF

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WO2009050696A2
WO2009050696A2 PCT/IL2008/001336 IL2008001336W WO2009050696A2 WO 2009050696 A2 WO2009050696 A2 WO 2009050696A2 IL 2008001336 W IL2008001336 W IL 2008001336W WO 2009050696 A2 WO2009050696 A2 WO 2009050696A2
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composition
light
group
nanoparticles
nanoparticle
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WO2009050696A3 (fr
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Rachel Lubart
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Qray Ltd.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/04—Sulfur, selenium or tellurium; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/08—Oxides; Hydroxides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/34—Copper; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • 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 is of compositions and methods for inducing cell stimulation and in particular, such compositions and methods which feature sub- cytotoxic nanoparticles or microparticles and light.
  • ROS reactive oxygen species
  • ROS include oxygen ions, free radicals, and peroxides, both inorganic and organic. They are generally very small molecules and are highly reactive due to the presence of unpaired valence shell electrons.
  • PDT photodynamic therapy
  • NIR infra-red
  • Cytotoxic amounts of photosensitizers or nanoparticles which destroy recipient cells via generation of cytotoxic ROS may be used for treating diseases such as cancer, viral and bacterial infections (3-6). At concentrations below those required for cytotoxicity, ROS have a wide range of positive stimulatory effects on the cell.
  • ROS promote cell growth (7-10) which in the case of fibroblasts can be exploited for wound healing and skin rejuvenation.
  • ROS can induce differentiation of neurons (11) which could be used for nerve regeneration.
  • ROS such as the superoxide anion and H 2 O 2
  • cardiac cells and in cardiomyocytes ROS function as an important regulator of cell survival (13), and small amounts of ROS were suggested to play a role in preconditioning against myocardial stunning (14).
  • GTP guanosine triphosphate
  • Rac-1 guanosine triphosphate
  • NO nitric oxide
  • VSM vascular smooth muscle
  • LEDs light-emitting diodes
  • broadband light sources in the visible and near IR ranges have emerged in recent years as having therapeutic uses such as nerve regeneration (22, 23), pain relief (24) and more.
  • nerve regeneration 22, 23
  • pain relief 234
  • the stimulatory effects of light in the visible and near IR regions is termed
  • photobiomodulation and has been reported to induce many cell processes, such as proliferation (25-28), spermatozoa fertilization (29) and motility (30), action potentials (31), cell differentiation (32), protection of cells from damage (33), and recovery of damaged cells (34).
  • Other reported effects are the stimulation of collagen synthesis (35), release of cytokines (36) and growth factors (37, 38).
  • the background art does not teach or suggest the use of sub-cytotoxic amounts of nanoparticles or microparticles, either alone or with light stimulation to produce cell-stimulatory amounts of ROS for cell stimulation and tissue regeneration.
  • the present invention overcomes these deficiencies of the background art by providing compositions and methods of use thereof, as well as methods of treatment, featuring administration of nanoparticles or microparticles, either alone or in combination with light stimulation to produce controlled, limited amounts of ROS for cell stimulation and tissue regeneration.
  • the nanoparticles or microparticles are introduced to the subject exogeneously, as described in greater detail below.
  • method refers to manners, means, techniques and procedures for accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • treating includes abrogating, substantially inhibiting, slowing or reversing the progression of a condition, substantially ameliorating clinical or aesthetical symptoms of a condition or substantially preventing the appearance of clinical or aesthetical symptoms of a condition.
  • composition or method may include additional ingredients and/or steps, but only if the additional ingredients and/or steps do not materially alter the basic and novel characteristics of the claimed composition or method.
  • nanoparticles refers to particles having a diameter of the order of about 200 run or less. Such particles exhibit properties different from those of the bulk material. Because of their ultra-small size, nanoparticles can penetrate cell membranes and integrate themselves into larger molecules. They can resist cellular defense systems but are large enough to interfere with cell processes.
  • microparticles refers to particles of diameter in the range of from about 1 to about 200 ⁇ m.
  • a “pharmaceutical composition” refers to a preparation of one or more of the active ingredients described herein, either compounds or physiologically acceptable salts thereof, with other chemical components such as traditional drugs, physiologically suitable carriers and excipients.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • physiologically suitable carrier 5 and “pharmaceutically acceptable carrier” are interchangeably used and refer to an approved carrier or a diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered conjugate.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with ⁇ which the therapeutic is administered.
  • excipient refers to an inert substance added to a pharmaceutical composition to further facilitate processes and administration of the active ingredients.
  • ROS treatment parameters as they impact upon the amount of ROS generated, as well as the location at which they are generated.
  • the present invention in some embodiments, preferably provides a method — for-generating_ROS for stimulatory purposes in cells and tissues, more preferably increasing their concentration, and hence their activity, in deep lying tissues by irradiating them with light in the visible and near IR region.
  • the present invention is able to overcome these known deficiencies of the background art, as well as to provide many other benefits, some of which are described in greater detail below.
  • FIG 1 shows an electon paramagnetic resonance (EPR) spectrum of zinc oxide in water, in which hydroxyl and super oxide anion radicals formation is clearly monitored.
  • EPR electon paramagnetic resonance
  • Figure 3 shows that incubation of fibroblasts with TiO 2 at 5OuM results in a stimulation of 40% in the cell number.
  • the present invention provides compositions and methods of use thereof, as well as methods of treatment, featuring nanoparticles or microparticles, either alone or in combination with light stimulation to produce limited amounts of ROS for cell stimulation and tissue regeneration.
  • nanoparticles to produce a cytotoxic effect via generation of high levels of ROS is known, and has been used for treatment of cancer, and viral and bacterial infections, as discussed in the Background section above.
  • the present inventors have surprisingly found that lower amounts of nanoparticles and microparticles than those which result in cytotoxicity can cause stimulation of cellular activity, including cell activation and tissue repair.
  • the nanoparticles or microparticles themselves contain stable ROS, including but not limited to hydroxyl, singlet oxygen and super oxide anion, hydrogen peroxide, and nitric oxide which stimulate cell activity.
  • stable ROS including but not limited to hydroxyl, singlet oxygen and super oxide anion, hydrogen peroxide, and nitric oxide which stimulate cell activity.
  • the nanoparticles or microparticles Upon introduction to the tissue, the nanoparticles or microparticles cause cell stimulation and tissue regeneration; further light stimulation increases the amount of ROS produced.
  • the nanoparticles can penetrate easily into cells, while microparticles generate ROS at the cell membrane.
  • a particle selected from the group consisting of a nanoparticle and a microparticle for inducing cell stimulation.
  • a method of inducing cellular activity comprising administering to a subject a particle consisting of a nanoparticle and a microparticle.
  • compositions for inducing cell stimulation comprising a particle selected from the group consisting of a nanoparticle and a microparticle and a pharmaceutically acceptable carrier.
  • the nanoparticles or microparticles are preferably present in sub-cytotoxic concentrations.
  • the sub-cytotoxic concentration varies according to the particular material and size of the nanoparticle or microparticle.
  • the present inventors have found that nanoparticles or microparticles at concentrations in the range of 1-100 ⁇ g/1 can stimulate skin cells.
  • the nanoparticles or microparticles may optionally comprise one or more metal oxides, more preferably metal dioxides of biologically compatible metals, semiconductors and metal oxides doped in silica.
  • suitable metal oxides include ZnO, TiO 2 , FeO, CuO Ag 2 O, Co 3 O 4 , Mn 3 O 4 or other metal oxides doped in silica, including but not limited to Fe 2 O 3 /SiO 2 .
  • a fullerene, carbon, a heterocrystal mineral, or a combination thereof may be used.
  • the heterocrystal mineral optionally includes but is not limited to rutile, sphere, loparite, perowskite, anatase, ilmenite, leukoxen, ferrite, argyrite, graphite, CaO, phosphoritemonooxides phosphoritedioxide, or CdSe/ZnS.
  • the bandgap size and consequently the electronic properties are very much dependent on the preparation of the nanoscale or microscale semiconductor.
  • the nanoparticle diameters are in the range of up to about 1000 nm.
  • the dimensions are in the range of from about 0.5 to about 200 nm, more preferably from about 0.5 to about 50 nm.
  • microparticle diameters are preferably in the range of 1 to about 200 ⁇ m, more preferably in the range of from about 1 to about 10- ⁇ m.
  • mixtures of different sized nanoparticles and microparticles at different ratios may be used.
  • the nanoparticles and microparticles of the present invention may have spherical and /or rod shapes.
  • the nanoparticles or microparticles are optionally coated with polyvinyl alcohol (PVA), poly-(N-vinyl-2-pyrrolidone) (PVP) Polyethylene Glycol (PEG), and/or other coatings to avoid aggregation.
  • PVA polyvinyl alcohol
  • PVP poly-(N-vinyl-2-pyrrolidone)
  • PEG Polyethylene Glycol
  • the nanoparticles and microparticles may optionally be administered to the cells by means of binding them to units (such as proteins) targeted to a specific location.
  • units such as proteins
  • magnetic nanoparticles such as Fe 2 O 3 can be targeted to a specific cell through an external static magnetic field.
  • coated nanoparticles or microparticles which form "quantum dots”.
  • Nanoparticles comprise a metal or metals, and/or carbon, and are coated with photosensitizers such as porphyrins derivatives or flavins which are excited by visible and near IR light and/or which have poor solubility in water and tend to aggregate in aqueous solutions (47, 48).
  • photosensitizers such as porphyrins derivatives or flavins which are excited by visible and near IR light and/or which have poor solubility in water and tend to aggregate in aqueous solutions (47, 48).
  • the nanoparticles facilitate penetration of the photosensitizers into the cells.
  • Nanoparticles and microparticles can serve as ideal
  • the use or method of the present invention further comprises irradiating the particles with light.
  • the optimal wavelength can be identified by methods known in the art, such as, for example, electron paramagnetic resonance (EPR) methods.
  • EPR electron paramagnetic resonance
  • This optimal wavelength is preferably balanced against one or more other treatment parameters, such as for example the need to penetrate deeply into tissue.
  • the irradiation can take place before, during or after introducing the 20 nanoparticle or microrparticle to the cells and/or tissue.
  • a light source in the visible and near infrared range (400-3 OOOnm), continuous wave (CW) and/or pulsed is preferably used.
  • the light could optionally be coherent, polarized or 400-500nm.
  • the light source is preferably selected from the group consisting of lasers, LEDs and broad band visible light devices.
  • the limit of the light intensity is such that it does not lead to a significant thermal effect to skin cells, when applied on the skin. For example, it may cause a 5 0 C increase in the tissue temperature, which is not considered to have a significant thermal effect on the tissue.
  • skin refers to the outlining tissue of a human or mammalian body, as well as other epithelial tissue. The nanoparticles or microparticles are introduced to the subject exogeneously.
  • subject it is meant any living cells or tissue, whether in vivo or ex vivo.
  • the subject may optionally comprise .any mammal or non-mammal.
  • mammal preferably includes any commercially important animal as well as humans.
  • pharmaceutical carriers of the composition of. the present invention can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • the pharmaceutically acceptable carrier of compositions of the present invention optionally comprises one or more of a physiological salt solution, dimethyl sulfoxide (DMSO), a solution of colloid liquid protein, a polymer solution, a suitable suspension etc.
  • DMSO dimethyl sulfoxide
  • the nanoparticles or microparticles could also optionally be added to a powder which would then be administered to the subject.
  • the pharmaceutical composition may optionally further comprise one or more components selected from binding agents, stabilizers, diluents, excipients, surfactants, , and odorants.
  • compositions of the present invention may be manufactured by processes well known in the art, e.g., by means of conventional mixing, dissolving, granulating, levigating, emulsifying, entrapping or lyophilizing processes.
  • Suitable pharmaceutical excipients include without limitation, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols, sodium stearate, glycerol monostearate, talc, sodium chloride, glycerol, propylene, glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, powders, sustained-release formulations and the like.
  • compositions herein described may also comprise suitable solid or gel phase carriers or excipients.
  • suitable solid or gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active ingredients into preparations which, can be used pharmaceutically.
  • Proper formulation is dependent upon the route of administration chosen.
  • administration is by the transdermal route.
  • Formulations for oral delivery can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should be suitable for the mode of administration.
  • composition for transdermal administration can be formulated in a form of a gel, a cream, an ointment, a paste, a lotion, a milk, a suspension, an aerosol, a spray, a foam, a serum, a swab, a pledget, a pad or a patch.
  • Formulations for transdermal delivery can typically include carriers such as water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid amides, liquid protein hydrolysates, liquid alkylated protein hydrolysates, liquid lanolin, lanolin derivatives, glycerin, mineral oil, silicone, petroleum jelly, lanolin, fatty acids, vegetable oils, parabens, waxes, and like materials commonly employed in topical compositions.
  • Various additives may be included in the transdermal formulations of the invention. For example, solvents may be used to solubilize certain active ingredients substances.
  • compositions herein described may also comprise suitable solid of gel phase carriers or excipients.
  • suitable solid of gel phase carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin and polymers such as polyethylene glycols.
  • compositions of the present invention may, if desired, be presented in a pack or dispenser device, such as an FDA approved kit, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may, for example, comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied by a notice associated with the container in a form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the compositions or human or veterinary administration. Such notice, for example, may be of labeling approved by the U.S. Food and Drug Administration for prescription drugs or of an approved product insert.
  • Compositions comprising the nanoparticles or microparticles of the invention, and optionally other active ingredients, formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition, as is detailed herein.
  • the cell stimulation induced by the present invention is one or more of cell growth, cell proliferation and differentiation, tissue regeneration (including regeneration of skin, stem cells, muscle, cartilage, connective tissue, epithelial tissue, heart and bone), skin rejuvenation, blood vessel dilation, and muscle relaxation.
  • ROS might act as modulators of neural processes, including synaptic transmission (50); also the kinetics of ROS production may determine whether nerve cells will differentiate or proliferate (51). Moreover it has been suggested that preconditioning-induced neuroprotection is mediated by ROS through activation of the transcription factor nuclear factor kappa ⁇ (52).
  • the 15 nanoparticles and microparticles of the present invention may thus be used to modulate synaptic transmission, differentiation and proliferation of nerve cells, and provide neuroprotection.
  • the -present- invention may be-used for nerve regeneration, the advantage of which is the generation of ROS in nerves lying not only in superficial sites. 5
  • Embodiments of the present invention may be used for treatment of any condition which is treatable by phototherapy.
  • phototherapy in the visible range has been shown to be beneficial in the treatment of tissue regeneration which leads to the healing of chronic and acute wounds (55).
  • Studies with fibroblasts and keratinocytes indicate that at0 specified relatively low energy doses of He-Ne laser or 780 nm diode laser, accelerated mitosis occurs (56).
  • Phototherapy also has beneficial effects on mouse, rat, dog and pig ischemic heart models. Phototherapy has a markedly beneficial effect on repair processes after injury or ischemia in skeletal and heart muscles (57).
  • the methods and compositions of the present invention may be used for wound healing, including healing of chronic and acute wounds.
  • the present inventors have previously shown, by using the electron paramagnetic resonance (EPR) coupled with the probe trapping technique, that the first step in photobiostimulation including stimulation of skin, sperm, and cardiac cells is ROS formation following irradiation (62, 63).
  • EPR electron paramagnetic resonance
  • tissue regeneration for example for regeneration of skin, epithelial cells, muscle, heart and bone, through the generation of small, controlled amounts of ROS using nanoparticles or microparticles, with or without light.
  • collagen was irradiated in-vitro with a broad band of visible light, 400-800 nm, 24-72J/cm 2 , after which the spin trapping method coupled with electron paramagnetic resonance (EPR) spectroscopy was used to detect ROS. Irradiated collagen resulted in hydroxyl radical formation.
  • EPR electron paramagnetic resonance
  • ROS reactive oxygen species
  • the present inventors showed, using the hamster egg penetration essay (SPA), that He-Ne radiation may improve poor human sperm egg penetration ability.
  • SPA hamster egg penetration essay
  • EPR Electron Paramagnetic Resonance
  • ROS are formed in illuminated sperm cells, which again proves the involvement of ROS in increasing the fertilization rates (92).
  • U.S. Patent No. 6,379,939 discloses that visible light enhances fertilization.
  • a method and compositions comprising nanoparticles and microparticles for increasing fertilization rates by sperm of animals, including humans, with or without light.
  • Methods for relieving pain from pain-affected body areas of a patient, by radiating light, are known in the art.
  • the pain affected area is irradiated with a beam of laser light, or a LED, of a particular wavelength in the visible or near IR region.
  • a beam of laser light or a LED
  • a beam of laser light or a LED
  • He-Ne (632nm) and GaAlAs (830nm) lasers are used for pain relief.
  • An updated summary concerning this modality has been written by Bijordal et al, review, Photoirradiation in acute pain.(2006), Photomedicine and Laser Surgery, 24, 2, 158-168.
  • the mechanism of light induced pain relief seems to be related to ROS formed by the irradiated nerve. For example it has been shown (93) that a high power 30OmW, 700mW/cm2
  • the light is in the visible range. More preferably, sufficiently penetrative light is used to treat deep lying tissues for pain relief.
  • the present invention in -at -least some embodiments,- provides ex- vivo - applications for cellular stimulation, for example for increasing the rate of cultivation of skin cells in order to rapidly obtain skin-like tissue for grafting onto burn wounds.
  • the subject is placed in a unit arranged to irradiate the subject with light, thereby activating the nanoparticles or microparticles
  • Example 1 Formation of ROS (hydroxyl and super oxide anion radicals) in water suspensions of ZnO nanoparticles with and without white light irradiation.
  • ROS hydroxyl and super oxide anion radicals
  • DMPO is a common spin probe that detects ' OH and 5 O 2 - to give the spin adduct DMPO-OH which yields a quartet EPR spectrum.
  • Samples containing ZnO nanoparticles (lOnm) solution and DMPO were drawn by a syringe into a gas-permeable Teflon capillary (Zeus Industries, Raritan, NJ) and inserted into a narrow quartz tube that was open at both ends. Then the tube was placed into the EPR cavity and the spectra were recorded while or after illumination with white light (40mW/cm 2 for lmin) through the EPR cavity on a Bruker EPR lOOd X-band spectrometer.
  • white light 40mW/cm 2 for lmin
  • the EPR measurement conditions were as follows: frequency: 9.75 GHz; microwave power: 20 mW; scan width: 60 G; resolution: 4096; receiver gain: 5x10 5 ; conversion time: 82 ms; time constant: 1310 sweep time: 335 s; scans: 2; modulation frequency 100 KHz.
  • HFSC values suggest that HO " and O 2 - " were generated from ZnO (Buettner, 1987) before (grey) and after (black) irradiation.
  • Example 2 Formation of ROS (hydroxyl and super oxide anion radicals) in water suspensions ofTi ⁇ 2 nanoparticles with and without white light irradiation.
  • ROS hydroxyl and super oxide anion radicals
  • Example 3 Stimulation of fibroblast proliferation following incubation with TiO 2 nanoparticles
  • Fibroblasts were incubated with TiO 2 nanoparticles (25nm) at concentration 2- 15OuM for 24h, and cell number was evaluated using the MTT method (95). As can be seen from Fig. 3, TiO2 at concentrations up to 70 ⁇ M stimulates fibroblasts proliferation.
  • Example 4 Nerve regeneration The sciatic nerve of injured rats is treated for 20 consecutive days, with the compositions of the present invention, with and without light, and the amplitude of the action potential is recorded in the corresponding gastrocnemius.
  • ZnO lamangiom
  • nanoparticles are injected into the infarcted area and its vicinity in a well controlled manner in a first group of rats.
  • low level blue light irradiation is applied in addition to the nanoparticle injection.
  • a third group of infarcted rats serve as sham (control) group and are injected only with the vehicle of the nanoparticles. Histological observations follow the changes in scar tissue of the treated hearts relative to non- treated ones.
  • Example 6 Effect on muscle repair Ischemia/reperfusion type of injury is induced in the skeletal leg muscles (3 h of ischemia) of rats. TiO 2 nanoparticles in a cream or lotion are smeared or injected at the site of injury, followed by white light illumination. Muscle regeneration following nanoparticle administration alone or with light irradiation is examined by heat shock proteins (HSP-70i) content, and an increase in total antioxidants.
  • HSP-70i heat shock proteins
  • Creams containing nanoparticles in the (ug/1 range are smeared twice a day for a period of one month, on the skin of patients suffering from acne scars and the improvement of the scars is evaluated by the physician.
  • Example 8 Effect on fertilization
  • a suspension of TiO 2 nanoparticles in water in the ug/1 range is added to human spermatozoa in the presence or absence of blue light at very low intensity (in the range of mW/cm 2 ) .
  • the zona-free hamster egg (SPA) assay is used for evaluating the percentage of penetrated eggs (SPA percent) in treated sperms compared to that of the control.
  • Example 9 Pain relief ZnO nanoparticles in a cream or lotion are smeared onto the wrist of patients suffering from Carpal Tunnel Syndrome (CTS) accompanied by an edema. White light irradiation follows the nanoparticle administration in some of the patients. The edema and the local tingling sensation are evaluated after 10 local treatments compared to non treated patients.
  • CTS Carpal Tunnel Syndrome
  • Burdon RH Superoxide and hydrogen peroxide in relation to mammalian cell proliferation. (1995) Free Radic. Biol. Med. 18: 115-19 A.
  • Banan A Fields JZ, Zhang Y, Keshavarzian A. (2001) iNOS upregulation mediates oxidant-induced disruption of F-actin and barrier of intestinal monolayers. Am. J. Physiol. Gastrointest. Liver Physiol. 280:G1234-G1246.
  • Flavins are source of visible-light-induced free radical formation in cells. Lasers Surg. Med. 37, 14-9. 45. Torimoto T, Murakami SY, Sakuraoka M, Iwasaki K, Okazaki K, Shibayama T, Ohtani B. (2006) J. Phys. Chem. B Condens. Matter Mater Surf Interfaces Biophys. 13: 110(27):13314-8.

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  • Medical Informatics (AREA)
  • Molecular Biology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition et ses procédés d'utilisation, ainsi que des procédés de traitement, qui comprennent la combinaison de l'administration de nanoparticules ou de microparticules avec ou sans stimulation lumineuse pour produire du ROS pour la stimulation cellulaire et la régénération tissulaire.
PCT/IL2008/001336 2007-10-18 2008-10-07 Composition et procédé pour l'activation cellulaire et la réparation tissulaire utilisant des nanoparticules et de la lumière WO2009050696A2 (fr)

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KR101793832B1 (ko) * 2016-08-02 2017-11-03 연세대학교 산학협력단 광에너지 유도 활성산소종을 이용한 줄기세포 분화유도장치 및 방법
US9999785B2 (en) 2014-05-30 2018-06-19 Dr. Todd Frank Ovokaitys Method and system for generation and use of activated stem cells
US10040728B2 (en) 2014-06-06 2018-08-07 Todd Frank Ovokaitys Methods and compositions for increasing the bioactivity of nutrients
US10202598B2 (en) 2014-05-30 2019-02-12 Todd Frank Ovokaitys Methods and systems for generation, use, and delivery of activated stem cells
CN109551855A (zh) * 2018-11-30 2019-04-02 河南永威安防股份有限公司 一种光催化高压装饰板及其制备方法
US10384985B2 (en) 2014-06-06 2019-08-20 B.K. Consultants, Inc. Methods and compositions for increasing the yield of, and beneficial chemical composition of, certain plants
US10398732B2 (en) 2016-10-13 2019-09-03 Marshall University Research Corporation Compositions and methods for treating striated muscle injury, treating striated muscle atrophy and/or for promoting striated muscle growth
CN113751079A (zh) * 2021-09-28 2021-12-07 中国药科大学 一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用

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US20050175709A1 (en) * 2003-12-11 2005-08-11 Baty Ace M.Iii Therapeutic microparticles
US20060002852A1 (en) * 2004-07-01 2006-01-05 Yale University Targeted and high density drug loaded polymeric materials

Patent Citations (2)

* Cited by examiner, † Cited by third party
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US20050175709A1 (en) * 2003-12-11 2005-08-11 Baty Ace M.Iii Therapeutic microparticles
US20060002852A1 (en) * 2004-07-01 2006-01-05 Yale University Targeted and high density drug loaded polymeric materials

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US10907144B2 (en) 2014-05-30 2021-02-02 Todd Frank Ovokaitys Methods and systems for generation, use, and delivery of activated stem cells
US9999785B2 (en) 2014-05-30 2018-06-19 Dr. Todd Frank Ovokaitys Method and system for generation and use of activated stem cells
US10202598B2 (en) 2014-05-30 2019-02-12 Todd Frank Ovokaitys Methods and systems for generation, use, and delivery of activated stem cells
US11905510B2 (en) 2014-05-30 2024-02-20 Todd Frank Ovokaitys Methods and systems for activating cells to treat aging
US10040728B2 (en) 2014-06-06 2018-08-07 Todd Frank Ovokaitys Methods and compositions for increasing the bioactivity of nutrients
US10384985B2 (en) 2014-06-06 2019-08-20 B.K. Consultants, Inc. Methods and compositions for increasing the yield of, and beneficial chemical composition of, certain plants
US10865157B2 (en) 2014-06-06 2020-12-15 B.K. Consultants, Inc. Methods and compositions for increasing the yield of, and beneficial chemical composition of, certain plants
KR101793832B1 (ko) * 2016-08-02 2017-11-03 연세대학교 산학협력단 광에너지 유도 활성산소종을 이용한 줄기세포 분화유도장치 및 방법
US10398732B2 (en) 2016-10-13 2019-09-03 Marshall University Research Corporation Compositions and methods for treating striated muscle injury, treating striated muscle atrophy and/or for promoting striated muscle growth
CN109551855A (zh) * 2018-11-30 2019-04-02 河南永威安防股份有限公司 一种光催化高压装饰板及其制备方法
CN109551855B (zh) * 2018-11-30 2020-07-07 河南永威安防股份有限公司 一种光催化高压装饰板及其制备方法
CN113751079A (zh) * 2021-09-28 2021-12-07 中国药科大学 一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用
CN113751079B (zh) * 2021-09-28 2022-06-10 中国药科大学 一种生物材料负载的钙钛矿-二氧化钛纳米复合光催化剂及其构建方法和应用

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