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WO2012166796A1 - Systèmes immunostimulateurs magnétiques et procédés associés - Google Patents

Systèmes immunostimulateurs magnétiques et procédés associés Download PDF

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WO2012166796A1
WO2012166796A1 PCT/US2012/039994 US2012039994W WO2012166796A1 WO 2012166796 A1 WO2012166796 A1 WO 2012166796A1 US 2012039994 W US2012039994 W US 2012039994W WO 2012166796 A1 WO2012166796 A1 WO 2012166796A1
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magnetic
present technology
amf
particles
nanoparticles
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Stephen Edward BARRY
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Aspen Medisys LLC
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Aspen Medisys LLC
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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
    • A61K9/5094—Microcapsules containing magnetic carrier material, e.g. ferrite for drug targeting
    • 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
    • A61K41/0052—Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy
    • 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
    • A61K9/5123—Organic compounds, e.g. fats, sugars

Definitions

  • thermotherapeutic compositions for example, thermotherapeutic compositions, medical systems incorporating such compositions, and methods of treatment using such compositions.
  • the present thermotherapeutic compositions stimulate the immune system to provide enhanced treatment of disease, such as, e.g., various cancers.
  • the technology provides a composition that includes a plurality of magnetic nanoparticles.
  • Each nanoparticle is comprised of i) a magnetic material that is capable of transferring at least 100 W of power per gram of magnetic material from an applied magnetic field to material in which the particles are located, and a coating material that provides for nanoparticle dispersibility in aqueous systems and for uptake and maturation of phagocytes.
  • the present technology provides a medical treatment system that includes a magnetic nanoparticle composition as described herein, and an applied magnetic field that produces at least 100 Oe and at most 2000 Oe in treated body tissues and that operates at a frequency from about 50 to about 200 kHz.
  • the present technology provides a method of treatment administering an effective amount of a thermotherapeutic composition described herein to a subject in need thereof; and applying energy comprising an alternating magnetic field to the subject.
  • FIGURE 1 is a schematic depicting an illustrative embodiment of a magnetic particle in which 100 denotes a magnetic material and 200 denotes a coating comprised of a phagocyte associating and stimulating carbohydrate.
  • FIGURE 2 is a schematic depicting an illustrative embodiment of a magnetic particle in which 100 denotes a magnetic material, and 200 denotes a coating comprised of a phagocyte associating and stimulating carbohydrate.
  • FIGURE 3 is a schematic depicting an illustrative embodiment of a magnetic particle in which 100 denotes a magnetic material, 200 denotes a coating comprised of a phagocyte associating and stimulating carbohydrate, and 300 denotes an antigen.
  • FIGURE 4 is a schematic depicting an illustrative embodiment of a magnetic particle in which 100 denotes a magnetic material, 200 denotes a coating comprised of a phagocyte associating and stimulating carbohydrate, 300 denotes an antigen and 400 denotes a targeting agent.
  • Absolute temperatures refers to temperatures of greater than about 45°C.
  • agglomeration refers to the formation of a cohesive mass consisting of particulate subunits held together by relatively weak forces (for example, van der Waals or capillary forces) that may break apart into particulate subunits upon processing, for example.
  • relatively weak forces for example, van der Waals or capillary forces
  • the resulting structure is called an "agglomerate.”
  • cluster means a collection of more than one magnetic domain and/or crystal that are attached or adherent to each other through physical or chemical bonds within a single nanoparticle.
  • alternating magnetic field refers to a magnetic field that changes the direction of its field vector periodically, typically in a sinusoidal, triangular, rectangular or similarly-shaped pattern, with a frequency in the range of from about 30 kHz to about 500 MHz.
  • an AMF may be added to a static magnetic field, such that only the AMF component of the resulting magnetic field vector changes direction.
  • duty cycle refers to the ratio of the time that an energy source is on to the total time that the energy source is on and off in one on-off cycle.
  • a "disease” or "health-related condition”, as used herein, can be any pathological condition of a body part, an organ, or a system resulting from any cause, such as infection, genetic defect, and/or environmental stress.
  • the cause may or may not be known.
  • the present technology may be used to treat or prevent any disease or health-related condition in a patient.
  • diseases may include, for example, infectious diseases, inflammatory diseases, hyperproliferative diseases such as, but not limited to, cancer, and degenerative diseases.
  • the cancer may originate in the bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testis, tongue, or uterus, or may be of an unknown tissue origin.
  • diseased tissue refers to tissue or cells associated with a disease.
  • diseased tissue may refer to tissue or cells associated with solid tumor cancers of any type.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial
  • diseased tissue may also refer to tissue or cells of the immune system, such as tissue or cells affected by AIDS; pathogen-borne diseases, which can be bacterial, viral, parasitic, or fungal, examples of pathogen-borne diseases include HIV, tuberculosis and malaria; hormone-related diseases, such as obesity; vascular system diseases; central nervous system diseases, such as multiple sclerosis; and undesirable matter, such as adverse angiogenesis, restenosis amyloidosis, toxins, reaction-by-products associated with organ transplants, and other abnormal cell or tissue growth.
  • pathogen-borne diseases which can be bacterial, viral, parasitic, or fungal
  • pathogen-borne diseases include HIV, tuberculosis and malaria
  • hormone-related diseases such as obesity
  • vascular system diseases such as central nervous system diseases, such as multiple sclerosis
  • undesirable matter such as adverse angiogenesis, restenosis amyloidosis, toxins, reaction-by-products associated with organ transplants, and other abnormal cell or tissue growth.
  • an "effective amount" of a composition is the amount which achieves a desired effect.
  • or “therapeutically effective amount” is the amount of a composition which provides a therapeutic benefit such as, without limitation, inhibiting, slowing, or reversing the progression of a disease or condition, or providing some other benefit to the subject to which the composition is administered.
  • the effective amount of a composition is a predetermined amount calculated to achieve the desired effect.
  • hypothermia refers to the heating of tissue to temperatures above about 39°C.
  • linker refers to any agent or molecule that bridges the particle heating element to the targeting moiety. This linker may be removed from the nanoparticle by chemical means, by enzymatic means, or spontaneously. In some embodiments, the linker may be pharmacologically inert or may itself provide added beneficial pharmacological activity. Linkers used in the present disclosure may include, for example, lipids, polypeptides, oligonucleotides, polymers, and the like. It is also within the scope of the present technology that more than one linker may be used to attach a targeting moiety.
  • nano refers to a special state of subdivision implying that a particle has an average dimension smaller than about 200 nm (200 x 10 "9 m).
  • patient refers to subjects to be treated including humans and other higher animals and laboratory models, such as, for example, mice, rats, dogs, pigs and monkeys.
  • stable or “stabilized”, as used herein, means a solution or suspension in a fluid phase wherein solid components (i.e., nanoparticles) possess stability against aggregation and agglomeration sufficient to maintain the integrity of the compound and preferably for a sufficient period of time to be useful for the purposes detailed herein.
  • the term “substantial” or “substantially”, when referring to a material means as an amount greater than about 20% of a given type of material. In other embodiments where the term “substantial” or “substantially” refers to an effect, such terms are defined as an amount sufficient to produce a desired effect.
  • the term "most” or “mostly”, when referring to a material, means as an amount greater than about 50% of a given type of material.
  • the terms "susceptor”, “magnetic particle”, “magnetic nanoparticle”, “nanoparticle”, “particle”, and “particle heating element” refer to a particle that absorbs energy from a power supply and produces heat.
  • target refers to the material, tissue, or cell(s) for which imaging, deactivation, rupture, disruption or destruction is desired.
  • targeting moiety refers to compounds that are attached to the nanoparticles disclosed herein and that direct the particle to a target.
  • targeting moieties are targeted to an antigen associated with cancer.
  • targeting moieties are targeted to healthy cells, stromal cells in diseased tissues or cells present in normal healthy conditions. Such targeting moieties may be directly targeted to a molecule or other target or indirectly targeted to a molecule or other target associated with a biological molecular pathway related to a condition.
  • tissue refers to any aggregation of similarly specialized cells that are united in the performance of a particular function.
  • Treatment and “treating” refer to administration or application of a composition embodied in the present technology to a patient or performance of a procedure or modality on a patient for the purpose of obtaining a therapeutic benefit of a disease or health-related condition.
  • treatment zone refers to an area or portion of the body of a patient.
  • a treatment zone may be comprised of diseased tissue and surrounding healthy tissue to which either or both therapy and energy sources are administered.
  • Thermotherapy holds promise as a treatment for cancer and other diseases. In some cases it is used to induce rapid necrosis at high temperatures (typically referred to as "thermo-ablation"). In other cases, various anti-tumor effects, including tumor oxygenation and immune system stimulation may be induced. These effects may be induced at temperatures that are lower than hyperthermically-ablative temperatures, for instance ranging from 38 °C to 45 °C.
  • thermotherapeutic compositions are directed to thermotherapeutic compositions, methods for using such thermotherapeutic compositions, and systems comprising therapeutic compositions and magnetic energy sources for treating disease.
  • thermotherapeutic compositions disclosed herein provide a plurality of nanoparticles, each nanoparticle of which includes a magnetic material that is capable of transferring at least 100 W of power per gram of magnetic material from an applied magnetic field to material in which the particles are located; and coating material that provides for nanoparticle dispersibility in aqueous systems and for binding and uptake by phagocytes.
  • the phagocytes mature to an antigen presenting phenotype as a result of the treatment.
  • medical treatment systems comprising the nanoparticle compositions and an applied magnetic field that produces at least 100 Oe and at most 2000 Oe in treated body tissues and that operates at a frequency from about 50 to about 200 kHz.
  • the medical system transfers at least 100 W/gram of magnetic material from an applied magnetic fields to the biological system in which the particles are located.
  • the methods described herein generally include the steps of administering an effective amount of a thermotherapeutic composition to a subject in need thereof and applying energy comprising an alternating magnetic field (AMF) to the subject.
  • AMF alternating magnetic field
  • the application of AMF energy transfers energy to the magnetic material that in turn transfers energy to the tissue to which the thermotherapeutic compounds were administered to produce a therapeutic effect.
  • the nanoparticle compositions disclosed herein also include a coating comprising a carbohydrate that provides for dispersibility in aqueous systems and for binding, uptake and stimulation by certain phagocytes in mammalian bodies.
  • the carbohydrate includes macromolecules that comprise mannose, fucose and/or glucose.
  • the carbohydrate is a polymannose, including without limitation, glyconjugates of synthetic polymers functionalized with mannose.
  • the carbohydrate is comprised of a material purified or derived from plant or microbial sources.
  • that coating material is comprised of mannan or is chemically modified mannan.
  • the coating material is comprised of beta-glucan, or is chemically modified beta-glucan.
  • the coating is comprised of carboxylated, for example carboxymethylated mannan.
  • the coating is comprised of reduced mannan, for example produced via sodium borohydride treatment.
  • the coating is comprised of oxidized mannan, for example produced by treatment of mannan with sodium periodate.
  • mannan carbohydrate chains may a combination of the foregoing transformation, e.g., they may have i) reduced terminals produced for example using sodium borohydride, ii) may be carboxymethylated for example using bromoacetic acid, and then iii) may have a portion of cis diols oxidized to aldehydes using sodium periodate, to produce oxidized, carboxymethylated reduced mannan material.
  • phagocytes Most cancers actively recruit large numbers of immunosuppressive phagocytes into the tumor microenvironment.
  • the specific delivery of mannan coated iron oxide nanoparticles into tumors can be mediated by peritoneal phagocytes, and this illustrates the potential for using phagocytes to deliver nanoparticles to peritoneal tumors.
  • These tumor infiltrating immunosuppressive phagocytes are critical for tumor progression because the selective depletion of these cells impairs the growth of peritoneal ovarian cancer.
  • Such phagocytes could be manipulated by nanoparticle technology in two ways. First, in some embodiments the phagocytes ingest and carry nanoparticles specifically into tumors and can deliver cytotoxic agents for cancer treatment.
  • the immunosuppressive phagocytes themselves can be eliminated by engulfment of nanoparticles, the tumor microenvironment could shift from immunosuppressive to immunostimulatory, and thereby contribute to enhanced anti-tumor immune responses.
  • the nanoparticles further include a targeting agent.
  • the nanoparticles may include antigens associated with a particular cancer to be treated.
  • the nanoparticles are comprised of targeting agents that bind to cancer cell associated biomolecules (e.g., antibodies to such biomolecules), or in other embodiments bind to T-cell markers.
  • the nanoparticles are comprised of both cancer-associated antigens and targeting agents that bind to T cell markers.
  • the nanoparticles and AMF driven excitations disclosed herein induce unexpectedly effective danger signals providing for anti-cancer immune system stimulation.
  • the nanoparticles and AMF driven excitations disclosed herein induce phenotypic and functional maturation of phagocytes that take up the particles.
  • uptake of the nanoparticles and AMF driven excitation induced functional maturation further induces Thl /cytotoxic T lymphocyte (CTL) responses.
  • CTL Thl /cytotoxic T lymphocyte
  • compositions comprising a plurality of magnetic nanoparticles.
  • heat evolved from the magnetic particles results from dissipative processes as the magnetization of the material(s) comprising the magnetic particle is forced to oscillate in response to the AMF.
  • the amount of heat generated per cycle of magnetic field and the mechanism responsible for the energy loss depend on the specific characteristics of both the magnetic particle and the magnetic field.
  • Magnetic nanoparticle composition, size and shape, directly affect heating properties, and one or more of these characteristics may be engineered to tailor the heating properties for a particular set of conditions found within a tissue type.
  • the magnetic nanoparticle compositions of some embodiments include a plurality of stable, unagglomerated and nonaggregated magnetic nanoparticles.
  • the magnetic nanoparticles are aggregated, and in still other embodiments, the magnetic nanoparticles are comprised of single-magnetic domain particles.
  • the magnetic particles may form collections in target cells of the tissue or in the space between cells due in part to interparticle attractions.
  • concentration of magnetic nanoparticles such as the in high concentration of particles within certain subcellular structures, may have a direct effect on the total heat produced by the particles.
  • particles may include material such as, but not limited to, elements that can be magnetized.
  • the magnetic nanoparticles are comprised of one or more of Fe, Co, Mn, Ni, metals comprising one or more of these elements, ordered alloys of these elements, crystals comprised of these elements, magnetic oxide structures, such as ferrites, and combinations thereof.
  • the magnetic nanoparticles comprise magnetic core material, which may be comprised of metals that can be magnetized, are prepared from materials such as, but not limited to, Fe, Co, Pt, Fe x Coioo- x or Fe x Pti 0 o- x , where x ranges from 1 to 99 and indicates the relative proportion of the element, FePt-Ag alloys, FePt alloys and combinations thereof, as well as FeCo/Si0 2 .
  • the magnetic core may be comprised of magnetite (Fe 3 C>4), maghemite (y-Fe 2 0 3 ), or divalent metal-ferrites provided by the formula Mei_ x OFe 3+x 0 3 where Me is for example Cu, Fe, Ni, Co, Mn, Mg, or Zn or combinations of these materials, where x ranges from 0.01 to 99.
  • the size of the magnetic core of the magnetic nanoparticles may vary among embodiments of the present technology.
  • the lower limit is a diameter below which a magnetic domain structure does not exist and the upper limit in size is where a substantial number of a plurality of magnetic nanoparticles have multiple domains or where particle size is larger than desired for in vivo applications, such as, for instance where the magnetic nanoparticles are large enough such that permeability in a tissue is hindered.
  • Large magnetic bodies may be divided by domain, or Bloch walls, into uniformly magnetized regions that minimizes the total energy of the particle, including magnetostatic, exchange, and anisotropic energies, as well as energies contributed by domain walls.
  • the final balance of energies determines both the number and shape of magnetic domains within a magnetic material, and as the size of a magnetic particle is reduced, the size of domains is also reduced.
  • Domain wall formation also has an associated energy cost that may limit the subdivision of domains to a certain number and size.
  • Certain magnetic crystals of the present technology may have one magnetic domain and are referred to as "single- magnetic domain crystals.”
  • Decreasing grain size may increase the fraction of atoms in a particle that are exposed to the surface of the particle and/or interface regions, which may increase the significance of surface and interface electronic structure effects on the magnetic properties of the particle.
  • the intrinsic magnetic properties of a material such as spontaneous magnetization and magnetocrystalline anisotropy, may, therefore, be strongly influenced by particle size.
  • the total anisotropy energy may increase with decreasing grain size because of a growing surface anisotropy contribution.
  • magnetostatic, shape and stress anisotropy may become increasingly important as the size of the particle is reduced and may combine with magnetocrystalline anisotropy to determine the total anisotropy energy of a single-magnetic domain particle.
  • single domain particles have the high coercivities, with coercivity increasing with single domain size for a given type of magnetic material until a multi-domain structure occurs, at which point coercivity drops.
  • Increased anisotropy leads to increased hysteresis losses when particles are subjected to AMF of sufficient amplitude to overcome the anisotropy energy barrier, thus producing higher specific absorption rates (SAR) and improved heating ability.
  • Any single-magnetic domain particle known in the art may be useful as a core for compositions and uses as disclosed herein.
  • the reorientation behavior of the magnetic moment, m is governed in part by the total anisotropy energy of the magnetic grain.
  • the variable m refers to a vector defining magnitude and direction of magnetization of the magnetic domain and may vary with respect to time, environment (temperature, external magnetic field, and the like), and orientation with respect to a crystalline axis of the magnetic nanoparticle.
  • m may be influenced by the anisotropy energy and physical environment, both past and present.
  • the total anisotropy energy per unit volume, K presents a barrier to changes in orientation of the magnetic moment, m.
  • the energy barrier has a low probability of being overcome on a defined timescale, for example a millisecond, by thermal energies.
  • Magnetization reorientation in such a thermally stable single-magnetic domain may be driven by application of an external magnetic field that is sufficiently strong to overcome the anisotropy energy.
  • the non-equilibrium forced change in the domain magnetic moment is dissipative and produces heat.
  • this hysteretic behavior may be produced in so-called "soft", or superparamagnetic cores if the frequency of the AMF cycling is higher than the spontaneous reorientation frequency. For example, if a single domain particle has a diameter of 10 nm and an anisotropy energy of 100 kJ/m , the reorientation time is about 1 ms, that is, reorientation occurs at a frequency of 1 kHz.
  • hysteretic behavior including hysteretic heating when particle anisotropy energy barrier is overcome will result.
  • operation at higher frequencies than the characteristic relaxation time of a domain's magnetic moment may advantageously produce high heating rates.
  • the heat dissipated by a core may be estimated from the maximum energy density of the core.
  • an effective coercive field strength may be defined as that needed to demagnetize the particle and is an indication of the anisotropy energy barriers. The higher the particle magnetization and the greater the effective coercivity of the particle, the greater the dissipated energy.
  • the maximum energy density of a ferromagnetic material is sometimes defined as the maximum value of the product of the B and H; in the second quadrant of a B-H; hysteresis loop and is useful in indicating the amount of energy that may be converted to heat per volume of core per cycle of AMF.
  • the particle heating element cores are comprised of material with a energy density of greater than 10 5 J/m 3.
  • a particle heating element core has a core density of 7 g/cm, and AMF is of sufficient strength and is operating at a frequency of 100 kHz
  • the potential power output of the particle heating element with an energy density of 10 5 J/m 3 is about 1400 W/g.
  • remnance and coercivity are a function of time and in the case of an AMF, the faster the cycling times, the higher the effective remnance and coercivity. The frequency at which a magnetic field is cycled thus affects energy dissipated. That is, for a sufficiently strong field a higher frequency results in a higher effective coercivity, thus more heat is produced per cycle.
  • Magnetic anisotropy, particle coercivity and domain reorientation barriers are strong functions of particle size. Materials with a plurality of particles, with particles having a wide distribution of size and concomitant magnetic domain reorientation, energy barriers are not desirable because domains with low reorientation energy barriers produces less heat, while domains with high reorientation energy barriers that prohibit domain reorientation produce no heat. Thus, in some embodiments, to produce the most heat, the plurality of particles should possess energy barriers such that substantially no dissipation occurs until a critical field strength is applied, at which point a substantial number of particle domain magnetic moments rapidly reorient. In this irreversible process, large and rapid energy release can thus result that may advantageously substantially disrupt tissue and cellular processes.
  • individual nanoparticles are comprised of more than one single magnetic domain crystal.
  • individual nanoparticles are comprised of clusters of crystals that are physically or chemically associated with one another. Such clusters may result in a higher rate of heat production under AMF.
  • the plurality of magnetic nanoparticles may have a mean polydispersity index, for instance as determined by z-average dynamic light scattering of less than about 0.2.
  • the polydispersity index is less than about 0.1.
  • the polydispersity index is less than about 0.08.
  • the polydispersity index is less than about 0.05.
  • the polydispersity index is less than about 0.02. In certain embodiments of the present technology, the polydispersity index is less than 0.01.
  • a plurality of magnetic nanoparticles incorporated in a material may have interparticle magnetic interactions.
  • a collection of particles may exhibit solutions and magnetic properties different than the sum of the magnetic properties of each individual particle because an additional contribution to domain reorientation energy may result from the collective behavior, with interparticle magnetic interaction producing a collective state that exhibits behavior uncharacteristic of the state of the individual non-interacting particles. In some circumstances, this results in an apparent increase in effective coercivity and a measured increase in SAR under certain AMFs.
  • a variety of forms of energy may be applied to the patient to activate the magnetic particles of the present technology including, but not limited to, AMFs.
  • magnetic field inductors may provide a substantial AMF field only to a desired portion of the patient's body.
  • Inductors may be in a variety of forms, including the form of solenoids, Helmholtz loops and a variety of other examples as described in Stauffer, IEEE Transactions on Biomedical Engineering, Vol. 41, 1994, 17-28, which is herein incorporated by reference in its entirety to the extent such reference is not inconsistent with the explicit teachings of this specification.
  • AMF frequency in the range of about 30 kHz to about 30 MHz is applied to the patient.
  • the AMF is in the range of about 30 kHz to about 5 MHz. In further embodiments, the AMF is in the range of about 30 kHz to about 500 KHz. In further embodiments, the AMF is in the range of about 50 kHz to about 200 KHz.
  • a plurality of magnetic nanoparticles may have an average saturation magnetism of about 1 Tesla (T) or higher.
  • the plurality of magnetic nanoparticles may have a specific absorption rate (SAR) of greater than 100 W per gram of transition metal in the core of the particle or higher when exposed to alternating magnetic fields of amplitude greater than about 100 Oe and at frequencies greater than about 50 kHz.
  • SAR specific absorption rate
  • relatively high amplitude AMFs are advantageous for particle heating because higher particle magnetizations may be achieved and particles with relatively high coercivities may be employed.
  • Relatively high frequencies are advantageous in part because a greater number of heating cycles produces more heat.
  • the applied field should be only strong enough to exceed the coercivity of a substantial fraction of a plurality of magnetic nanoparticles to substantially drive the magnetic reorientation on the desired time scale of AMF cycling
  • about 50% or more of the cores of the plurality of magnetic nanoparticles each have a probability of greater than about 50% of magnetic moment reorientation under the action of the AMF when the magnetic field maximum amplitude is greater than about 50 Oe. In some embodiments, about 50% of the cores of the plurality of magnetic nanoparticles each have a probability of greater than about 50% of magnetic moment reorientation under the action of the AMF when the magnetic field maximum amplitude is greater than about 100 Oe. In some embodiments, about 50% or more of the cores of the plurality of magnetic nanoparticles each have a probability of greater than about 50% of magnetic moment reorientation under the action of the AMF when the magnetic field maximum amplitude is greater than about 200 Oe.
  • about 50% or more of the cores of the plurality of magnetic nanoparticles each have a probability of greater than about 50% of magnetic moment reorientation under the action of the AMF when the magnetic field maximum amplitude is greater than about 300 Oe. In some embodiments, about 50% or more of the cores of the plurality of magnetic nanoparticles each have a probability of greater than about 50% of magnetic moment reorientation under the action of the AMF when the magnetic field maximum amplitude is greater than about 400 Oe.
  • the magnetic nanoparticles of the present technology may be coated for various purposes, including providing for dispersibility in aqueous systems, to promote uptake rate of particles by certain types of cells, thereby concentrating particles in the desired cells and directing treatment to desired cells and not to cells or tissues and reducing treatment effect on non-targeted cell types and tissues.
  • the nanoparticle coating also facilitates attachment of various materials, including antigens and biomolecular targeting agents.
  • Suitable materials for the coating may include synthetic polymer, biological polymers, copolymers and polymer blends, small organic compounds, inorganic materials and combinations thereof.
  • Bio materials that may be used to coat particle heating elements include polysaccharides, carbohydrates, polyaminoacids, proteins, lipids, glycerols, fatty acids and the like, and combinations thereof.
  • biological materials such as heparin, heparin sulfate, chondroitin sulfate, chitin, chitosan, mannan, glucan, beta-glucan, cellulose, dextran, alginate, starch, hydroxyethyl starch, glycosaminoglycan at various levels of purity and combinations thereof or proteins such as extracellular matrix proteins, proteoglycans, glycoproteins, albumin, gelatin and combinations thereof may be used as coatings.
  • chemically modified versions of the above materials are employed.
  • the form of polymannose of glyconjugates comprised of synthetic polymers functionalized with mannose.
  • the carbohydrate is comprised of a material purified or derived from plant or microbial sources.
  • that coating material is comprised of mannan or is chemically modified mannan.
  • the coating material is comprised of beta-glucan, or is chemically modified beta-glucan.
  • the coating is comprised of carboxylated, for example carboxymethylated mannan.
  • the coating is comprised of reduced mannan, for example produced via sodium borohydride treatment.
  • the coating is comprised of oxidized mannan, for example produced by treatment of mannan with sodium periodate.
  • mannan carbohydrate chains may have i) reduced terminals produced for example using sodium borohydride, ii) may be carboxymethylated for example using bromoacetic acid, and then iii) may have a portion of cis diols oxidized to aldehydes using sodium periodate, to produce oxidized, carboxymethylated reduced mannan material.
  • the coatings have moieties that promote uptake by certain types of phagocytic cells.
  • the material may be comprised of saccharide moieties such as mannose or mannose derivatives, fucose and glucose.
  • Such carbohydrates can promote endocytosis, for instance by binding to endocytic pattern recognition receptors, mannose receptors (CD206) and other members of the mannose receptor family, such as DEC-205 (CD205), on certain phagocytes, including for example immature DC cells.
  • the nanoparticle coating promotes endosomal escape.
  • the nanoparticle coating is associated with the phenotypic modification of cells to which it binds and by which it is taken up.
  • cancer cells also express the same or different receptors that bind to carbohydrate moieties comprising the nanoparticle coating, promoting uptake of the particles by cancer cells.
  • the nanoparticles effectively bring together phagocytes and cancer cells.
  • the nanoparticle coating additionally comprises T cell binding agents
  • polymer coating materials include, but are not limited to, various combinations of acrylates, siloxanes, styrenes, acetates, akylene glycols such as polyethylene glycol (PEG), alkylene oxides, alkylenes, parylenes, polyglycerols lactic acid, glycolic acid, hydrogel polymer, histidine-containing polymer, and combinations thereof.
  • the coating is physically or chemically crosslinked.
  • the coatings are comprised of dendritic materials.
  • synthetic polymer main chains with glycosylated side chains and lipid tails are employed.
  • mannan, oligomannan, and chemically modified mannan moieties are conjugated to the polymer coating material.
  • the materials in the coating described above may be physically associated or chemically attached to magnetic material. In some embodiments, there may be a combination of physical-associated and chemically attached materials on the surface.
  • components of the coating may disintegrate from the nanoparticle structure at a desired rate.
  • the coating substantially disintegrates from the magnetic material prior to cell uptake in in vivo applications.
  • the coating substantially disintegrates from the magnetic material prior to application of AMF.
  • the magnetic material may produce an unexpectedly large therapeutic effect.
  • targeting agents may be attached to the nanoparticles of the present technology.
  • targeting agents may be attached directly to the coating through functionalities present on the targeting agent.
  • the targeting agent may be attached to the magnetic nanoparticles through the use of one or more linkers.
  • the linker may be a bifunctional compound that contacts and binds to the coating or the intermediate shell while covalently binding to a targeting agent thereby attaching the targeting agent to the outer surface of the susceptor.
  • the linker either hinders or promotes uptake of the nanoparticle by the reticuloendothelial system (RES).
  • RES reticuloendothelial system
  • functionalization with a polyethylene glycol (PEG) linker through a process known in the art as "pegylation” may be effective in hindering opsonization and uptake by the RE System and in displaying targeting agents.
  • linker can affect the properties of the final conjugates.
  • Linkers of various embodiments include a hydrophobic or hydrophilic organic, inorganic or a mixture of chemically different compounds.
  • the linker may include an alkyl, alkene, alkyne, haloalkyl, epoxide, vinyl, or heterocumulene compound, and in other embodiments, the linker may include a multi-subunit compound.
  • linkers of such embodiments are not limited by the number and/or type of subunits in a multi-subunit compound and may include subunits of, for example, epoxypropene, polyethylene glycol, polypropylene glycol, and the like and combinations thereof.
  • the linkers include one or more epichlorohydrin, diepoxide or combinations thereof.
  • Examples of linkers that are encompassed by embodiments of the present technology include, but are not limited to, poly(ethylene glycol) epoxyether, poly(ethylene glycol) diglycidyl ether, and a mixture of epichlorohydrin and poly(ethylene glycol) diglycidyl ether, and block copolymers comprised of these materials.
  • Linkers of various embodiments further include one or more terminal reactive groups.
  • the type of terminal reactive group may vary depending on the type of reaction chemistry required to couple a susceptor of a particular type to a certain type of targeting agent, form a covalent bond with a certain targeting agent or otherwise bind a susceptor to such targeting agent.
  • the reactivity of the terminal group may be based on substitution or addition chemistry.
  • Exemplary terminal reactive groups may include, but are not limited to, carboxylic acids, amines, hydrazines, azides, thiols, disulphides, sulphonic acid, vinyl, 1 ,2-diacylethene, maleimides and derivatives and combinations thereof, and in particular embodiments, the terminal reactive group may be an amine, thiol or carboxylic acid moiety.
  • the carboxylic acid terminal group may be a poly(ethylene glycol) ether based carboxylic acid
  • the azide terminal group may be a 5-azido-2-nitrobenzamide
  • the disulfide terminal group may be a 3-(2-pyridylithio) propionamide
  • the 1 ,2-diacylethene terminal group may be a maleimide or a 3- maleinidylpropionamide.
  • linker, linker functionalities and chemistries that may be employed in embodiments of the present technology can be found in Bioconjugate Techniques, Second Edition, Greg Hermansonn, Academic Press, 2008, which is herein incorporated by reference in its entirety to the extent such reference is not inconsistent with the explicit teachings of this specification.
  • click chemistries may be used for targeting agent attachment, such as, for example azide-alkyne cycloadditions with non-limiting examples described by Lutz JF and Zarafshani, Advanced Drug Delivery Reviews, 2008; 60(9): 958-70, which is herein incorporated by reference in its entirety to the extent such reference is not inconsistent with the explicit teachings of this specification.
  • Targeting agents of embodiments of the present technology may be selected to promote binding to selected targets.
  • targeting agents allow the targeting of cancer or disease markers on cells.
  • targeting agents facilitate the targeting of a specific type of biological matter in a patient.
  • Examples of targeting agent embodiments include, but are not limited to, proteins, glycoproteins, engineered proteins, peptides, antibodies, antibody fragments, saccharides, carbohydrates, glycans, cytokines, chemokines, nucleotides, oligonucleotides, R A, siRNA, aptamers, lectins, lipids, receptors, steroids, neurotransmitters, imprinted polymers, and combinations thereof.
  • protein targeting agents include, for example, cell surface proteins, membrane proteins, proteoglycans, glycoproteins, peptides, and the like; nucleotide targeting agents may comprise natural and synthetic nucleotides and include, for example, single-stranded nucleotides, double stranded nucleotides, complimentary nucleotides, and polynucleotide fragments; and lipid targeting agents may be comprised of, for example, phospholipids, glycolipids, and the like.
  • Antibodies useful in embodiments of the present technology are not limited by a particular type of antibody.
  • Antibodies useful in some embodiments may be genetically engineered, such as for example, chimeric antibodies (e.g. , humanized murine antibodies) and heteroconjugate antibodies (e.g., bispecific antibodies).
  • Antigen binding forms of antibodies may be used, including fragments with antigen-binding capability, such as, Fab', F(ab') 2 , Fab, Fv and rlgG, and recombinant single chain Fv fragments (scFv).
  • Other targeting agent embodiments encompass endogenous proteins, engineered proteins, and bivalent or bispecific molecules such as, but not limited to, those described in Kostelny et al. J.
  • modified antibodies can be produced by reacting an antibody or antibody fragment with a modifying agent.
  • modified human antibodies or antigen-binding fragments are prepared by reducing disulfide bonds (e.g. , intra-chain disulfide bonds) of an antibody or antigen-binding fragment. The reduced antibody or antigen-binding fragment may then be reacted with a thiol-reactive modifying agent to covalently bond the antibody to the linker.
  • Modified human antibodies and antigen-binding fragments of aspects of the present technology comprising an organic moiety that is bonded to specific sites of an antibody may be prepared using suitable methods, such as reverse proteolysis; see Fisch et al, Bioconjugate Chem. 3: 147 153 (1992); Werlen et al, Bioconjugate Chem. 5:411 417 (1994); Kumaran et al, Protein Sci. 6(10):2233 2241 (1997); Itoh et al, Bioorg. Chem., 24(1): 59 68 (1996); Capellas et al, Biotechnol. Bioeng., 56(4):456 463 (1997)) and the methods described in Hermanson Bioconjugate Techniques, Academic Press: San Diego, Calif. (1996), which are herein incorporated by reference in their entirety to the extent such references are not inconsistent with the explicit teachings of this specification.
  • Targets include, but are not limited to, biomolecules that may be classified variously as cell surface markers, members of the vascular endothelial growth factor receptor (VEGFR) family, members of carcino embryonic antigen (CEA) family, a type of anti- idiotypic mAB, a type of ganglioside mimic, a cluster designation/differentiation (CD) antigen, a member of the epidermal growth factor receptor (EGFR) family, a type of a cellular adhesion molecule, including Ig (immunoglobulin) superfamily (IgSF, CAMs) including EpCAM, the integrins, the cadherins, the selectins and the lymphocyte homing receptors, a member of the MUC-type mucin family, a cancer antigen (CA), a matrix metalloproteinase, a glycoprotein antigen, a melanoma associated antigen (MAA), a proteolytic enzyme, a calmodulin, a
  • CA
  • targeting agents may be targeted to an antigen associated with a disease of a patient's immune system.
  • the marker or markers to which the targeting agent is targeted may be selected such to include viable targets on, for instance, T cells, B cells, monocytes, macrophages, neutrophils, dendritic cells and natural killer (NK) cells.
  • the targeting agent may have an affinity for a target associated with an immune system disease such as, for example, a protein, a cytokine, a chemokine, an infectious organism, and the like.
  • multiple types of targeting moieties may be coupled to the nanoparticles.
  • the nanoparticles may be optimized with a specific ratio of complexed to noncomplexed surface area. Any amount of surface area of the particle heating elements may be complexed with the targeting moieties.
  • 5%, about 10%, about 15%, about 20%>, about 25%, about 30%>, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% of the surface area of nanoparticles may be complexed with one or more targeting moieties, or any range of surface areas derivable therein may be complexed with one or more targeting moieties.
  • magnetic nanoparticles comprise antigens to induce enhance and direct an immune response.
  • Magnetic nanoparticles may comprised of one or more type of antigen.
  • Antigens and may be a polysaccharide or protein, or may be fragments of polysaccharide or protein antigens. Peptides comprising one or more epitopes from one or more distinct antigens may be incorporated into the nanoparticle structure. Antigens that may be used include those overexpressed in diseased tissues and disease associated cells.
  • Examples include but are not limited to carbohydrate and peptides that comprise muc-1, mesothelin, EpCAM, TAG-72, vascular endothelial growth factor receptor (VEGFR) family, members of carcinoembryonic antigen (CEA) family, a type of anti-idiotypic mAB, a type of ganglioside mimic, vaious cluster designation/differentiation (CD) antigen, a member of the epidermal growth factor receptor (EGFR) family, a type of a cellular adhesion molecule, including Ig (immunoglobulin) superfamily (IgSF, CAMs), the integrins, the cadherins, the selectins and the lymphocyte homing receptors, a member of the MUC-type mucin family, a cancer antigen (CA), a matrix metalloproteinase, a glycoprotein antigen, a melanoma associated antigen (MAA), a proteolytic enzyme, a calmodul
  • Antigens may be conjugated to the nanoparticle coating using the various techniques disclosed herein for attaching targeting agents to the particles. Stimulating an Immune Response
  • a patient's immune system may be stimulated to treat disease through the use of the magnetic nanoparticles, systems and methods of the present technology. Such treatments may promote an immune response through one or more mechanisms operating alone or together.
  • a T cell mediated immune response may be mediated via several mechanisms.
  • immature and in some cases immunosuppressive dendritic cells, tumor associated macrophages and other antigen presenting cells (APCs) have been in some cancers shown to be engaged by tumors to enhance tumor growth, hinder immune response, and promote metastasis.
  • APCs antigen presenting cells
  • phenotypically modifying or killing tumor associated macrophages, dendritic cells (DCs), and other APCs may facilitate an anti-tumor immune response.
  • coatings that are comprised of carbohydrate moieties that target particles to immature DCs and that play a role in phenotypic and functional maturation are employed herein. Macrophages, DCs and other phagocytic cells may have enhanced antigen presentation after the particles are heated via AMF application.
  • the application of AMF is in part responsible for endosomal escape of nanoparticulate components into the cytosol. Cytosol location of the energized particles allows a MHC class I antigen display and a desirable T helper 1 (Thl) response to drive cytotoxic antigen specific T lymphocytes (CTLs).
  • T helper 1 Thl
  • macrophages, DCs and other APCs may be killed directly or as a result of AMF application after these cells have taken up the magnetic nanoparticles of the present technology.
  • Tumor selective-specific antigen presentation may be another mechanism by which the thermotherapy treatments of the present technology stimulate an immune response.
  • magnetic nanoparticles in tumors may effectively thermally kill multiple cancer cells.
  • Tumor-specific antigens may be chaperoned by heat-shock proteins (HSPs) and/or processed by APCs in tumors and presented to T cells, providing a more tumor specific immune response than would be obtained if the heat were applied more broadly to healthy and diseased tissue.
  • HSPs heat-shock proteins
  • APCs processed by APCs in tumors and presented to T cells, providing a more tumor specific immune response than would be obtained if the heat were applied more broadly to healthy and diseased tissue.
  • treatment may modify tumor cells in ways that elicit an immune response.
  • Reported heat sensitive cellular targets affected by hyperthermia on tumor cells include HSPs, MICA and MHC Class I proteins.
  • NK cell activation is another mechanism by which the thermotherapy treatments of the present technology may stimulate an immune response.
  • NK cells are part of the innate immune system, do not require antigen recognition for activation, and are particularly heat sensitive. NK cells are activated to release granzymes and cytokines through cytokine and Fc receptors, with other activating and inhibiting receptors also involved. Without wishing to be bound by theory, NK cell activation is maximized when both NK and tumor cell targets are heated. In NK cells, plasma membrane reorganization may occur after mild heat stress. Thus, targeting particle heating elements to NK cells and then applying the particles such that the NK cells are stressed, but not killed may effectively promote an immune response.
  • thermotherapy treatments of the present technology may promote an immune response.
  • Particle heating in the tumor perivascular space may increase the permeability of tumors to a variety of materials, proteins and cells, thus, for example allowing immune system components such as CTLs better access into tumors and to tumor cells.
  • magnetic nanoparticles of the present technology may serve as adjuvants.
  • adjuvant refers to a compound having the ability to enhance an immune response to a particular antigen.
  • macrophages When stimulated by such magnetic nanoparticles, macrophages may produce TNFa, which may cause tumor cell death directly and may also bind to receptors on endothelial cells of the tumor vasculature, leading to effect such as endothelial cell death and enhanced vascular permeability.
  • Enhanced vascular permeability facilitates entry of leukocytes into the tumor.
  • adjuvant activity may activate DCs as described above that release cytokines that stimulate a CTL response.
  • the magnetic nanoparticles are functionalized with tumor- associated antigens. By heating in the presence of the antigens, increased antigen presentation may be accomplished.
  • the combination of adjuvants and antigen presentation on AMF-activated particles may effectively promote an adaptive immune response tumor-specific CTL mediated immune response.
  • about 50% or more of a plurality of particle magnetic cores are each less than about 200 nm in any linear dimension or direction. In certain embodiments, about 50% or more of the plurality of particle cores are each less than about 100 nm in any linear dimension. In other embodiments, about 50% or more of the plurality of particle cores are each less than about 70 nm in any linear dimension. In still other embodiments, about 50% or more of the plurality of particle cores are each less than about 30 nm in any linear dimension and in further embodiments about 50% or more of the plurality of particle cores are each less than about 20 nm in any linear dimension.
  • about 50%> or more of the plurality of particles have an overall size of less than about 500 nm in any linear dimension or direction. In some embodiments, about 50% or more of the plurality of particles are less than about 400 nm in any linear dimension or direction. In other embodiments, about 50% or more of the plurality of particles are less than about 300 nm in any linear dimension or direction. In some embodiments, about 50% or more of the plurality of particles are less than about 200 nm in any linear dimension or direction. In some embodiments, about 50% or more of the plurality of particles are less than about 300 nm in any linear dimension or direction.
  • the magnetic nanoparticles of various embodiments may be incorporated into a pharmaceutically acceptable carrier according to techniques known and practiced in the art.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art.
  • preservatives e.g., antibacterial agents, antifungal agents
  • isotonic agents e.g., absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof
  • a pharmaceutically acceptable carrier is preferably formulated for administration to a human, although in certain embodiments it may be desirable to use a pharmaceutically acceptable carrier that is formulated for administration to a non-human animal, but which would not be acceptable (e.g., due to governmental regulations) for administration to a human. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
  • the carrier may be liquid or solid and is selected with the planned manner of administration in mind.
  • therapeutic formulations encompassed by embodiments of the present technology may vary.
  • therapeutic formulations of the present technology may include from about 0.01 % to about 95% by weight of particles mixed with a pharmaceutically acceptable carrier such as, for example, water, buffered water, normal saline, 0.4%> saline, 0.3%) glycine, dextrose, dextran, hyaluronic acid and the like.
  • the magnetic nanoparticles may make up from about
  • a dose may also comprise from about 1 microgram/kg/body weight, about 5 microgram/kg/body weight, about 10 microgram/kg/body weight, about 50 microgram/kg/body weight, about 100 microgram/kg/body weight, about 200 microgram/kg/body weight, about 350 microgram/kg/body weight, about 500 microgram/kg/body weight, about 1 milligram/kg/body weight, about 5 milligram/kg/body weight, about 10 milligram/kg/body weight, about 50 milligram/kg/body weight, about 100 milligram/kg/body weight, about 200 milligram/kg/body weight, about 350 milligram/kg/body weight, about 500 milligram/kg/body weight, to about 1000 mg/kg/body weight or more per administration, and any range derivable therein.
  • a range of about 5 ⁇ g/kg/body weight to about 100 mg/kg/body weight, about 5 ⁇ g/kg/body weight to about 500 mg/kg/body weight, may be administered.
  • compositions may include saccharides not closely associated with the nanoparticles.
  • Therapeutic compositions encompassed by the present technology may also include conventional pharmaceutical excipients and/or additives.
  • excipients means pharmaceutically acceptable excipients, including carriers, stabilizers, and permeation enhancers that are non-toxic to the patient being exposed thereto at the dosages and concentrations employed.
  • suitable excipients include, but are not limited to stabilizers, antioxidants, osmolality adjusting agents, buffers, and pH adjusting agents.
  • Suitable additives may include physiologically biocompatible buffers (e.g., tromethamine hydrochloride), additions of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTP A, CaNaDTPA-bisamide), or optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate), or nonionic species such as carbohydrates.
  • physiologically biocompatible buffers e.g., tromethamine hydrochloride
  • additions of chelants such as, for example, DTPA or DTPA-bisamide
  • calcium chelate complexes as for example calcium DTP A, CaNaDTPA-bisamide
  • additions of calcium or sodium salts for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate
  • nonionic species such as carbohydrates.
  • particles may be prepared in an injectable form, such as, for example, a dispersion, suspension, emulsion, in a medium such as, for example, water, saline, Ringer's solution, dextrose, albumin solution or oils.
  • an injectable form such as, for example, a dispersion, suspension, emulsion
  • a medium such as, for example, water, saline, Ringer's solution, dextrose, albumin solution or oils.
  • a therapeutic composition with relatively low viscosity to thicken to form a gel, thereby substantially retaining the particles in the tissue to which the particles were injected.
  • the particles are formulated in a pharmaceutically acceptable carrier that gels upon injection into the patient.
  • specific polymers may be incorporated into a therapeutic composition so that the composition is fluid in the condition in which it is stored, but such therapeutic composition forms a physical gel when exposed to physiological conditions encountered after administration to the patient.
  • pectic material may be included in the therapeutic composition.
  • the magnetic nanoparticles may be formulated into a depot, for example, an implantable composition comprising the magnetic nanoparticles and a porous material, wherein the magnetic nanoparticles are encapsulated by or diffused throughout the porous material.
  • the magnetic nanoparticle depot may be positioned in a desired location affiliated with the patient's body upon which the nanoparticles may be released from the implant at a predetermined rate by diffusing through the porous material.
  • the therapeutic composition may promote interstitial diffusion of the particles. In some embodiments, particle diffusion is promoted by providing a hypertonic, or hyperosmolar formulation.
  • the high osmolality when interstitially administered to tissues, the high osmolality may cause intracellular water to be drawn out of the cells, thus shrinking the cells and concomitantly providing for greater interstitial fluidity, with the combination of cell shrinkage and increased interstitial water content increasing the rate of particle diffusion.
  • High osmolarity may be achieved using a solute such as, but not limited to, the excipients and additives listed above or solutes at sufficient concentrations.
  • salts such as sodium chloride in the range of about 0.2 M to about 2 M
  • saccharides such as mannitol, sucrose, and dextran 1000 MW in the range of about 0.3 M to about 2 M may be incorporated into the therapeutic composition.
  • hypertonicity may transiently and reversibly inhibit clathrin-coated pit mediated endocytosis, allowing material in the therapeutic compositions disclosed herein to better permeate the tissue into which it is administered.
  • compositions of the present technology may be prepared for administration as a solid, semisolid, suspension, dispersion, or emulsion.
  • Conventional nontoxic solid carriers may be incorporated into such compositions and may include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, dextran, magnesium carbonate and the like.
  • pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, dextran, magnesium carbonate and the like For example, about 1 to about 95% by volume or, in a further embodiment, about 25% to about 75% by volume of any of the carriers and excipients listed above may be mixed with the nanoparticles of the present technology.
  • the magnetic nanoparticle formulations of the present technology can be administered by any suitable route. Accordingly, there are a variety of suitable formulations of the pharmaceutical composition of the present inventive methods. One skilled in the art will appreciate that these routes of administering the particles of the present technology are known, and, although more than one route can be used to administer a particle, a particular route of administration may provide a more immediate and more effective response relative to another route of administration.
  • particle may be administered parenterally by methods including, but not limited to, intraperitoneal injection, peri- and intra-tissue injection, subcutaneous injection or deposition, or subcutaneous infusion, intravascular administration, intra-organ injection, intramuscular injection and direct administration at or near a site of diseased tissue to facilitate efficient treatment of the diseased tissue.
  • intraperitoneal injection peri- and intra-tissue injection
  • subcutaneous injection or deposition or subcutaneous infusion
  • intravascular administration intra-organ injection
  • intramuscular injection intramuscular injection and direct administration at or near a site of diseased tissue to facilitate efficient treatment of the diseased tissue.
  • Pharmaceutically acceptable carriers suitable for parenteral administration include aqueous and non-aqueous liquids, isotonic sterile injection solutions, which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that may include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the magnetic nanoparticles can be administered parenterally in a physiologically acceptable diluent in a pharmaceutically acceptable carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions,
  • parenteral formulations of certain embodiments may be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • the magnetic nanoparticles prepared according to embodiments of the present technology can be made into aerosol formulations to be administered via inhalation.
  • These aerosol formulations can be placed into pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • the particle may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.
  • the amount or dosage of nanoparticles or pharmaceutical compositions containing such nanoparticles administered to a patient may vary and may depend on the body weight, age, and health of the patient, the size and structure of the particle to be delivered, the disease being treated or imaged, and the location of diseased tissue. Moreover, the dosage may vary depending on the mode of administration.
  • the magnetic nanoparticles may be administered in a single dose or in multiple doses in various embodiments of the present technology.
  • the dosage regimen may also vary depending upon a number of factors such as, for example, the disease or condition being treated and the health of the patient.
  • the magnetic nanoparticles may be administered to the subject once as, for instance, a single injection or deposition at or near the site of diseased tissue.
  • the single administration may be followed by a single application of AMF.
  • particles may be administered once or twice daily to a subject for a period of from about one to about twenty-eight days, or from about one to about ten days.
  • magnetic nanoparticles may be injected at or near the site of diseased tissue once a day for several days in a month.
  • delivery of nanoparticles to a target site may be assisted by applying a static magnetic field to the target area due to the magnetic nature of the particles. Assisted delivery may depend on the location of the target.
  • the pharmaceutical formulations of the present technology may be administered in a dose of 100 or more ⁇ g of magnetic nanoparticles per dose. Each dose may be in a volume of 1, 10, 50, 100, 200, 500, 1000 or more ⁇ or ml.
  • an interval between particle administration and AMF application may be employed to allow particles to be taken up by phagocytic cells prior to the application of AMF.
  • the magnetic nanoparticles may be engineered to achieve desired features, such as, for example, a desired rate of metabolism in certain cell types and in certain intracellular environments.
  • desired features such as, for example, a desired rate of metabolism in certain cell types and in certain intracellular environments.
  • nanoparticle characteristics such as surface functionality, surface charge, particle size, zeta ( ⁇ ) potential, hydrophobicity, and the like, may be optimized depending on the particular application of the particles.
  • the magnetic nanoparticles are stable in water or other liquid carrier without substantial agglomeration or aggregation for at least 30 days, in other embodiments 90 days, and in still other embodiments for at least 120 days.
  • the magnetic nanoparticles may be administered at one or more injection sites through one or more needles with each needle having one or more exit ports. Multiple needles that extend from a single catheter may be used to distribute the particles.
  • AMF energy may be applied to a portion of the subject's body or the entire body.
  • Application of the AMF energy to power the magnetic nanoparticles may commence immediately upon completion of a single administration of the particles, and may be repeated daily after each administration or after the completion of several administrations.
  • AMF application may begin after a period of time, such as, for example, several minutes to several days after administration of the particles. Duration of each AMF application session may range from about 1 minute to about 10 hours.
  • various duty cycles may be employed.
  • the period of time from administration of the magnetic nanoparticles to AMF energy application may facilitate the particles being taken up by cells within the treatment zone.
  • the interval between particle administration and AMF application may range from about 1 hour to about 10 days.
  • the magnetic nanoparticles may be confined within cells such that the particles are brought within close proximity to one another, such as, for example, within endosomes. In this confined, packed state, an enhanced therapeutic effect may be produced as compared to an unconfmed state.
  • diseased tissue and/or fluid may be removed from a subject and AMF energy may be applied to such tissue and/or fluid extracorporeally.
  • the susceptors may be administered to the subject prior to removal of the diseased tissue and/or fluid.
  • susceptors may be applied to the diseased tissue following removal of the diseased tissue and/or fluid. Exposing the diseased tissue and/or fluid treated with the susceptors of the present technology to an energy source may cause portions of the diseased tissue to lyse, denature, or otherwise be treated. The treated tissue may then be returned to the body of the patient.
  • a patient's ascetic fluid is removed from the patient and incubated with a magnetic nanoparticle formulations, and AMF is applied to the fluid outside of the patient's body.
  • the AMF energy source may be a part of the operational space and thus be covered in sterile material.
  • all surgical tools are made from non-magnetic materials such as plastic, ceramic, glass or non-magnetic metals or metal-alloys.
  • the AMF energy source may be located in close proximity to the surgical site in order to achieve high fields in the targeted tissues, and the patient can be moved in and out of the AMF energy field, in a manual or automatic manner.
  • thermotherapy may be administered once or more prior to, at least partly during or following surgery or other interventional technique, or any combination thereof.
  • the advantages of providing energy to the magnetic nanoparticles extracorporeally may include the ability to apply higher intensity AMF, and the ability to reduce or eliminate exposure of the body to the AMF.
  • Embodiments of the present technology include methods for treating a number of diseases and health-related conditions.
  • susceptors may be administered directly to diseased tissue to treat diseased states in which heat may be applied to a tissue to ablate tissue.
  • susceptors may be administered directly to a solid tumor by, for example, direct injection of a fluid comprising a dispersion of magnetic particles, and an AMF may be applied to the portion of the patient containing the tumor.
  • thermotherapy treatments as disclosed herein may be used on any type of cancer, and in certain embodiments such treatment is used to treat localized solid tumors, such as, for example, cancers of the skin, head and neck, tongue, throat, larynx, brain, breast, lung, liver, pancreas, oesophagus, stomach, small intestine, colon, rectum, lymph nodes, joint or synovial, uterine, ovary or cervix, peritoneum or other specific organ cancers and the like.
  • susceptors as disclosed herein may be used to treat leukemia and lymphoma (e.g., cancers of the blood-forming cells and lymphatic system, respectively).
  • target tissue may include cells involved in immune response and inflammation such as, for example, monocytes, macrophages or leukocytes, which may engulf the particles after administration.
  • Immature dendritic cells and macrophages are often associated with pathological tissues and diseases. Applying energy to monocytes, macrophages, dendritic cells, and other professional phagocytes or antigen presenting cells that have taken up particles, may destroy such cells or modulate their cellular processes and, thus retard or reverse disease progression or otherwise treats the disease.
  • thermotherapy treatment systems for treating patients having various ailments, diseases, illnesses, and conditions are disclosed herein.
  • thermotherapy treatment systems comprise a controlled heating system and a controlled cooling system.
  • the controlled heating system includes magnetic nanoparticles, AMF power supply, and one or more temperature probes, which measure temperature in a lesion or next to a lesion that is fed to a controller, which turns the AMF power supply on and off.
  • the controlled cooling system includes a cooling device and one or more temperature probes that measure temperature in healthy tissue, including on or under the skin surface in the treatment zone (e.g., within 1 cm of maximum field exposure in the patient).
  • thermotherapy treatment systems are further comprised of two control loops, wherein one control loop regulates the heat generated from particles that have been administered to the patient through the modulation of AMF equipment and a second feedback loop controls the cooling of the patient through the modulation of a cooling device.
  • an apparatus, equipment or material for cooling one or more portions of a patient's body is used in conjunction with AMF application to cool, maintain or reduce temperature rise in healthy tissues.
  • the cooling apparatus and related methods cool, maintain or reduce the temperature rise of at least one portion of the surface of the patient and underlying tissue where eddy current heating may be of particular concern.
  • the cooling equipment embodied in the present technology may take several forms, for instance, in some embodiments, the cooling equipment comprises ice packs, cold gel packs, one or more plastic parts, cooling pads, cooling sheets and the like. In certain embodiments, one or more cooling pads are placed between the AMF applicator and the skin of the patient. In other embodiments, a cooling pad may be integral to the AMF applicator.
  • coolant channels through which coolant fluid passes are utilized.
  • the coolant fluid utilized in the cooling equipment is comprised of water.
  • the cooling equipment comprises gas streams, gas streams saturated with water, or gas streams containing water droplets.
  • the gas is air, with forced air supplying the cooling mechanism.
  • the air is blown by a fan over the patient in proximity to the treatment zone.
  • the air is cooled to below room temperature, such as, for example, by passing the air through or over evaporator coils prior to the air being directed to the patient.
  • the gas stream passes through one or more nozzles, such as, for example, venturi nozzles, prior to impinging on the surface of the patient.
  • the cooling element coincides with the surface of the body in close proximity to the area of maximum eddy current heating.
  • the cooling element may be comprised of a ring of the approximate circumference of the inductor coil through which cooling fluid flows or through which pressurized air flowing through multiple holes is impinged upon the patient.
  • the cooling embodiments of the present technology may be performed before and/or concurrent with and/or after the application of AMF.
  • an apparatus for facilitating the exclusion of healthy tissue from zones of high AMF near the skin surface may be used.
  • an apparatus that cools tissue exposed to AMF and/or excludes certain tissue from the AMF may be used.
  • safety may be enhanced and efficacy improved by allowing more intense and/or longer AMF applications.
  • one or more fiber optic temperature probes may be incorporated at the skin contact surface to monitor temperature.
  • the probes may be part of a temperature control system, where the probes provide a voltage to a controller that operates the cooling device.
  • the cooling device may be turned on or off depending upon the temperature, as measured by a skin probe or other probe, such as, for instance, a sub-dermal probe.
  • nanoparticles, systems comprised of nanoparticles and AMF and methods of treating disease described herein may be used alone, or in combination with one or more additional forms of therapy.
  • susceptors may be introduced into diseased tissue prior to, during, or after treatments including, but not limited to, radiotherapy, chemotherapy, external beam therapy, surgery, photodymanic therapy (PDT), therapy using biologies or any combination of therapies.
  • PDT photodymanic therapy
  • the magnetic nanoparticles set forth herein may enhance the therapeutic or protective effect, and/or increase the therapeutic effect of another therapy.
  • Therapeutic and prophylactic methods and compositions can be provided in a combined amount effective to achieve the desired effect.
  • the therapeutic effect may be the killing of a cancer cell and/or the inhibition of cellular hyperproliferation.
  • the magnetic nanoparticles may be administered before, during, after or in various combinations relative to a secondary form of therapy.
  • the administrations may be in intervals ranging from concurrently to minutes to days to weeks to months.
  • thermotherapy methods of the present technology is "A” and an secondary therapy is "B": A/B/A B/A/B B/B/A A/A/B A/B/B B/A/A A/B/B/B B/A/B/B B/B/B/A B/B/A/B A/A/B/B A/B/A/B A/B/B/A B/B/A B/B/A B/A/A/B A/A/A/B B/A/A/A/B B/A/A/A A/B/A/A A/B/A/A A/B/A/A A/B/A/A A, among others.
  • a standard therapy regime will include one or more of: chemotherapy, radiotherapy, immunotherapy, surgical therapy, or gene therapy employed in combination with the thermotherapy methods as set forth herein.
  • radiotherapy or radiation therapy may be used in combination with thermotherapy methods disclosed herein. Radiotherapy may be applied at least once prior to, during, or after the AMF energized treatments disclosed herein, or any combination thereof. Radiotherapy, also referred to as radiation therapy.
  • radiation may be delivered to cancer cells through radioactive implants placed directly in or on a tumor or in a body cavity, and in another embodiment of the present technology, internal radiotherapy is used in combination with the thermotherapy methods disclosed herein.
  • This is referred to as internal radiotherapy, and is commonly used for, for example, brachytherapy, interstitial irradiation, and intracavitary irradiation types of internal radiotherapy.
  • the implant may include a material that heats during the AMF treatment by eddy current or hysteretic heating, or that does not heat under AMF exposure, such as plastic, ceramic, glass, or transplanted human tissue.
  • radiolabeled antibodies which when injected into a subject selectively bind to the cancerous cells and destroy the cells using radiation, may be used to deliver doses of radiation directly to the cancer site in combination with targeted thermotherapy.
  • the radiolabeled antibody may be administered separately from susceptors, and in others, the radiolabeled antibody may be administered simultaneously with susceptors.
  • at least one radioisotope may be attached to a susceptor, and the susceptor can be a dual therapy susceptor.
  • chemotherapy may be used in combination with the thermotherapy methods disclosed herein.
  • Chemotherapy is the treatment of diseases, such as cancer, with drugs.
  • chemotherapy often requires the use of a number of different drugs or agents; this is referred to as combination chemotherapy.
  • a chemotherapeutic drug or agent may be attached to the susceptor, and such a susceptor would constitute a dual therapy susceptor.
  • chemotherapeutic agents may be used in accordance with combination regimens of the present technology.
  • the term "chemotherapy” refers to the use of drugs to treat disease, such as cancer.
  • a "chemotherapeutic agent” is used to connote a compound or composition that is administered in the treatment of disease, such as cancer.
  • These agents or drugs are categorized by their mode of activity within a cell, for example, whether and at what stage they affect the cell cycle.
  • an agent may be characterized based on its ability to directly cross-link DNA, to intercalate into DNA, or to induce chromosomal and mitotic aberrations by affecting nucleic acid synthesis.
  • Most chemotherapeutic agents are identified as belonging to one the following categories: alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, and nitrosoureas.
  • thermotherapeutic agents may be used in combination with therapies that involve biologic agent such as, for example, antibodies that are not attached to chemo therapeutic agents.
  • a mAb that is not attached to a chemotherapeutic agent may be administered.
  • Such a mAb may induce an immune response against the cancerous tissue which may facilitate treatment.
  • the drug or agent is incorporated into a susceptor coating and released when the AMF is applied.
  • Such coating may include one or more layers, where the layers may be of the same or different material, and the drug or agent may be incorporated into one or more of the coating layers.
  • the drug or agent can be deactivated or destroyed when the AMF is applied to the patient.
  • thermotherapy and chemotherapy may be administered along with an agent that increases the permeability of the blood vessels within the tumor to permit more therapeutic drug to reach and kill substantially more cancer cells.
  • vasopermeation enhancement agents are drugs that increase the uptake of cancer therapeutics and imaging agents at the tumor site, potentially resulting in greater efficacy.
  • VEA's work by using monoclonal antibodies, or other targeting agents, to deliver known vasoactive compounds (i.e., molecules that cause tissues to become more permeable) selectively to solid tumors. Once localized at the tumor site, VEA's alter the physiology and the permeability of the vessels and capillaries that supply the tumor.
  • VEA's In pre-clinical studies, drug uptake has been increased up to 400% in solid tumors when VEA's were administered several hours prior to the therapeutic treatment.
  • VEA's are intended for use as a pre- treatment for most existing cancer therapies and imaging agents.
  • VEA's may be effective across multiple tumor types. Examples of VEA's include the commercially available COTARA® and ONCOLYM® (Peregrine Pharmaceuticals, Inc., Tustin, California).
  • VEA's can be used with the targeted thermotherapeutic therapy to enhance the blood flow and hence the uptake of susceptors at the tumor cells.
  • PDGF receptors may be inhibited to increase vascular permeability decrease tumor interstitial pressure and increase particle accumulation in the tumor.
  • imatinib which inhibits phosphorylated-PDGFR-beta and decreases tumor interstitial pressure, may be administered before or at about the same time as the particle heating elements.
  • thermotherapy may be combined with photodynamic therapy (PDT).
  • PDT is based on light-sensitive molecules, photosensitizers (PS's) that concentrate in tumor tissues. When irradiated with light of an appropriate wavelength, PS's absorb light and become excited, transferring their energy to nearby molecular oxygen to form reactive oxygen species (ROS's), which in turn oxidize and damage vital components of nearby tumor cells.
  • ROS's reactive oxygen species
  • particle heating elements may be administered to a subject prior to, during or following PDT and activated either simultaneously or separately from one another, and in other embodiments, particles may be coated with photosensitive drugs.
  • silica-based or other optically activated nanoparticles with a magnetic core may be produced and a PDT drug may be used to coat these nanoparticles.
  • These heating elements may then be irradiated with light to activate the drug, and they are irradiated later with the AMF of the targeted thermotherapy system to further destroy the target via heat.
  • Light irradiation and AMF may also be applied simultaneously.
  • photodynamic therapy in combination with thermotherapy may be used alone or in combination with chemotherapy, surgery or both.
  • Curative surgery is a cancer treatment that may be used in conjunction with other therapies, such as the thermotherapy treatment of the present technology, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy and/or alternative therapies.
  • Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed.
  • Tumor resection refers to physical removal of at least part of a tumor.
  • treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically controlled surgery (Mohs' surgery). It is further contemplated that the present technology may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.
  • a cavity may be formed in the body.
  • Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • thermotherapy may be combined with bone marrow and/or stem cell transplantation.
  • thermotherapy is administered prior to, during, or after bone marrow or stem cell transplantation, or any combination thereof.
  • thermotherapy can be administered to transplanted bone marrow or stem cells excorporeally, prior to transplantation.
  • Example 1 iron oxide coating comprising mannan
  • Example 2 Iron oxide coating comprising oxidized mannan
  • Mannan from bakers yeast was oxidized by adding a 0.1 M sodium periodate in DI water, mixing and allowing reaction to proceed for 4 °C fridge for 1 hour. Ethylene glycol was then used to quench excess NaI0 4 . Ultrafiltration was used to remove by-products and dilute to 0.1 g/mL oxidized mannan in DI water. Then about 130 mg of iron in the form of iron oxide materials dispersed in water at pH 11 was thoroughly mixed with 1 gram of oxidized mannan from bakers yeast. After mixing the particles were magnetically collected. The Z average size of the particle as determined by dynamic light scattering was determined to be 157 nm with a Pdl of 0.07.
  • Example 3 Iron oxide coating comprising carboxymethylated, reduced mannan
  • Sodium borohydride (0.5 g) was added to a 20 mL vial.
  • a solution of 1 : 1 sodium hydroxide (5g) in water was made and 0.0625 g sodium hydroxide was added to the sodium borohydride.
  • a solution of 3 g mannan from bakers yeast and 6 mL D.I. water was added to the vial containing sodium borohydride and base; another 6 mL D.I. water was added to reduce viscosity, and the materials was stirred at room temperature overnight.
  • a fresh solution of 1 : 1 sodium hydroxide (5g) was added, the mixture stir for 20 minutes at room temperature; 0.74 g bromoacetic acid was then added.
  • the modified carbohydrate was then mixed with a basic (pH 11) aqueous dispersion of iron oxide crystals at a weight ratio of 5 : 1 carbohydrate to iron. After mixing the particles were magnetically collected.
  • the carbohydrate coated iron oxide particles dynamic light scattering indicated have a Z-average particle diameter of 148 nm with a Pdl of 0.116.
  • Example 4 Iron oxide coating comprising periodate -oxidized carboxymethylated reduced mannan

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Abstract

L'invention concerne des nanoparticules magnétiques composées d'un matériau magnétique qui peut être excité par l'application de champs magnétiques alternés et un matériau de revêtement qui fournit la dispersibilité dans un système aqueux et l'absorption par des phagocytes. L'invention concerne également des systèmes composés de ces particules afin de produire un effet anti-tumoral, ainsi que des procédés d'utilisation de telles compositions et de tels systèmes.
PCT/US2012/039994 2011-05-31 2012-05-30 Systèmes immunostimulateurs magnétiques et procédés associés Ceased WO2012166796A1 (fr)

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US10888227B2 (en) 2013-02-20 2021-01-12 Memorial Sloan Kettering Cancer Center Raman-triggered ablation/resection systems and methods
US10912947B2 (en) 2014-03-04 2021-02-09 Memorial Sloan Kettering Cancer Center Systems and methods for treatment of disease via application of mechanical force by controlled rotation of nanoparticles inside cells
US10688202B2 (en) 2014-07-28 2020-06-23 Memorial Sloan-Kettering Cancer Center Metal(loid) chalcogen nanoparticles as universal binders for medical isotopes
US10919089B2 (en) 2015-07-01 2021-02-16 Memorial Sloan Kettering Cancer Center Anisotropic particles, methods and uses thereof
WO2017040915A1 (fr) * 2015-09-06 2017-03-09 Memorial Sloan Kettering Cancer Center Systèmes de traitement de la maladie par application d'une force mécanique par rotation contrôlée de cellules à l'intérieur de nanoparticules
EP3311838A1 (fr) * 2016-10-21 2018-04-25 Nanobacterie Nanoparticules magnétiques associées aux entités immunogènes pour la destruction de cellules pathologiques chez un individu
EP3311839A1 (fr) * 2016-10-21 2018-04-25 Nanobacterie Nanoparticules magnétiques pour la destruction de cellules pathogènes chez un individu
EP3747467A3 (fr) * 2019-06-03 2021-03-03 Nanobacterie Système cryogénique comprenant des nanoparticules pour le traitement d'une partie du corps d'un individu par cryothérapie
AU2020203591B2 (en) * 2019-06-03 2023-04-06 Alphaonco A Cryosystem Comprising Nanoparticles for Treating a Body Part of an Individual by Cryotherapy
US11744629B2 (en) 2019-06-03 2023-09-05 Nanobacterie Cryosystem comprising nanoparticles for treating a body part of an individual by cryotherapy
US12150689B2 (en) 2019-06-03 2024-11-26 Nanobacterie Cryosystem comprising nanoparticles for treating a body part of an individual by cryotherapy

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