WO2020078520A1 - Nanoparticules enrobées de lipide pour une thérapie anticancéreuse par résonance plasmonique - Google Patents

Nanoparticules enrobées de lipide pour une thérapie anticancéreuse par résonance plasmonique Download PDF

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WO2020078520A1
WO2020078520A1 PCT/DK2019/050317 DK2019050317W WO2020078520A1 WO 2020078520 A1 WO2020078520 A1 WO 2020078520A1 DK 2019050317 W DK2019050317 W DK 2019050317W WO 2020078520 A1 WO2020078520 A1 WO 2020078520A1
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antibody
nanoparticle
treatment
transition metal
lipid bilayer
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PCT/DK2019/050317
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English (en)
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Lene Broeng ODDERSHEDE
Andreas Kjaer
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Lantern Aps
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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
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
    • 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
    • A61K9/0012—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
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to lipid-coated nanoparticles and their use in plas- monic photothermal cancer therapy.
  • Nanoparticle-assisted photothermal therapy is a technique that exploits the strong light-to-heat conversion of plasmonic nanoparticles when irradiated with resonant or near-resonant light.
  • the therapy is particularly well-suited for cancer because tumours in general are known to have leaky vasculature that enables nano-sized drugs and particles to passively accumulate in the tumour tissue when injected into the bloodstream.
  • the leaky vasculature gives rise to the enhanced permeability and retention (EPR) effect and is a consequence of the chaotic vascular growth during tumour angiogenesis.
  • EPR enhanced permeability and retention
  • the EPR effect varies between tumour types, but in general favours accumulation of sub-100 nm structures..
  • the photo-induced heating of the nanoparticles is highly localised and can be triggered by an external light source minimizing adverse effects on sur- rounding healthy tissue. Furthermore, using near-infrared (NIR) light as nano- particle-excitation source reduces unspecific tissue heating due to the high tis- sue transparency in this wavelength window. Since the first implementation of nanoparticle-assisted photothermal therapy, much effort has been put into de- veloping novel NIR resonant nanoparticles that provide good heat generation as well as accumulate efficiently in tumours.
  • NIR near-infrared
  • AuNSs Silica-gold nanoshells
  • AuNSs composite structures with a silica core surrounded by a thin gold shell
  • AuNSs show good photothermal efficacy at NIR wavelengths, however, a relatively large ratio of scattering to absorption effi- ciency, as well as diameters > 100 nm which limit the EPR-based tumour de- livery, lower their potential.
  • Gold nanorods which have efficient longitudinal mode absorption in the NIR even at sub-100 nm dimensions, have also been put forward as efficient light-to-heat converters and as candidates for photo- thermal therapy.
  • nanorods are only efficient light-to-heat converters if they are aligned with the polarization vector of the irradiating laser light, and they have been shown to restructure into non-resonant shapes upon irradiation, even at relatively low intensities.
  • Spherical, solid gold nanoparticles AuNPs are easily synthesized, albeit that in the size range, i.e. , in the sub-100 nm range, useful for EPR-based tumour delivery their plasmonic resonance peaks are in the visible region, leading them to being disregarded for photothermal therapy.
  • Macrophage uptake is the principle mode of systemic nanoparticle clear- ance, thus making macrophage evasion a key strategy in producing long-cir- culating polymeric nanoparticles having a significant clinical impact.
  • the cur- rent standard for nanoparticle stealth coating is polyethylene glycol (PEG).
  • PEG polyethylene glycol
  • the adoption of PEG as a stealth moiety on nanoparticle surfaces has led to suc- cess with several clinical products, but recent observation of anti-PEG immu- nological response has triggered doubts over its biological relevance.
  • new approaches for the encapsulation of nanoparticles ensuring better capacity of tumour targeting and reduced macrophage cell uptake is highly de- sirable.
  • WO 201 1/163646 discloses method for treating a cancer in a subject, which comprises administering to the subject an effective dose of a mul- tidomain biotag that targets a cancer cell and exposing the subject to radiation, to selectively kill the cancer cells targeted by the biotag.
  • the biotag may have a reporter domain that is chelated to a noble metal nanoparticle tag. The method is thought to selectively target tumour or metastatic cells while leaving healthy cells intact.
  • WO 201 1/005916 discloses a composition comprising a nanoparticle core with a lipid bilayer disposed around the exterior surface of the nanoparticle core.
  • the bilayer improves dispersion in organic solvents.
  • WO 2018/172942 discloses lipid nanoparticle and a pharmaceutical corn- position comprising the lipid nanoparticle.
  • the lipid nanoparticle may be used for treating a cancer, and lipid nanoparticle are considered to provide improved bioavailability, improved metabolic stability, enhanced delivery to a target site, a high loading efficiency, and enhanced anti-tumour effects
  • each ac- tive particle comprises a solid spherical nanoparticle having a diameter in the range of 20 nm to 150 nm comprising a transition metal or a transition metal oxide, and a lipid bilayer, which lipid bilayer coats said solid spherical nanopar- ticle, and wherein the active particle has a diameter in the range of 30 nm to 160 nm.
  • the solid spherical nanoparticle preferably consists of the transition metal or the transition metal oxide.
  • the pharmaceutically acceptable carrier may be chosen freely, and any pharmaceutically acceptable carrier is appro- priate for the invention. It is to be understood that the wording“for cancer treat- ment” also covers variations of this wording, e.g. the invention also relates to the active particles defined above for use in the treatment of cancer. Further- more, the invention relates to the active particles defined above per se.
  • the inventors have demonstrated that solid, spherical gold or other transition metal or a transition metal oxide nanoparticles show surprisingly good photothermal efficacy at NIR wavelengths, e.g. 700 nm to 1 100nm.
  • solid spherical nanoparticles with a diameter in the range of 20 nm to 150 nm, such as in the range of 30 nm to 130 nm, such as in the range of 40 nm to 1 10 nm, such as in the range of 50 nm to 100 nm have shown appropriate light-to-heat conversion efficiencies.
  • Spherical gold nano- particles in the size ranges mentioned herein above for instance are also easy to produce in high-quality, homogeneous and bio-compatible quality and less toxic than gold nanorods.
  • Spherical nanoparticles are also thermally stable and show improved stability against degradation within the organism.
  • Spherical na- noparticles may also show improved light-to-heat conversion capability over that of other shapes.
  • Spherical gold nanoparticles in the size ranges mentioned herein above for instance are also easy to produce in a homogeneous and bio-compatible quality and less toxic than gold nanorods. Spherical nanoparticles also show improved light-to-heat conversion capability over that of other shapes.
  • transition metal oxides such as tita- nium oxide or iron oxide
  • transition metal oxides show good photothermal efficacy at NIR wavelengths.
  • electromagnetic absorption by spherical metal oxide nanoparticles may improve the effects of low energy light when compared to nanoparticle with other shapes.
  • nanoparticles of the active particles of the present invention being plasmonic, their electron density can couple with electromagnetic radiation of wavelengths that are larger than the particle due to the nature of the dielectric- metal interface between the medium and the particles, which advantageously enables the use of electromagnetic wavelengths that can easily penetrate living tissues, such as near infrared radiation, with a wavelength in the range of 700 nm to 1200 nm.
  • Lipid bilayer coated solid spherical gold nanoparticles exhibit a less negative Zeta potential albeit displaying an unaffected absorbance spec- trum upon UV-visible spectroscopic analysis, in comparison to the same non- coated nanoparticles.
  • the solid spherical nanoparticle is a nanoparticle comprising, e.g. consisting of, a transition metal.
  • the transition metal is gold. In another pre- ferred embodiment, the transition metal is platinum. In other embodiments, the transition metal is palladium, silver, rhodium, iridium, titanium or iron.
  • the solid spherical nanoparticle is a nanoparticle comprising, e.g. consisting of, a transition metal oxide.
  • the transition metal oxide is titanium oxide. In another embodiment, the transition metal oxide is iron oxide.
  • the spherical nanoparticle is solid.
  • the spherical nanoparticle consists of a transition metal.
  • the spherical nanoparticle consists of a transition metal oxide.
  • the solid nanoparticle comprises more than one transition metal or transition metal oxide.
  • the solid nanoparticle comprises a transition metal and a transition metal oxide.
  • the materials are layered on top of each other to form solid nanoparticles.
  • tran- sition metal oxides such as iron oxide or titanium oxide may be layered on top of a solid gold core.
  • gold may form an outer layer covering an inner core composed of iron oxide or titanium oxide.
  • an outer layer of one transition metal or transition metal oxide may be layered on another transition metal or transition metal oxide as defined herein.
  • Platinum for instance, may form a core upon which titanium oxide is layered, or be itself layered on a tita- nium oxide core.
  • Such configurations may increase the quality of the product, such as light-to-heat conversion capability, homogeneity, bio-compatibility, thermal stability and resistance against degradation within the organism.
  • the solid spherical nanoparticles of the invention have a diameter in the range of 20 nm to 150 nm. By not exceeding 150 nm in diameter, the nanopar- ticles of the invention may accumulate at tumour sites more efficiently. It is known that tumours in general have leaky vasculature that enables nano-sized drugs and particles to passively accumulate in the tumour tissue when injected into the bloodstream. This effect is known as enhanced permeability and reten- tion (EPR) and is a consequence of the chaotic vascular growth during tumour angiogenesis. The EPR effect varies between tumour types, but in general fa- vours accumulation of structures below 150 nm in diameter.
  • EPR enhanced permeability and reten- tion
  • an iron oxide solid spherical nanoparticle is a superparamagnetic iron oxide nanoparticle.
  • Said superparamagnetic iron oxide particle could be either a y-Fe 2 0 3 (maghemite) or a Fe 3 0 4 (magnetite) particle, or a combination of maghemite and magnetite.
  • Magnetic, in particular super- paramagnetic, iron oxide nanoparticles may be advantageously guided with the help of an external magnetic field to its target within the patient’s body.
  • the magnetic, e.g. superparamagnetic, nature of such particles makes handling the particles before injection easier.
  • magnetic, e.g. su- perparamagnetic, particles can be more easily handled by the doctor for mak- ing a final preparation for use in personalised medicine. Therefore, magnetic, e.g. superparamagnetic, active particles of the invention are especially useful in personalised medicine.
  • the solid spherical nanoparticle is coated with a lipid bilayer.
  • the ability to escape immune mechanisms is significantly increased. Avoiding an immune reaction may sub- stantially reduce systemic clearance and thereby increase residency and ac- cumulation of the nanoparticles at the tumour site.
  • the lipid bilayer is derived from a cell membrane.
  • chemical composition is retained and transferred to the active particles of the invention.
  • physical properties such as fluidity, permea- bility to ions and solutes, and immune system evasion capability may be ad- vantageously transferred to the active particle of the invention.
  • the cell membrane from which the lipid bilayer is derived may be obtained from the patient to be treated; when the lipid bilayer is obtained from the patient to be treated, the prepared active nanoparticles are considered ap- basementte for“personalised medicine”.
  • the lipid bilayer will retain said physical and chemical properties and in this manner, macrophage uptake and systemic clearance from the patient may be avoided.
  • a pa- tient’s own cells such as erythrocytes, macrophages or stem cells may be ad- vantageous for obtaining active particles according to the invention.
  • the lipid bilayer is an artificial membrane. Artificial membranes offer the opportunity to control the lipid and protein composition of the lipid bilayer.
  • the molecular composition across the lipid bilayer may be varied accordingly.
  • the hydrated region of the lipid bilayer formed by the hydrophilic headgroups can be extended further than usual, for instance by including lipids with a large protein or long sugar chain grafted to the phosphate group head. Altering lipid bilayer composition by in- creasing the hydrated region may help retain a water layer around the active particles and prevent dehydration, e.g. before administration.
  • artificial membranes By offering the opportunity to control protein composition of the lipid bi- layers, artificial membranes also enable the inclusion of e.g. transmembrane targeting molecules.
  • enzymatic molecules may be incorporated to the li- pid bilayer, such as transmembrane lipid transporter proteins including flip- pases, floppases and scramblases. The incorporation of such enzymes may establish and/or prolong asymmetry between the inner and outer lipid leaflets.
  • compositions of the inner and outer mem brane leaflets are different.
  • Phospholipid content for example, may be advan- tageously regulated.
  • Use of artificial membranes may also facilitate the production of asym- metric bilayers, e.g. by utilizing two different monolayers in Langmuir-Blodgett or Langmuir-Schaefer deposition or a combination of Langmuir-Blodgett and vesicle rupture deposition.
  • the inner membrane leaflet comprises phos- phatidylethanolamine, phosphatidylserine and phosphatidylinositol and its phosphorylated derivatives and the outer membrane leaflet comprises phos- phatidylcholine, sphingomyelin and a variety of glycolipids.
  • the outer membrane leaflet does not comprise phosphatidylserine in a significant proportion or amount.
  • the amount of phosphatidylserine is not sufficient to elicit an immune reaction, e.g. macrophage uptake.
  • lipids such as sphingomyelin and cholesterol, may also be advan- tageously incorporated to either one or both of the inner and outer artificial membrane leaflet.
  • a lipid membrane derived from the patient to be treated may be altered according to techniques used to generate an artificial membrane and thereby modulate its lipid and protein content. Such alterations may lead to the patient derived membrane to display improved properties, such as improved macrophage uptake avoidance.
  • the lipid bilayer comprises a targeting mole- cule.
  • a targeting molecule may include antibodies, antibody mimetics, artificial antibodies, antibody fragments, epitopes, receptors, ligands; nucleic acids, such as cDNAs, RNAs, oligonucleotides, primers, and probes; and/or small molecules that facilitate the specific or non-specific binding of an active particle to a target cell.
  • the lipid bilayer may ad- vantageously help in targeting the active particles of the invention to the tumour site.
  • the active particles of the invention may accumulate more efficiently in tumours.
  • the composition as described herein is effec- tive for plasmonic photo-treatment when irradiated with a wavelength in the range of 700 nm to 1 100 nm.
  • the solid spherical nanoparticle is effective for plasmonic photo-treatment when irradiated with light at in the range of 0.5 W/cm 2 to 30 W/cm 2
  • irradiating the solid spherical nanoparticle with en- ergy at an intensity below 30 W/cm 2 damage to tissues surrounding the tumour is limited.
  • a temperature between 40°C and 100°C is achieved.
  • the solid spherical nanoparticles are irradiated for a period of time in a range of 1 minutes to 10 minutes, e.g. about 5 minutes.
  • a second aspect of the present invention relates to a method for treating cancer said method comprising the steps of:
  • the invention relates to the use of the active nanopar- ticles of the invention in the manufacture of a medicament, e.g. a medicament for the treatment of a cancer, e.g. glioblastoma.
  • a third aspect of the present invention relates to method for evaluating the efficacy of treatment to prevent, delay and/or alleviate cancer, wherein said method comprises:
  • 18 F-FET 2'-deoxy-2'- 18 F-fluoro-D-glucose ( 18 F-FDG), 3'-deoxy-3'- 18 F-fluorothymi- dine ( 18 F-FLT), and 0-(2’- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) are used as trac- ers in PET/CT scanning to image and measure treatment induced changes in glucose uptake, cell proliferation, and amino acid transport, respectively. Of the three, use of 18 F-FET is optimal for measurement of treatment response of gli- oblastoma. Any embodiment of any aspect of the invention is relevant for any other aspect of the invention, and in particular, any effect obtained for a specific em bodiment is also relevant when this embodiment is used in other aspects.
  • Figure 1 shows the effect of irradiated plasmonic nanoparticles on glioblastoma cells and controls.
  • Figure 2 is a schematic representation summarising the membrane coating procedure of metallic nanoparticles.
  • Figure 3 evidences the lipid membrane coating of gold nanoparticles and for- mation of the active particles of the invention.
  • Figure 4 shows quantitative data supporting the biological membrane coating of gold nanoparticles and formation of the active particles of the invention.
  • Figure 5 shows results from positron emission tomography (PET) evaluation of treatment efficiency using gold nanoshells.
  • PET positron emission tomography
  • Figure 6 shows tumour volume following thermoplasmonic treatment with gold nanoshells measured by PET-CT.
  • Figure 7 shows tumour surface temperatures, tumour volumes and mouse sur- vival following thermoplasmonic treatment with gold nanoshells.
  • Figure 8 shows NIR absorptive properties of platinum nanoparticles.
  • Figure 9 shows the potential of platinum nanoparticles for thermoplasmonic cancer treatment.
  • the present disclosure is based on the development of lipid bilayer- coated solid spherical nanoparticles that are configured to evade macrophage uptake and systemic clearance. This disclosure will be better understood in view of the following definitions, which are provided for clarification and are not intended to limit the scope of the subject matter that is disclosed herein.
  • nanoparticle refers to matter with at least one dimension sized in the range of 1 and 150 nanometres (nm).
  • a particle is to be understood as a small object that behaves as a whole unit with respect to its transport and properties.
  • the term“nanoparticle” may be used interchangeably with terms“particle”,“nanosphere”,“solid spherical na- noparticle” or“solid spherical particle” throughout this disclosure.
  • pharmaceutical acceptable carrier refers to a fluid, liquid, or solid e.g. gelatinous composition, comprising materials of natural or synthetic origin, e.g. phosphate buffer solutions, salts, polymers, collagen gels, which can coexist with living tissues without causing substantial harm and are suitable vehicles for delivery of any active agent to a living tissue, for ex- ample for the delivery of nanoparticles to the site of a tumour.
  • the pharmaceutical acceptable carrier is an injectable solution carrier.
  • Pharmaceutically acceptable carriers are well-known to the skilled person.
  • treatment may refer to any kind of treatment.
  • the treatment may be a curative treatment, or it may also be an ameliorating treatment and/or a treatment reducing the effects of cancer.
  • the treatment may also be a treatment which delays progression of cancer, for example the treat- ment may reduce the growth rate or size of a cancerous tumour.
  • the treatment may also reduce the metastatic capability of cancerous cells.
  • patient refers to a human or non-human ani- mal.
  • plasmonic photothermal nanoparticles refers to particles whose electron density can couple with electromagnetic radiation of wave- lengths that are far larger than the particle, and thereby emit heat.
  • transition metal may refer to an element whose atom has a partially filled d sub-shell, or which can give rise to cations with an incomplete d sub-shell.
  • a transition metal may be any element in the d-block of the periodic table.
  • metal oxide refers to a chemical compound that contains at least one oxygen atom and one other metallic element in its chem- ical formula.
  • solid refers to a body that is not intentionally hollow or contain- ing spaces or gaps. It may also refer to a body that is made up of a variety of materials, said spaces or gaps being filled with another such transition metal of metal oxide as defined herein.
  • spherical refers to particles with a more or less rounded profile, may present facets on the surface and should be understood to include other terms, such as“quasi-spheres” and“spheroids”. For example, the spherical particles may be described with three axes, e.g.
  • an X-axis, a Y- axis and a Z-axis, which intersect at right angles, and in general the ratio be- tween the lengths of the axes will be in the range of 1 :2 to 2: 1 , e.g. the length of the X-axis may be in the range of 1 :2 to 2: 1 to the Y-axis and/or the Z-axis; any of the three axes may be the X-axis.
  • NIR near infrared
  • lipid bilayer refers to a polar membrane made of two layers of lipid molecules.
  • the terms“lipid bilayer”,“membrane” and “lipidic membrane” may be used interchangeably and as equivalents.
  • These membranes are flat sheets that form a continuous barrier to water and solutes.
  • Such membranes are suitably selected from lipid-containing biochemical as- semblies such as liposomes, micelles, filomicelles, lipid-coated bubbles, poly- mersomes, synthosomes, niosomes, microvesicles, droplet interface bilayers (DIBs) and exosomes.
  • DIBs droplet interface bilayers
  • Lipid bilayers are usually composed of amphiphilic phospholipids that have a hydrophilic phosphate head and a hydrophobic tail consisting of two fatty acid chains. Phospholipids with certain head groups can alter the surface chemistry of a bilayer and can, for example, serve as signals as well as "an- chors" for other molecules in the membranes of cells.
  • the tails of lipids can also affect membrane properties, for instance by determining membrane fluidity and phase transition temperature of the bilayer.
  • the packing of lipids within the bilayer also affects its mechanical properties, including its resistance to stretch- ing and bending.
  • Cell-derived membranes according to the invention typically include sev- eral types of molecules other than phospholipids. Examples include choles- terol, which helps strengthen the bilayer and decrease its permeability. Choles- terol also helps regulate the activity of certain integral membrane proteins. In- tegral membrane proteins are held tightly to the lipid bilayer with the help of an annular lipid shell. Annular lipids (also called shell lipids or boundary lipids) represent a select set of lipids or lipidic molecules which preferentially bind or stick to the surface of membrane proteins. They constitute a layer, or an annu- lus/ shell, of lipids which are highly immobilized due to the existence of strong lipid-protein (binding) interactions.
  • lipid bilayer as disclosed herein is composed of several distinct chemical regions across its cross-sec- tion. These regions and their interactions with the surrounding water may be characterized by methods known to the person skilled in the art, such as x-ray reflectometry, neutron scattering and nuclear magnetic resonance techniques.
  • An artificial membrane as referred to herein is any bilayer assembled in vitro, as opposed to the bilayer of natural cell membranes.
  • An artificial bilayer can be made with either synthetic or natural lipids or with mixtures of several synthetic or natural lipids.
  • the mode of production of artificial membranes is known to the person skilled in the art.
  • the centre of this bilayer contains almost no water and excludes molecules like sugars or salts that dissolve in water. The assembly process is driven by the hydrophobic effect.
  • such membranes may be produced by thin film hydration, physical or solvent dispersion, detergent solubilization, or by hydration of pro- liposomes.
  • Suitable lipid bilayers that may be used in the active particles disclosed herein include, for example, those lipid bilayers that (1 ) reduce macrophage uptake and systemic clearance, (2) increase circulation time, (3) reduce nano- particle cytotoxicity, (4) increase nanoparticle hydrophilicity or hydrophobicity, and/or (5) provide a surface that can be modified with one or more functional groups or targeting molecules.
  • Functional groups may be tethered using cross- linking agents.
  • Targeting molecules may be directly tethered to the lipid bilayer or may also be tethered using crosslinking agents.
  • targeting mol- ecules may be lipidic membrane-penetrating molecules.
  • Suitable functional groups that may be attached to membranes disclosed herein include, for example, amino groups (-NH2), sulfhydryl groups (-SH), car- boxyl groups (-COOH), guanylyl groups, hydroxyl groups (-OH), azido groups (-N3), and/or carbohydrates.
  • Such functional groups can attach directly to a membrane-penetrating molecule, and/or a crosslinking agent through, for ex- ample, an amino, sulfhydryl, or phosphate group.
  • Suitable crosslinking agents that may be used in the active particles dis- closed herein include long-chain succinimidyl 4-(N-maleimidomethyl) cyclohex- ane-1 - carboxylate (LC-SMCC); sulfosuccinimidyl 4-(N-maleimidom ethyl) cy- clohexane-1 - carboxylate (sulfo-SMCC); long-chain sulfosuccinimidyl 4-(N-ma- leimidomethyl) cyclohexane-l-carboxylate (sulfo-LC-SMCC); N-Succinimidyl-3- (pypridyldithio)- proprionate (SPDP); long-chain N-Succinimidyl-3-(pypridyl- dithio)-proprionate (LC- SPDP); sulfo-N-Succinimidyl-3-(pypridyldithi
  • Suitable targeting molecules comprised in the active particles as de- scribed herein include, but are not limited to antibodies, antibody mimetics, ar- tificial antibodies, antibody fragments, receptors, ligands; nucleic acids, such as cDNAs, RNAs, oligonucleotides, primers, and probes; and/or molecules that can mediate specific or non-specific binding of an active particle to a target molecule, such as through a cell-surface marker, through antibody-antigen recognition or through receptor-ligand interactions.
  • Suitable target molecules that may be used for binding of the active par- ticles disclosed herein include, for example, antibodies, antibody mimetics, ar- tificial antibodies, antibody fragments, epitopes, receptors, ligands; nucleic ac- ids, such as cDNAs, RNAs, oligonucleotides, primers, and probes; and/or small molecules that facilitate the specific or non-specific binding of an active particle to a target cell.
  • antibody-epitope interaction can be found in the targeting of glioblastoma cells with the specific interaction between D2C7 scFv, MR1 scFv, transforming growth factor a, or monoclonal antibody mAb14E scFv and EGFR.
  • receptor-ligand interaction is that of EGF and EGFR.
  • Suitable cell membrane-penetrating molecules that may be used in the active particles disclosed herein include full-length proteins, polypeptides, pep- tides, nucleic acids, and small molecules.
  • Exemplary peptides include those having from five to nine or more basic amino acids, such as lysine and arginine, and include peptides having from five to nine or more contiguous basic amino acids, such as lysine and arginine.
  • an antibody, or a fusion protein antibody mimetic resulting from recombinant technology may have a Fc or Fab fragment comprising from five to nine or more basic amino acids, such as lysine and arginine in their C-terminal regions.
  • Lipid components within membranes can be determined by methods known to the person skilled in the art, such as thermodynamic phase diagrams, nuclear magnetic resonance, confocal microscopy and fluorescence correla- tion spectroscopy, photon fluorescence microscopy or secondary ion mass spectrometry.
  • the diameter of a nanoparticle core may be measured by photon corre- lation spectroscopy (PCS) or by transmission electron microscopy (TEM).
  • PCS photon corre- lation spectroscopy
  • TEM transmission electron microscopy
  • An aqueous drop of a nanoparticle solution i.e. a nanofluid
  • PCS photon corre- lation spectroscopy
  • TEM transmission electron microscopy
  • An aqueous drop of a nanoparticle solution i.e. a nanofluid
  • the nanoparti- cle core may then be visualized under an 80 kV electron beam.
  • na- noparticle cores are visible, while polymer or lipid coatings are transparent to the electron beam and therefore invisible by TEM.
  • the active particle comprises a solid spherical gold or platinum nanoparticle having a diameter of about 70 nm coated with a lipid bilayer of around 8 nm in thickness, this lipid bilayer comprising an inner membrane leaflet comprising phosphatidylethanolamine, phosphatidylserine and phosphatidyl-inositol and possibly its phosphorylated derivatives, and an outer membrane leaflet comprising phosphatidylcholine, sphingomyelin and in- sufficient phosphatidylserine to elicit an immune reaction.
  • said active particles display a good photothermal efficacy at NIR wavelengths, i.e. at wavelengths in the range of 700 nm to 1 100 nm while being irradiated for about 5 minutes.
  • the active particle comprises a solid spherical titanium oxide or iron oxide nanoparticle having a diameter of about 70 nm coated with a lipid bilayer of around 8 nm in thickness, this lipid bilayer comprising an inner membrane leaflet comprising phosphatidylethanolamine, phosphatidylserine and/or phosphatidyl-inositol, and an outer membrane leaflet comprising phosphatidylcholine and/or sphingomyelin and insufficient phos- phatidylserine to elicit an immune reaction.
  • said active par- ticles display a good photothermal efficacy at NIR wavelengths i.e. at wave- lengths in the range of 700 nm to 1 100 nm while being irradiated for about 5 minutes.
  • Additional item 1 1 A method for treating cancer said method compris- ing the steps of:
  • Additional item 12 The method for treating a cancer according to item 12, wherein the solid spherical nanoparticle is a solid palladium, silver, plati- num, gold, rhodium, iridium, titanium or iron, or titanium oxide or iron oxide sphere with a diameter between 20 nm to 150 nm and wherein the active par- ticle has a diameter between 30 nm to 160 nm.
  • Additional item 13 The method for treating cancer according to any one of items 12 or 13, wherein the cancer is glioblastoma.
  • Additional item 14 The method for treating cancer according to any one of items 12 to 14, wherein the lipid bilayer comprises an antibody, an anti- body mimetic, an artificial antibody, an antibody fragment, a receptor, a ligand or a fusion protein.
  • Additional item 15 The method for treating cancer according to item 15, wherein said antibody, antibody mimetic, artificial antibody, antibody frag- ment, receptor, ligand or fusion protein selectively binds a cancer cell-surface marker.
  • Additional item 16 The method for treating cancer according to any one of items 12 to 16, wherein the lipid bilayer is derived from a cell membrane.
  • Additional item 17 The method for treating cancer according to any one of items 12 to 17, wherein the lipid bilayer is an artificial membrane.
  • Additional item 18 The method for treating cancer according to any one of items 16 or 17, wherein the lipid bilayer comprises an outer lipid layer and an inner cytoplasmic lipid layer, and wherein the outer lipid layer does not comprise phospholipids that elicit an immune response.
  • Additional item 19 The method for treating cancer according to any one of items 12 to 19, wherein the solid spherical transition metal nanoparticle is irradiated with light with a wavelength comprised between 700-1 100 nm.
  • Additional item 20 The method for treating cancer according to any one of items 12 to 20, wherein the solid spherical transition metal nanoparticle is irradiated with light at around 0.5 W/cm 2 - 30 W/cm 2
  • Additional item 21 The method for treating cancer according to any one of items 12 to 21 , wherein the solid spherical transition metal nanoparticle is effective for plasmonic photo-treatment when its temperature is between 40°C and 100°C.
  • Additional item 22 A method for evaluating the efficacy of treatment to prevent, delay and/or alleviate cancer, wherein said method comprises:
  • Additional item 23 The method according to item 23, wherein the dis- ease is glioblastoma.
  • Example 1 Metallic nanoparticles are coated with lipid bilayer membrane fragments obtained from macrophages, cancer cells or stem cells.
  • Example 2 Plasmonic nanoparticle treatment if efficient against glioblas- toma cell survival.
  • glioblastoma cell death Plasmonic nanoparticles applied to areas of a dish containing glioblas- toma cells and irradiated with NIR results in glioblastoma cell death (Fig. 1 ).
  • PET tracer 18 F-FDG, 18 F-FLT and 18 F-FET uptake is correspondingly reduced 2 days after treatment (Fig. 5): For all of the tracers there was no significant difference in the mean tumour uptake at baseline between the three different treatment groups (Fig 5A). Flowever, the tumour accumulation of 18 F-FLT showed a larger variation between groups, whereas the mean tumour uptake of 18 F-FET was slightly lower than for 18 F-FDG and 18 F-FLT.
  • tumour volume from CT scans 7 days after therapy was evaluated (see Fig. 6). This confirmed inhibited tumour growth in the NS groups compared to the two control groups that both had significant increase in tumour volume at day 7 compared to baseline.
  • Figure 7A shows the average maximum temperature development during laser irradiation measured using a thermographic camera on the surface of the tumour.
  • the average maximum temperature was 50.6 ⁇ 1.6 °C.
  • the average maximum temperature in the saline group was 43.5 ⁇ 0.4 °C.
  • the average maximum temperature in the sham group was ⁇ 31 °C.
  • the maximum temperature reached in the NS group after 5 min of irradiation was significantly higher than in both the control groups (p ⁇ 0.01 ).
  • Figure 7B shows that the tumour growth overall was inhibited in animals in the NS group and for all three studies, at least one animal had complete tumour disappearance. In comparison, the tumour growth in the two control groups progressed in a similar manner. This indicates that even though the laser in itself can induce a temperature rise of ⁇ 10 °C, as represented in the saline groups, it does not inflict enough tissue damage to inhibit tumour growth.
  • the survival curves for all three studies are shown in Figure 7C. The median survival was 25 days in the NS group, 12 days in the saline group, and 11 days in the sham group.
  • Example 3 Platinum nanoparticles exhibit extreme NIR absorptive prop- erties at sizes suitable for EPR delivery.
  • Platinum nanoparticles with diameters of 50 nm and 70 nm, perfect for EPR delivery, are shown to efficiently kill cancer cells in culture (Fig. 9c-f). Also, Fig. 9a-b show that these two sizes of platinum nanoparticles are not toxic within relevant concentrations.

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Abstract

La présente invention concerne une composition comprenant des particules actives et un support pharmaceutiquement acceptable pour le traitement du cancer par traitement photo-thermique plasmonique, chaque particule active comprenant une nanoparticule sphérique solide d'un métal de transition ou d'un oxyde de métal de transition, et une bicouche lipidique. Les particules actives sont efficaces dans le traitement du cancer.
PCT/DK2019/050317 2018-10-17 2019-10-17 Nanoparticules enrobées de lipide pour une thérapie anticancéreuse par résonance plasmonique WO2020078520A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
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WO2011005916A1 (fr) 2009-07-08 2011-01-13 William Marsh Rice University Compositions de nanoparticules comprenant une bicouche lipidique et procédés associés
WO2011163646A2 (fr) 2010-06-25 2011-12-29 Marek Malecki Procédés de détection, de diagnostic et d'éradication sélective de néoplasmes et de cellules tumorales circulantes à l'aide de bio-étiquettes multidomaines
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Publication number Priority date Publication date Assignee Title
WO2011005916A1 (fr) 2009-07-08 2011-01-13 William Marsh Rice University Compositions de nanoparticules comprenant une bicouche lipidique et procédés associés
WO2011163646A2 (fr) 2010-06-25 2011-12-29 Marek Malecki Procédés de détection, de diagnostic et d'éradication sélective de néoplasmes et de cellules tumorales circulantes à l'aide de bio-étiquettes multidomaines
WO2018172942A1 (fr) 2017-03-20 2018-09-27 The University Of North Carolina At Chapel Hill Nanoparticules de quercétine

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