WO2019195207A1 - Composés cannabinoïdes activés par la lumière et leurs procédés d'utilisation - Google Patents

Composés cannabinoïdes activés par la lumière et leurs procédés d'utilisation Download PDF

Info

Publication number
WO2019195207A1
WO2019195207A1 PCT/US2019/025277 US2019025277W WO2019195207A1 WO 2019195207 A1 WO2019195207 A1 WO 2019195207A1 US 2019025277 W US2019025277 W US 2019025277W WO 2019195207 A1 WO2019195207 A1 WO 2019195207A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
compound
light
mbc94
ir700dx
Prior art date
Application number
PCT/US2019/025277
Other languages
English (en)
Inventor
Mingfeng Bai
Xiaoxi LING
Original Assignee
Vanderbilt University
University Of Pittsburgh-Of The Commonwealth System Of Higher Education
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Vanderbilt University, University Of Pittsburgh-Of The Commonwealth System Of Higher Education filed Critical Vanderbilt University
Publication of WO2019195207A1 publication Critical patent/WO2019195207A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0834—Compounds having one or more O-Si linkage
    • C07F7/0838—Compounds with one or more Si-O-Si sequences
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • 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 disclosure relates to light-activated cannabinoid compounds and methods of use for photodynamic therapy and for treating cancer, inflammation, and infection.
  • Photodynamic therapy is an attractive treatment strategy that is minimally invasive with little to no systemic toxicity.
  • PDT utilizes photosensitizers (PS) to harvest the power of light and transform it into reactive oxygen species (ROS), a powerful cancer-killing grenade.
  • ROS reactive oxygen species
  • the reaction is highly localized and the ROS are short-lived, limiting the effect of PDT to the irradiated area only.
  • ROS reactive oxygen species
  • a new advance of PDT agent design is to include a ROS-cleavable linker for on demand drug release.
  • a heterobifunctional thioketal linker was developed for such a purpose.
  • prodrugs were reported that can be activated by ROS produced from photosensitizers and encouraging combinatory therapeutic effects have been observed.
  • a light-activatable paclitaxel prodrug for combined PDT and chemotherapy was developed.
  • this light- activatable paclitaxel prodrug showed improved therapeutic outcome in ovarian cancer cells.
  • this prodrug has aggregation issues in aqueous solution and thus lacks proper targeting functionality.
  • PEGylated folic acid molecules with different sizes of polyethylene glycol (PEG) was attached to the light-activatable paclitaxel prodrug for improved water solubility and targeted delivery.
  • PEG polyethylene glycol
  • cannabinoid compounds for target-specific photodynamic therapy (PDT) and cannabinoid therapy.
  • These prodrug compounds comprise three components: a cannabinoid, a reactive oxygen species (ROS)-sensitive linker, and a photosensitizer.
  • Cannabinoids have attracted great attention as promising antitumor drugs as they can produce ROS, inhibit pro-metastatic gene expression, and upregulate autophagy- mediated cell death.
  • ROS reactive oxygen species
  • the photosensitizer produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. Therefore, this prodrug provides targeted and on-demand combinatory PDT and cannabinoid therapy.
  • a compound comprising: a cannabinoid, a reactive oxygen species (ROS)-sensitive linker, and a photosensitizer.
  • ROS reactive oxygen species
  • X is a cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive linker
  • Z is a photosensitizer
  • the cannabinoid specifically binds to the type 2 cannabinoid receptor (CB 2 R). In some embodiments, the cannabinoid is:
  • the reactive oxygen species (ROS)-sensitive linker is a thioketal linker. In some embodiments, the reactive oxygen species (ROS)-sensitive linker is:
  • the photosensitizer is hydrophilic. In some embodiments, the photosensitizer is:
  • the compound comprises:
  • a pharmaceutical composition comprising a pharmaceutical carrier and a pharmaceutically effective amount of a compound of Formula I.
  • a method of treating a cancer comprising: administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof; and irradiating the compound with light.
  • the cancer is a CB2R-expressing cancer.
  • the cancer is selected from glioma, lymphoma, skin cancer, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, gastric cancer, bladder cancer, head & neck cancer, oral cancer, cholangiocarcinoma, ovarian cancer, cervical cancer, or esophageal cancer.
  • the cancer is glioma.
  • the cancer is lymphoma.
  • the cancer is skin cancer.
  • die cancer is prostate cancer.
  • the cancer is lung cancer.
  • the cancer is breast cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colon cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is head and neck cancer. In some embodiments, the cancer is oral cancer. In some embodiments, the cancer is cholangiocarcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is esophageal cancer.
  • the subject is a mammal. In some embodiments, the subject is a human.
  • the light comprises a far-red light. In some embodiments, the light comprises a near infrared light. In some embodiments, the light comprises a wavelength from about 650 nm to about 900 nm. In some embodiments, die light comprises a wavelength of about 690 nm.
  • a method of photodynamic therapy (PDT) comprising:
  • a method of treating inflammation comprising: administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof; and irradiating the compound with light.
  • a method of treating an infection comprising: administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof; and irradiating the compound with light.
  • a method for image-guided surgery comprising: administering a compound of Formula I to a subject in need thereof prior to surgery and/or during surgery, visualizing the compound, and performing said surgery.
  • FIG. 1 Structures of IR700DX-TK-mbc94 and IR700DX-mbc94.
  • FIG. 2 Fluorescence intensity of CPM over 30 min of light irradiation at 690 nm is compared among four groups, including IR700DX-TK-mbc94, IR700DX-mbc94, IR700DX and vehicle.
  • FIG. 3 ROS production of IR700DX-TK-mbc94 and IR700DX-mbc94 analyzed by AFP (type I ROS) and SOSG (type II ROS) assays.
  • FIG. 4 PDT treatment using IR700DX-TK-mbc94 led to increased cancer cell death as compared to PDT with IR700DX-mbc94.
  • A,B Concentration-dependent and progressive cell death caused by PDT using 0.5 (A) or 1 mM
  • B IR700DX-TK-mbc94 or lR700DX-mbc94. Progressive cell death was observed after PDT treatment (24 hour post-PDT versus right after PDT treatment).
  • C Cellular uptake of IR700DX-TK-mbc94 can be blocked by a CBaR ligand, SR144528.
  • D Light dose-dependent cell death caused by PDT using IR700DX-TK-mbc94. Cells were treated with 18, 36 or 54 J/cm 2 690 nm light after incubation with 1 or 2 mM IR700DX-TK-mbc94.
  • FIG. 5 Competitive binding study of IR700DX-TK-mbc94 using [ 3 H]CP-55940.
  • FIG. 6. Competitive binding study of IR700DX-mbc94 using [ 3 H]CP-55940.
  • FIG. 7 Competitive binding study of mbc94-SH using [ 3 H]CP-55940.
  • FIG. 9 Normal cell control (HEK-293) showed negligible death as compared to CBaR- expressing DBT-2D4 cells after treatment with PDT using IR700DX-TK-mbc94.
  • cannabinoid compounds for target-specific photodynamic tiierapy (PDT) and cannabinoid therapy.
  • These prodrug compounds comprise three components: a cannabinoid, a reactive oxygen species (ROS)-sensitive linker, and a photosensitizer.
  • Cannabinoids have attracted great attention as promising antitumor drugs as they can produce ROS, inhibit pro-metastatic gene expression, and upregulate autophagy- mediated cell death.
  • ROS reactive oxygen species
  • the photosensitizer produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases the cannabinoid drug. Therefore, this prodrug provides targeted and on-demand combinatory PDT and cannabinoid therapy.
  • the terms“may,”“optionally,” and“may optionally” are used interchangeably and are meant to include cases in which the condition occurs as well as cases in which the condition does not occur.
  • the statement that a formulation “may include an excipient” is meant to include cases in which die formulation includes an excipient as well as cases in which the formulation does not include an excipient.
  • beneficial agent and“active agent” are used interchangeably herein to refer to a chemical compound or composition that has a beneficial biological effect.
  • beneficial biological effects include both therapeutic effects, i.e., treatment of a disorder or other undesirable physiological condition, and prophylactic effects, i.e., prevention of a disorder or other undesirable physiological condition.
  • the terms also encompass pharmaceutically acceptable, pharmacologically active derivatives of beneficial agents specifically mentioned herein, including, but not limited to, salts, esters, amides, prodrugs, active metabolites, isomers, fragments, analogs, and the like.
  • the term includes the agent per se as well as pharmaceutically acceptable, pharmacologically active salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, analogs, etc.
  • treating or “treatment” of a subject includes the administration of a drug to a subject with the purpose of curing, healing, alleviating, relieving, altering, remedying, ameliorating, improving, stabilizing or affecting a disease or disorder, or a symptom of a disease or disorder.
  • the terms“treating” and“treatment” can also refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage.
  • the term“preventing” a disease, a disorder, or unwanted physiological event in a subject refers to the prevention of a disease, a disorder, or unwanted physiological event or prevention of a symptom of a disease, a disorder, or unwanted physiological event
  • an“effective amount” of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect.
  • the amount of beneficial agent that is“effective” will vary from subject to subject, depending on the age and general condition of the subject, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact“effective amount.” However, an appropriate“effective” amount in any subject case may be determined by one of ordinary skill in the art using routine experimentation. Also, as used herein, and unless specifically stated otherwise, an“effective amount” of a beneficial can also refer to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
  • An“effective amount” of a drug necessary to achieve a therapeutic effect may vary according to factors such as the age, sex, and weight of the subject. Dosage regimens can be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • a“therapeutically effective amount” of a therapeutic agent refers to an amount that is effective to achieve a desired therapeutic result
  • a“prophylactically effective amount” of a therapeutic agent refers to an amount that is effective to prevent an unwanted physiological condition.
  • Therapeutically effective and prophylactically effective amounts of a given therapeutic agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the subject.
  • therapeutically effective amount can also refer to an amount of a therapeutic agent, or a rate of delivery of a therapeutic agent (e.g., amount over time), effective to facilitate a desired therapeutic effect.
  • the precise desired therapeutic effect will vary according to the condition to be treated, die tolerance of the subject, the drug and/or drug formulation to be administered (e.g., the potency of the therapeutic agent (drug), the concentration of drug in the formulation, and the like), and a variety of other factors that are appreciated by those of ordinary skill in the art.
  • the term“pharmaceutically acceptable” component can refer to a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the invention and administered to a subject as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
  • the term“pharmaceutically acceptable” is used to refer to an excipient, it is generally implied that the component has met die required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.
  • the term“pharmacologically active” can refer to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having die same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • the term“mixture” can include solutions in which the components of the mixture are completely miscible, as well as suspensions and emulsions, in which the components of the mixture are not completely miscible.
  • tire term“cannabinoid” includes naturally occurring and non-natural derivatives of cannabinoids which can be obtained by derivation of natural cannabinoids and which are unstable tike natural cannabinoids.
  • the cannabinoid used herein may be natural, semi-synthetic, or synthetic.
  • the cannabinoid may be included in its free form, or in the form of a salt; an acid addition salt of an ester; an amide; an enantiomer; an isomer; a tautomer; a prodrug; a derivative of an active agent of the present invention; different isomeric forms, both in pure form and in admixture, including racemic mixtures.
  • photosensitizer refers to a compound capable of undergoing photoactivation. Accordingly, photosensitizers can be characterized functionally as those chemicals which absorb electromagnetic energy, such as optical energy, and convert it primarily to chemical energy. As used herein, the term“photoactivation” is used generally to describe the process by which energy in the form of electromagnetic radiation is absorbed by a compound which becomes“excited” and then functions to convert the energy to another form of energy, preferably chemical energy. The chemical energy will be in the form of reactive oxygen species.
  • the term“subject” or“host” can refer to living organisms such as mammals, including, but not limited to humans, livestock, dogs, cats, and other mammals. Administration of the therapeutic agents can be carried out at dosages and for periods of time effective for treatment of a subject. In some embodiments, the subject is a human.
  • a compound comprising: a cannabinoid, a reactive oxygen species (ROS)-sensitive tinker, and a phthalocyanine photosensitizer.
  • ROS reactive oxygen species
  • X is a cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive linker
  • Z is a photosensitizer
  • the cannabinoid specifically binds to the type 2 cannabinoid receptor.
  • the cannabinoid is a CB2 selective (or CB2 specific) cannabinoid.
  • Examples of cannabinoids and CB2 selective cannabinoids can be found, for example, in the following articles: Nevalainen, T. Recent development of CB2 selective and peripheral CB1/CB2 cannabinoid receptor ligands. Curr Med Chem 2014;21(2):187-203; and Ling, X., et al. A novel near-infrared fluorescence imaging probe that preferentially binds to cannabinoid receptors CB2R over CB1R. Biomaterials.
  • the cannabinoid is mbc94:
  • the reactive oxygen species (ROS)-sensitive linker is selected from a thioether, alkyl selenide, alkyl telluride, alkyl diselenide, thioketal, arylboronic ester, polysaccharide, aminoacrylate, oligoproline, peroxalate ester, or mesoporous silicon linker.
  • ROS reactive oxygen species
  • Examples of reactive oxygen species (ROS)-sensidve linkers can be found, for example, in the following articles: Liang, J. and B. Liu. ROS-responsive drug delivery systems. Bioeng Transl Med. 2016 Jul 5;1(3):239-251. doi: 10.1002/btm2.10014. eCoUection 2016 Sep; Tao, W. and Z. He. ROS-responsive drug delivery systems for biomedical applications. Asian Journal of Pharmaceutical Sciences. Volume 13, issue 2, March 2018, Pages 101-112; each of which is expressly incorporated herein by reference.
  • the reactive oxygen species (ROS)-sensitive linker is a thioketal linker.
  • the thioketal linker is:
  • the photosensitizer is hydrophilic. In some embodiments, the photosensitizer is a phthalocyanine photosensitizer. In some embodiments, the photosensitizer is a near-infrared (NIR) photosensitizer.
  • NIR near-infrared
  • the photosensitizer is IR700DX:
  • Additional photosensitizers are known in the art and can be based on porphyrin, chlorin and bacteriochlorin structures. Additional photosensitizers can be found for example, in the following articles: Wu Z, et al. Molecular imaging of human tumor cells that naturally overexpress type 2 cannabinoid receptors using a quinolone-based near-infrared fluorescent probe. J Biomed Opt. 2014;19(7):76016; Ling X, et al. A novel near-infrared fluorescence imaging probe that preferentially binds to cannabinoid receptors CB2R over CB1R. Biomaterials. 2015 Jul;57: 169-78; Zhang, J. et al.
  • the compound comprises:
  • X is a cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive linker
  • Z is a phthalocyanine photosensitizer.
  • X is a CB2 selective cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive linker
  • Z is a photosensitizer
  • X is a cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive thioketal linker
  • Z is a photosensitizer.
  • X is a cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive thioketal linker
  • Z is a phthalocyanine photosensitizer.
  • X is a CB2 selective cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive thioketal linker
  • Z is a photosensitizer
  • X is a CB2 selective cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive linker
  • Z is a phthalocyanine photosensitizer.
  • X is a CB2 selective cannabinoid
  • Y is a reactive oxygen species (ROS)-sensitive thioketal linker
  • compositions are a phthalocyanine photosensitizer.
  • compositions comprising a pharmaceutical carrier and a pharmaceutically effective amount of a compound of Formula I.
  • the compound comprises a pharmaceutically acceptable salt of a compound of Formula I.
  • Compositions, as described herein, comprising an active compound and an excipient of some sort may be useful in a variety of applications.
  • pharmaceutical compositions comprising an active compound and an excipient may be useful, for example, for treating cancer, inflammation, or infection.
  • Excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • General considerations in formulation and/or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).
  • excipients include, but are not limited to, any non-toxic, inert solid, semi- solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as com starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; com oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide
  • the excipients may be chosen based on what the composition is useful for.
  • the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intracistemally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, com starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g.
  • stearyl alcohol cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. car boxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl- pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Plutonic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • polyoxyethylene ethers e.g. polyoxyethylene lauryl ether [Brij 30]
  • poly(vinyl- pyrrolidone) diethylene glycol monolaurate
  • triethanolamine oleate sodium oleate
  • potassium oleate ethyl oleate
  • oleic acid ethyl laurate
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g.
  • acacia sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic add, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chloriiexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SEES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Gennall 115, Germaben II, Neolone, Kathon, and Euxyl.
  • the preservative is an anti-oxidant.
  • the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, camauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rape seed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimcthicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.
  • composition may further comprise a polymer.
  • exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar
  • composition may further comprise an emulsifying agent.
  • emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly(meth)acrylic acid, and esters amide and hydroxyalkyl amides thereof, natural emulsifiers (e.g.
  • acacia agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pecdn, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g.
  • carboxy polymethylene polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer
  • carrageenan cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g.
  • Cremophor polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Plutonic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.
  • the emulsifying agent is cholesterol.
  • Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.
  • tire liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspend
  • injectable compositions for example, injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the particles are suspended in a carrier fluid comprising 1% (w/v) sodium caiboxymethyl cellulose and 0.1% (v/v) Tween 80.
  • the injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles.
  • Solid compositions include capsules, tablets, pills, powders, and granules.
  • the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay,
  • the dosage form may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and tire like.
  • Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
  • compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches.
  • the active compound is admixed with an excipient and any needed preservatives or buffers as may be required.
  • the ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the particles in a polymer matrix or gel.
  • the active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result.
  • the exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular active ingredient, its mode of administration, its mode of activity, and the like.
  • the active ingredient, whether the active compound itself, or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the active ingredient may be administered by any route.
  • the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol.
  • routes including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, buccal, enteral, sublingual;
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc.
  • an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a method of treating a cancer comprising:
  • a method of treating a cancer comprising:
  • a method of treating a cancer comprising:
  • NIR near infrared
  • the cancer is a CB2R-expressing cancer.
  • the cancer is selected from glioma, lymphoma, skin cancer, prostate cancer, lung cancer, breast cancer, pancreatic cancer, colon cancer, gastric cancer, bladder cancer, head & neck cancer, oral cancer, cholangiocarcinoma, ovarian cancer, cervical cancer, or esophageal cancer.
  • the cancer is glioma.
  • the cancer is lymphoma.
  • the cancer is skin cancer.
  • die cancer is prostate cancer.
  • the cancer is lung cancer.
  • the cancer is breast cancer.
  • the cancer is pancreatic cancer.
  • the cancer is colon cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, die cancer is head and neck cancer. In some embodiments, the cancer is oral cancer. In some embodiments, die cancer is cholangiocarcinoma. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is a solid tumor.
  • the methods described herein are used for die treatment or the prevention of a cancer, for example, melanoma, lung cancer (including lung adenocarcinoma, basal cell carcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, bronchogenic carcinoma, non-small-cell carcinoma, small cell carcinoma, mesothelioma); breast cancer (including triple negative breast cancer (TNBC), ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma, serosal cavities breast carcinoma); colorectal cancer (colon cancer, rectal cancer, colorectal adenocarcinoma); anal cancer; pancreatic cancer (including pancreatic adenocarcinoma, islet cell carcinoma, neuroendocrine tumors); prostate cancer; prostate adenocarcinoma; ovarian carcinoma (ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cysta
  • lung cancer
  • a compound or composition disclosed herein can be administered in combination with an additional chemotherapeutic agent.
  • a composition comprising a compound represented by Formula I and an additional chemotherapeutic agent.
  • Additional chemotherapeutic agents include, but are not limited to, radioactive molecules, toxins, also referred to as cytotoxins or cytotoxic agents, which includes any agent that is detrimental to the viability of cells, agents, and liposomes or other vesicles containing chemotherapeutic compounds.
  • chemotherapeutic agents include but are not limited to 1 -dehydrotestosterone, 5-fluorouracil decarbazine, 6-mercaptopurine, 6- thioguanine, actinomycin D, adriamycin, aldesleukin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, anthramycin (AMC)), anti-mitotic agents, cis- dichlorodiamine platinum (P) (DDP) cisplatin), diamino dichloro platinum, anthracyclines, antibiotics, antis, asparaginase, BCG live (intravesical), betamethasone sodium phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, calcium leucouorin, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), Chloramb
  • Additional chemotherapeutic agents or therapeutic agents that can be administered in combination with the compounds disclosed herein can include bevacizumab, sutinib, sorafenib,
  • the subject is a mammal. In some embodiments, the subject is a human.
  • the light comprises a far-red light.
  • Far-red light is light at the extreme red end of the visible spectrum, just before infra-red light, usually regarded as the region between about 710 and about 850 nm wavelength.
  • the light comprises a near infrared light. Near-infrared is the region closest in wavelength to the radiation detectable by the human eye, usually regarded as the region from about 780 nm to about 2500 nm.
  • the light comprises a wavelength from about 650 nm to about 900 nm In some embodiments, the light comprises a wavelength of about 650, about 660, about 670, about 680, about 690, about 700, about 710, about 720, about 730, about 740, about 750, about 760, about 770, about 780, about 790, about 800, about 810, about 820, about 830, about 840, about 850, about 860, about 870, about 880, about 890, or about 900. In some embodiments, the light comprises a wavelength of about 690 nm.
  • a method of photodynamic therapy comprising:
  • a method of photodynamic therapy comprising:
  • a method of treating an inflammation disorder including autoimmune diseases in a subject.
  • a method of treating inflammation comprising: administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof; and irradiating the compound with light.
  • the method comprises administering to said subject a therapeutically effective amount of a compound, a combination of compounds, or a composition provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical composition as provided herein.
  • a pharmaceutically acceptable form e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives
  • autoimmune diseases include but are not limited to acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, autoimmune skin disease, coeliac disease, Crohn’s disease, Diabetes mellitus (type 1), Goodpasture’s syndrome, Graves' disease, Guillain-Barrd syndrome (GBS), Hashimoto’s disease, lupus erythematosus, multiple sclerosis, myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, oemphigus, polyarthritis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, Reiter's syndrome, Takayasu's arteritis, temporal arteritis (also known as“giant cell arteritis”), warm autoimmune hemolytic
  • Inflammation takes on many forms and includes, but is not limited to, acute, adhesive, atrophic, catarrhal, chronic, cirrhotic, diffuse, disseminated, exudative, fibrinous, fibrosing, focal, granulomatous, hyperplastic, hypertrophic, interstitial, metastatic, necrotic, obliterative, parenchymatous, plastic, productive, proliferous, pseudomembranous, purulent, sclerosing, seroplastic, serous, simple, specific, subacute, suppurative, toxic, traumatic, and/or ulcerative inflammation.
  • Exemplary inflammatory conditions include, but are not limited to, inflammation associated with acne, anemia (e.g., aplastic anemia, haemolytic autoimmune anaemia), asthma, arteritis (e.g., polyarteritis, temporal arteritis, periarteritis nodosa, Takayasu's arteritis), arthritis (e.g., crystalline arthritis, osteoarthritis, psoriatic arthritis, gout flare, gouty arthritis, reactive arthritis, rheumatoid arthritis and Reiter's arthritis), ankylosing spondylitis, amylosis, amyotrophic lateral sclerosis, autoimmune diseases, allergies or allergic reactions, atherosclerosis, bronchitis, bursitis, chronic prostatitis, conjunctivitis, Chagas disease, chronic obstructive pulmonary disease, cermatomyositis, diverticulitis, diabetes (e.g., type I diabetes mellitus,
  • the inflammatory disorder is selected from arthritis (e.g., rheumatoid arthritis), inflammatory bowel disease, inflammatory bowel syndrome, asthma, psoriasis, endometriosis, interstitial cystitis and prostatistis.
  • the inflammatory condition is an acute inflammatory condition (e.g., for example, inflammation resulting from infection).
  • the inflammatory condition is a chronic inflammatory condition (e.g., conditions resulting from asthma, arthritis and inflammatory bowel disease).
  • the compounds can also be useful in treating inflammation associated with trauma and non-inflammatory myalgia.
  • Immune disorders such as auto-immune disorders include, but are not limited to, arthritis (including rheumatoid arthritis, spondyloarthopathies, gouty arthritis, degenerative joint diseases such as osteoarthritis, systemic lupus erythematosus, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amylosis, acute painful shoulder, psoriatic, and juvenile arthritis), asthma, atherosclerosis, osteoporosis, bronchitis, tendonitis, bursitis, skin condition (e.g., psoriasis, eczema, bums, dermatitis, pruritus (itch)), enuresis, eosinophilic disease, gastrointestinal disorder (e.g., selected from peptic ulcers,
  • provided herein is a method of treating a CB2R-mediated inflammation disorder, including a CB2R-mediated autoimmune diseases in a subject.
  • provided herein is a method of treating an infection in a subject.
  • a method of treating an infection comprising: administering a therapeutically effective amount of a compound of Formula I to a subject in need thereof; and irradiating the compound with light.
  • the method comprises administering to said subject a therapeutically effective amount of a compound, a combination of compounds, or a composition provided herein, or a pharmaceutically acceptable form (e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives) thereof, or a pharmaceutical composition as provided herein.
  • a pharmaceutically acceptable form e.g., pharmaceutically acceptable salts, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives
  • the infection is selected from a viral infection, bacterial infection, or a fungal infection.
  • the infection is selected from HIV, influenza, or other viral infections. Examples of infections that can be treated can be found, for example in the following: Hemindez-Cervantes, R., et al. Immunoregulatory Role of Cannabinoids during Infectious Disease. Neuroimmunomodulation. 2017;24(4-5):183-199; Turcotte C, et al. The CB 2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016;73(23):4449-4470; each of which is incorporated herein in its entirety.
  • the invention provides a method for image-guided surgery (or visually-guided surgery), the method comprising administering a compound according to Formula I to a subject in need thereof prior to surgery and/or during surgery, visualizing the compound, and performing said surgery.
  • Example 1 A Light-activata ble Cannabinoid Prodrug for Combined and Target-specific Photodynamic and Cannabinoid Therapy
  • Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, a far-red light activatable cannabinoid prodrug was developed, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy.
  • This prodrug consists of a phthalocyanine photosensitizer, reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type 2 cannabinoid receptor (CB2R) overexpressed in various types of cancers.
  • ROS reactive oxygen species
  • Photodynamic therapy is an attractive treatment strategy that is minimally invasive with little to no systemic toxicity [1, 2].
  • PDT utilizes photosensitizers (PS) to harvest the power of light and transform it into reactive oxygen species (ROS), a powerful cancer- killing grenade. The reaction is highly localized and the ROS are short-lived, limiting the effect of PDT to the irradiated area only.
  • ROS reactive oxygen species
  • a major drawback of common PSs is their lack of specific uptake.
  • PDT toxicity is limited in the region exposed to light irradiation only, normal cells in the same region still suffer from unnecessary PDT damage.
  • This limitation can be overcome by adding targeting ligand to the PS design.
  • PDT benefits from two advantages: (1) Specific targeting can lead to significantly higher uptake in malignant cells, which leads to more efficient treatment outcome with less damage to innocent cells and (2) lower dose of PSs would be needed for similar therapeutic efficacy, which further lowers side effects of the treatment.
  • PDT agents were developed that target type-2 cannabinoid receptor (CB2R) [4, 5] or translocator protein [6, 7] with anti-cancer therapy outcome in murine tumor models.
  • a new advance of PDT agent design is to include ROS-cleavable linker for on demand drug release.
  • a heterobifunctional thioketal linker was developed for such a purpose [8].
  • the You laboratory recently reported several prodrugs that can be activated by ROS produced from photosensitizers and encouraging combinatory therapeutic effects have been observed [9-12].
  • a light-activatable paclitaxel prodrug for combined PDT and chemotherapy was synthesized [13].
  • this light-activatable paclitaxel prodrug showed improved therapeutic outcome in ovarian cancer cells.
  • this prodrug has aggregation issues in aqueous solution and thus lacks proper targeting functionality.
  • PEGylated folic acid molecules with different sizes of polyethylene glycol (PEG) was attached to the light- activatable paclitaxel prodrug for improved water solubility and targeted delivery [14].
  • PEG polyethylene glycol
  • these targeted prodrugs still suffer from aggregation issues and the structures involve many components, including a phthalocyanine PS, folic acid, PEG, ROS-cleavable linker and paclitaxel. It is more desirable to develop a water soluble, targeted and light activatable prodrug to target tumors with less side effects.
  • a light-activatable cannabinoid Prodrug (IR700DX-TK-mbc94) was synthesized for combined and target-specific PDT and cannabinoid therapy.
  • This prodrug consists of only three components, a highly hydrophilic phthalocyanine photosensitizer, ROS- sensitive thioketal linker, and cannabinoid.
  • Cannabinoids have attracted great attention as promising antitumor drugs as they can produce ROS, inhibit pro-metastatic Idl gene expression and upregulate autophagy-mediated cell death [15].
  • the cannabinoid molecule chosen here targets CB 2 R overexpressed in various types of cancers, such as glioma, lymphoma, skin, prostate, lung and breast cancer [16, 17].
  • the photosensitizer produces cytotoxic ROS, which simultaneously cleaves the ROS-sensitive linker and subsequently releases cannabinoid drug. Therefore, this prodrug offers targeted and on-demand combinatory PDT and cannabinoid therapy. It was found that treatment with IR700DX -TK-mbc94 caused remarkably improved therapeutic outcome as compared to non-activatable IR700DX-mbc94.
  • Coupling patterns are abbreviated as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), dd (doublet of doublets), ddd (doublet of doublet of doublets) and m (multiplet).
  • Electrospray mass spectra were recorded on SYNAPT G2S TOF-MS mass spectrometer (Waters, Milford, MA) in positive ion mode. 7-Diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) was obtained from Fischer Scientific (Pittsburgh, PA).
  • IR700DX-TK-mbc94 (3).
  • IR700DX-NHS (4 mg, 2 pmol) and 2b (9.8 mg, 12 pmol) were dissolved in DMSO (1 mL). The resulting mixture was stirred under Ar atmosphere and dark condition at room temperature for 2 d. Water (15 mL) was added before the mixture was lyophilized to give a green paste. The solid residue was washed with ethyl acetate (5.0 mL x 3) and redissolved in methanol. The methanol solution was evaporated to dryness and dried under vacuum to yield compound 3 as a green powder (2.2 mg, 41%).
  • binding affinities of IR700DX-TK-mbc94, IR700DX-mbc94 and mbc94-SH to human CB 2 receptor were determined using established radioligand displacement assays [19, 20J. Briefly, binding studies were carried out using 50 pL of 3 nM [ 3 H]CP-55940 with 100 pL of 5 pg human CB 2 membrane protein (PerkinElmer Life Sciences), 30 pL of binding buffer (50 mM Tris-HCl, 2.5 mM EGTA, 5 mM MgCh, and 0.5 mg/mL fatty acid free bovine serum albumin, and 20 pL of substrate at various concentrations.
  • a mixture of tested compound (5 mM of IR700DX-TK-mbc94 or IR700DX-mbc94, or 1 mM of disulfide 4 or thiol 5) and 100 mM of CPM in PBS buffer were added to 96 well plate.
  • the light irradiated groups was irradiated with LED light (L690- 66-60, Marubeni America Co., New York, NY) at wavelengths of 670-710 nm (peak at 690 nm) and a power density of 30 mW/cm 2 for 30 min (54 J/cm 2 ).
  • the control groups were kept under ambient light for 30 min. Tire results were obtained using fluorescence plate reader with an excitation wavelength of 384 nm and emission wavelength of 470 nm to quantify the amount of activated CPM.
  • a mixture of tested compound (5 mM of IR700DX-TK-mbc94, IR700DX-mbc94 or IR700DX) and 100 mM of CPM in PBS buffer was added to 96 well plate.
  • the light irradiated groups were irradiated with LED light at wavelengths of 670-710 nm and a power density of 30 mW/cm 2 as measured with an optical power meter (PM100, Thorlabs) for 5 min interval up to 30 min total irradiation time.
  • the results were obtained using fluorescence plate reader with an excitation wavelength of 384 nm and emission wavelength of 470 nm to quantify the amount of activated CPM.
  • ROS production was determined using 10 mM of the free radical indicator, aminophenyl fluorescein (APF, Molecular Probes), or 10 mM of the singlet oxygen OO2) sensor green (SOSG, Molecular Probes).
  • Fluorescence intensities of APF at 500 nm (Excitation at 480 nm) or that of SOSG at 520 nm (Excitation at 500 nm) were recorded using a SynergyTM H4 Hybrid Multi-Mode Microplate Reader.
  • CB2-mid DBT is a transfected mouse delayed brain tumor cell line expressing CB2R at the endogenous levels [21].
  • CB 2 -mid DBT cells were cultured in DMEM containing 10% fetal bovine serum, 4 mM glutamine, 100 units/ml penicillin and 100 pg/ml streptomycin, the same methods as described in previously published work [22]. 2.9. In vitro PDT study
  • CB2-mid DBT cells were grown to confluence in T75 flasks, harvested, seeded into 96- well optical plates and incubated in a water-jacketed incubator for 24 h prior to treatment. Cells were incubated with 0.5 or 1 mM of lR700DX-TK-mbc94 or IR700DX-mbc94 at 37 °C overnight and cell medium was then replaced with ftesh medium to remove unbound PS. Next, cells were irradiated with an LED light with wavelengths of 670-710 nm and a power density of 30 mW/cm 2 for 30 min.
  • Cell viability was determined by CellTiter-Glo Luminescent Cell Viability Assay kit (Promega) right after or 24 hr post PDT treatment.
  • cells were treated with 1 or 2 mM of IR700DX-TK-mbc94 and three light doses were used, including 18 J/cm 2 (10 min of 30 mW/cm 2 irradiation), 36 J/cm 2 (20 min) and 54 J/cm 2 (30 min). Cell viability was measured right after PDT treatment.
  • 2a was prepared by coupling mbc94 and 1 via amide coupling using HBTU. The trifluoroacetamide protection was then removed using base hydrolysis to give 2b. Finally, 2b was mixed with IR700DX-NHS in dimethyl sulfoxide to yield compound IR700DX-TK- mbc94 (3).
  • mbc94-SH was synthesized by attaching 3-(Tritylthio)propionic acid to mbc94 through amide coupling, followed by deprotection of the thiol group in an acidic condition (Scheme 2).
  • IR700DX Upon light irradiation, IR700DX generates ROS, which can cleave the nearby thioketal linker and subsequently produce two thiol fragments and one acetone. Over the 30 min light irradiation period, steady increase of fluorescence was observed from CPM mixed with IR700DX-T K-mbc94 ( Figure 2). Light irradiation of TR700DX-mbc94 and IR700DX caused similarly low level of CPM fluorescence and the vehicle group showed negligible signal, showing that ROS production alone may also lead to CPM fluorescence activation.
  • CPM fluorescence caused by light activation of IR700DX-TK-mbc94 is much higher than the other groups (p ⁇ 0.0001).
  • type I and type P ROS produced from IR700DX-TK-mbc94 and IR700DX-mbc94 were compared ( Figure 3).
  • IR700DX-TK-mbc94 produced almost the same amount of type I (APF indicating free radical, RFU APF: 7731 for IR700DX-TK-mbc94 vs 7760 for IR700DX-mbc94 after 30 min irradiation), and less amount of type II (SOSG indicating singlet oxygen, RFU SOSG: 8901 for IR700DX-TK-mbc94 vs 11412 for IR700DX-mbc94 after 30 min irradiation, 22% less) ROS than IR700DX-mbc94, indicating that ROS production did not contribute to the increased CPM fluorescence in the IR700DX-TK-mbc94 group.
  • cleavable linkers Although dozens of cleavable linkers have been developed, the cleavage is usually controlled only spatially, but not temporally. In addition, these drug delivery systems are typically difficult to develop, involving multi-functional nanosystems or small molecules with many components.
  • a multifunctional prodrug was developed, which allows for targeted combinatory therapy and on demand activation both spatially and temporally. This was achieved by utilizing a unique ROS-activatable heterobifimctional linker, a CBaR-targeted cannabinoid prodrug and a highly hydrophilic photosensitizer with 6 sulfonate groups.
  • IR700DX-TK-mbc94 and IR700DX-mbc94 bind to CB 2 R with a much higher (-20 fold) affinity than mbc94-SH. This is surprising because typically attachment of a large dye molecule to a small targeting ligand compromises the binding, as observed in previous studies [18, 30]. Although the exact binding mechanism is yet to be investigated, it is possible that IR700DX facilitated the interaction by binding to additional sites on CB 2 R. It has been previously reported that phthalocyanine dyes can bind to certain proteins [31].
  • IR700DX-TK-mbc94 and IR700DX-mbc94 share the same photosensitizer and therefore, the amount of ROS produced from each agent is presumed to be the same.
  • the singlet oxygen produced from IR700DX-TK-mbc94 appears to be less that that from IR700DX-mbc94. This is in fact expected because some singlet oxygen produced from IR700DX-TK-mbc94 was consumed to cleave the ROS-activatable thioketal linker and therefore not able to be detected by SOSG.
  • IR700DX-TK-mbc94 Because singlet oxygen is the main phototoxicity source from IR700DX [4], such loss of singlet oxygen would reduce the therapeutic outcome of IR700DX-TK-mbc94 as compared to IR700DX-mbc94. In contrast, it was found that IR700DX-TK-mbc94 produced much higher therapeutic outcome than IR700DX-mbc94, showing that the ROS-activated prodrug, mbc94-SH, greatly contributed to the treatment. interesting, mbc94-SH alone, even with a concentration of 5 mM, did not show significant therapeutic effect, whereas IR700DX-TK-mbc94 treatment with much lower concentrations caused dramatic cell death. The remarkable therapeutic outcome from IR700DX-TK-mbc94 is attributed to the synergism between PDT and cannabinoid therapy.
  • IR700DX-TK-mbc94 far red light-activatable prodrug
  • Bomhop N. Stella, NIR-mbc94, a fluorescent ligand that binds to endogenous CB(2) receptors and is amenable to high-throughput screening, Chem Biol 18(5) (2011) 563-8.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés cannabinoïdes activés par la lumière et des procédés d'utilisation pour une thérapie photodynamique et pour le traitement du cancer, d'une inflammation et d'une infection.
PCT/US2019/025277 2018-04-03 2019-04-02 Composés cannabinoïdes activés par la lumière et leurs procédés d'utilisation WO2019195207A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862651860P 2018-04-03 2018-04-03
US62/651,860 2018-04-03

Publications (1)

Publication Number Publication Date
WO2019195207A1 true WO2019195207A1 (fr) 2019-10-10

Family

ID=68101334

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/025277 WO2019195207A1 (fr) 2018-04-03 2019-04-02 Composés cannabinoïdes activés par la lumière et leurs procédés d'utilisation

Country Status (1)

Country Link
WO (1) WO2019195207A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113264879A (zh) * 2021-05-27 2021-08-17 上海科技大学 一种基于喹诺酮结构的光控配体及其应用
US11746113B2 (en) 2020-03-19 2023-09-05 Alexandros Makriyannis Labelled cannabinergic ligands and related analogs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030129579A1 (en) * 2001-09-04 2003-07-10 Bornhop Darryl J. Multi-use multimodal imaging chelates
US20090105128A1 (en) * 2007-08-28 2009-04-23 Vanderabilt University Cannabinoid receptor targeted agent

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030129579A1 (en) * 2001-09-04 2003-07-10 Bornhop Darryl J. Multi-use multimodal imaging chelates
US20090105128A1 (en) * 2007-08-28 2009-04-23 Vanderabilt University Cannabinoid receptor targeted agent

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JIA ET AL.: "Cannabinoid CB2 Receptor as a New Phototherapy Target for the Inhibition of Tumor Growth", MOLECULAR PHARMACEUTICALS, vol. 11, no. 6, 29 April 2014 (2014-04-29), pages 1919 - 1929, XP055640994, Retrieved from the Internet <URL:https://pubs.acs.org/doi/10.1021/mp5001923> [retrieved on 20190517] *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11746113B2 (en) 2020-03-19 2023-09-05 Alexandros Makriyannis Labelled cannabinergic ligands and related analogs
CN113264879A (zh) * 2021-05-27 2021-08-17 上海科技大学 一种基于喹诺酮结构的光控配体及其应用
CN113264879B (zh) * 2021-05-27 2023-02-10 上海科技大学 一种基于喹诺酮结构的光控配体及其应用

Similar Documents

Publication Publication Date Title
EP3362443B1 (fr) Composés utiles en tant qu&#39;immunomodulateurs
JP6777626B2 (ja) セリネクソールの多形体
EP3759093A1 (fr) Composés utiles en tant qu&#39;immunomodulateurs
WO2018183171A1 (fr) Dérivés d&#39;isoquinoléine substitués utilisés en tant qu&#39;immunomutateurs
EP2968278A1 (fr) Procédés de promotion de la cicatrisation d&#39;une plaie à l&#39;aide d&#39;inhibiteurs de crm1
EP3907226A2 (fr) Composé dimère de pyrrolobenzodiazépine présentant une sécurité améliorée et son utilisation
US10759803B2 (en) Asparagine endopeptidase (AEP) inhibitors for managing cancer and compositions related thereto
US20180235948A1 (en) (s,e)-3-(6-aminopyridin-3-yl)-n-((5-(4-(3-fluoro-3-methylpyrrolidine-1-carbonyl)phenyl)-7-(4-fluorophenyl)benzofuran-2-yl)methyl)acrylamide for the treatment of cancer
WO2019195207A1 (fr) Composés cannabinoïdes activés par la lumière et leurs procédés d&#39;utilisation
KR20210148157A (ko) Hsp90-결합 접합체 및 이의 제형
WO2021150792A1 (fr) Nouveaux composés et composition pour la thérapie ciblée de cancers associés au rein
WO2017117406A1 (fr) Benzofuranyles et benzoxazolyles substitués et leurs utilisations
CN101605763A (zh) 防辐射化合物及相关方法
WO2013163321A1 (fr) Lieurs labiles à l&#39;oxygène singulet et procédés de production et d&#39;utilisation associés
JP2021014409A (ja) タンパク質結合性薬物
JP2019523783A (ja) がんの治療に有用なポルフィリン化合物及び組成物
EP4326260A1 (fr) Inhibiteurs de pi3k, nanoformulations et leurs utilisations
WO2018101434A1 (fr) Dérivé de chlorine e6 glycosylé ou son sel pharmaceutiquement acceptable, composition pharmaceutique, procédé de destruction de cible, et procédé de production d&#39;un dérivé de chlorine e6 glycosylé ou d&#39;un sel pharmaceutiquement acceptable de celui-ci
AU2004298907B2 (en) Use of a compound having two gold (I) atoms each covalently bonded to a carbon atom in a covalent link connecting the two gold (I) atoms for the treatment of cancer
CN113710323A (zh) 偶联物及癌治疗剂
KR20200052350A (ko) 다발성 골수종의 새로운 치료
US20210128592A1 (en) REVERSING THE UNDESIRABLE pH-PROFILE OF DOXORUBICIN VIA ACTIVATION OF A DISUBSTITUTED MALEAMIC ACID PRODRUG AT TUMOR ACIDITY
US9592226B2 (en) Solenopsin and derivatives, therapeutic compositions; and methods related thereto
AU2017303280A1 (en) Boron-containing compound
WO2016147185A1 (fr) Dérivés d&#39;adénosine thiophosphate et leurs utilisations

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19781171

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19781171

Country of ref document: EP

Kind code of ref document: A1