CA3100633A1 - Biodegradable nanocarrier(s) (bpmos) for neutron capture therapy and methods thereof - Google Patents
Biodegradable nanocarrier(s) (bpmos) for neutron capture therapy and methods thereof Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
- A61K41/009—Neutron capture therapy, e.g. using uranium or non-boron material
- A61K41/0095—Boron neutron capture therapy, i.e. BNCT, e.g. using boronated porphyrins
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- 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
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
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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
- A61K9/0012—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
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
Abstract
Biodegradable Periodic Mesoporous Organosilica (BPMO) nanomaterials and methods of making BPMOs loaded with Neutron Capture Agents are disclosed herein. Consequently, the BPMOs loaded with Neutron Capture Agents provide a method of treating cancer, immunological disorders and other disease by utilizing a Neutron Capture Therapy modality.
Description
Biodegradable Nanocarrier(s) (BPM0s) for Neutron Capture Therapy and Methods Thereof CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to United States Provisional Patent Application number 62/763,156 filed 01-June-2018, the contents of which are fully incorporated by reference herein.
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH
Not applicable.
FIELD OF THE INVENTION
The invention described herein relates to the field of nanotechnology and cancer therapy.
Specifically, the invention relates to biodegradable mesoporous silica nanoparticles used as a vehicle for neutron capture therapy in humans. The invention further relates to the treatment of cancers and other immunological disorders and diseases.
BACKGROUND OF THE INVENTION
Cancer is the second leading cause of human death next to coronary disease.
Worldwide, millions of people die from cancer every year. In the United States alone, as reported by the American Cancer Society, cancer causes the death of well over a half-million people annually, with over 1.2 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise.
Worldwide, several cancers stand out as the leading killers. In particular, carcinomas of the lung, prostate, breast, colon, pancreas, ovary, and bladder represent the primary causes of cancer death. These and virtually all other carcinomas share a common lethal feature.
With very few exceptions, metastatic disease from a carcinoma is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered. Many cancer patients experience strong anxieties driven by the awareness of the potential for recurrence or treatment failure. Many cancer patients experience physical debilitations following treatment. Furthermore, many cancer patients experience a recurrence.
Although cancer therapy has improved over the past decades and survival rates increased, the heterogeneity of cancer still demands new therapeutic strategies utilizing a pluriality of treatment modalities. This is especially true in treating solid tumors at anatomical crucial sites (e.g., glioblastoma, head and neck squamous cell carcinoma, and lung adenocarcinoma) which are sometimes limited to Date Recue/Date Received 2020-11-25 standard radiotherapy and/or chemotherapy. Nonetheless, detrimental effects of these therapies are chemo- and radioresistance, which promote locoregional recurrences, distant metastases and second primary tumors, in addition to severe side-effects that reduce the patients' quality of life.
Therefore, it is of utmost importance to develop new therapeutic strategies to overcome resistances and to reduce side-effects by targeted therapy. One possibility is to embrace the enhanced permeability and retention (EPR) effect of solid tumors. Due to a leaky vasculature and the lack of lymphatic drainage small structures such as nanoparticles can accumulate in the tumor. Therefore, exploiting nanoparticles as drug delivery vehicles is a promising approach.
Additionally, Neutron Capture Therapy (NCT) is a promising form of radiation therapy. Even though the conceptual techniques of NCT and specifically Boron Neutron Capture Thereapy ("BNCT") is well known, the technological limitations associated with this type of treatment have slowed progress. However, given the technological improvements in both (i) the infusion or delivery of a capture compound, which preferably concentrates in the tumor, and (ii) the irradiation of the tumor site by neutrons, there has been a resurgence in NCT treatment methods.
From the aforementioned, it will be readily apparent to those skilled in the art that a new treatment paradigm is needed in the treatment of cancers and other immunological diseases. By using modern nanocarriers and optimized NCT modalities, a new disease treatment can be achieved with the overall goal of more effective treatment, reduced side effects, and lower production costs.
Given the current deficiencies associated with NCT, it is an object of the present invention to provide new and improved methods of treating cancer(s), immunological disorders, and other diseases utilizing nanocarriers and NCT.
SUMMARY OF THE INVENTION
The invention provides for nanomaterials fabricated for use as a drug delivery modality to treat human diseases such as cancer, immunological disorders, including but not limited to rheumatoid arthritis, ankylosing spondylitis, and other cellular diseases, including but not limited to Alzheimer's disease. In certain embodiments, the nanomaterials comprise mesoporous silica nanoparticles ("MSN"
or "MSNs", as the case may be). In a further embodiment, an MSN of the invention comprises a bodegradable bond within the framework of the MSN. Generally speaking, and for the purposes of this invention, biodegradable MSNs tuned for biodegradation by incorporating disulfide, tetrasulfide bonds, or protease sensitive bonds are hereinafter referred as Biodegradable Periodic Mesoporous Organosilica ("BPMO" or "BPM0s", as the case may be).
In one embodiment, the surface of a BPM0 is modified with phosphonate.
In another embodiment, a MSN or BPM0 of the invention is loaded with a Neutron Capture Agent.
This application claims priority to United States Provisional Patent Application number 62/763,156 filed 01-June-2018, the contents of which are fully incorporated by reference herein.
STATEMENT OF RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH
Not applicable.
FIELD OF THE INVENTION
The invention described herein relates to the field of nanotechnology and cancer therapy.
Specifically, the invention relates to biodegradable mesoporous silica nanoparticles used as a vehicle for neutron capture therapy in humans. The invention further relates to the treatment of cancers and other immunological disorders and diseases.
BACKGROUND OF THE INVENTION
Cancer is the second leading cause of human death next to coronary disease.
Worldwide, millions of people die from cancer every year. In the United States alone, as reported by the American Cancer Society, cancer causes the death of well over a half-million people annually, with over 1.2 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise.
Worldwide, several cancers stand out as the leading killers. In particular, carcinomas of the lung, prostate, breast, colon, pancreas, ovary, and bladder represent the primary causes of cancer death. These and virtually all other carcinomas share a common lethal feature.
With very few exceptions, metastatic disease from a carcinoma is fatal. Moreover, even for those cancer patients who initially survive their primary cancers, common experience has shown that their lives are dramatically altered. Many cancer patients experience strong anxieties driven by the awareness of the potential for recurrence or treatment failure. Many cancer patients experience physical debilitations following treatment. Furthermore, many cancer patients experience a recurrence.
Although cancer therapy has improved over the past decades and survival rates increased, the heterogeneity of cancer still demands new therapeutic strategies utilizing a pluriality of treatment modalities. This is especially true in treating solid tumors at anatomical crucial sites (e.g., glioblastoma, head and neck squamous cell carcinoma, and lung adenocarcinoma) which are sometimes limited to Date Recue/Date Received 2020-11-25 standard radiotherapy and/or chemotherapy. Nonetheless, detrimental effects of these therapies are chemo- and radioresistance, which promote locoregional recurrences, distant metastases and second primary tumors, in addition to severe side-effects that reduce the patients' quality of life.
Therefore, it is of utmost importance to develop new therapeutic strategies to overcome resistances and to reduce side-effects by targeted therapy. One possibility is to embrace the enhanced permeability and retention (EPR) effect of solid tumors. Due to a leaky vasculature and the lack of lymphatic drainage small structures such as nanoparticles can accumulate in the tumor. Therefore, exploiting nanoparticles as drug delivery vehicles is a promising approach.
Additionally, Neutron Capture Therapy (NCT) is a promising form of radiation therapy. Even though the conceptual techniques of NCT and specifically Boron Neutron Capture Thereapy ("BNCT") is well known, the technological limitations associated with this type of treatment have slowed progress. However, given the technological improvements in both (i) the infusion or delivery of a capture compound, which preferably concentrates in the tumor, and (ii) the irradiation of the tumor site by neutrons, there has been a resurgence in NCT treatment methods.
From the aforementioned, it will be readily apparent to those skilled in the art that a new treatment paradigm is needed in the treatment of cancers and other immunological diseases. By using modern nanocarriers and optimized NCT modalities, a new disease treatment can be achieved with the overall goal of more effective treatment, reduced side effects, and lower production costs.
Given the current deficiencies associated with NCT, it is an object of the present invention to provide new and improved methods of treating cancer(s), immunological disorders, and other diseases utilizing nanocarriers and NCT.
SUMMARY OF THE INVENTION
The invention provides for nanomaterials fabricated for use as a drug delivery modality to treat human diseases such as cancer, immunological disorders, including but not limited to rheumatoid arthritis, ankylosing spondylitis, and other cellular diseases, including but not limited to Alzheimer's disease. In certain embodiments, the nanomaterials comprise mesoporous silica nanoparticles ("MSN"
or "MSNs", as the case may be). In a further embodiment, an MSN of the invention comprises a bodegradable bond within the framework of the MSN. Generally speaking, and for the purposes of this invention, biodegradable MSNs tuned for biodegradation by incorporating disulfide, tetrasulfide bonds, or protease sensitive bonds are hereinafter referred as Biodegradable Periodic Mesoporous Organosilica ("BPMO" or "BPM0s", as the case may be).
In one embodiment, the surface of a BPM0 is modified with phosphonate.
In another embodiment, a MSN or BPM0 of the invention is loaded with a Neutron Capture Agent.
2 Date Recue/Date Received 2020-11-25 In a further embodiment, the Neutron Capture Agent comprises the Boron isotope 10B.
In a further embodiment, the Neutron Capture Agent comprises the Lithium isotope 6Li.
In a further embodiment, the Neutron Capture Agent comprises the He isotope 3He.
In a further embodiment, the Neutron Capture Agent comprises the Cadmium isotope 113Cd.
In a further embodiment, the Neutron Capture Agent comprises the Samarium isotope 1465m.
In a further embodiment, the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
In a further embodiment, the Neutron Capture Agent comprises an istope of Au (Gold).
In a further embodiment, the Neutron Capture Agent comprises an isotope with a favorable neutron capture cross section.
In a further embodiment, the invention comprises methods of concentrating neutrons in a cell comprising (i) loading a MSN and/or BPM0 with a Neutron Capture Agent; (ii) administrering the loaded MSN or BPM0 to a patient, and (iii) irradiating the cell with neutrons.
In another embodiment, the present disclosure teaches methods of fabricating MSN and/or BPM0s with Neutron Capture Agents.
In another embodiment, the present disclosure teaches methods of treating cancer(s), immunological disorders and other diseases in humans.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Synthesis of BPM0 loaded with 10BPA and surface modified with phosphonate.
Figure 2. Characterization of BPM0 nanoparticles. Figure 2(1)(a) shows the BPM0 of the invention analyzed by SEM. Figure 2(1)(b) shows the BPM0 of the invention analyzed by TEM. Figure 2(2) shows degradation analysis performed on the BPM0 using TEM.
Figure 3. A scheme to evaluate tumor targeting of BPA-loaded phosphonate modified BPM0.
Figure 4. Tumor targeting of BPA-loaded phosphonate modified BPM0.
Figure 5. Tumor targeting of BPA-loaded phosphonate modified BPM0.
Figure 6. Flowchart of Experimental Protocol Using BNCT with BPA-loaded BPM0 in Chicken Egg Tumor Model.
DETAILED DESCRIPTION OF THE INVENTION
Outline of Sections 1) Definitions II.) Mesoporous Silica Nanoparticles (MSN) & Periodic Mesoporous Organosilica (PMO) III.) Neutron Capture Agents
In a further embodiment, the Neutron Capture Agent comprises the Lithium isotope 6Li.
In a further embodiment, the Neutron Capture Agent comprises the He isotope 3He.
In a further embodiment, the Neutron Capture Agent comprises the Cadmium isotope 113Cd.
In a further embodiment, the Neutron Capture Agent comprises the Samarium isotope 1465m.
In a further embodiment, the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
In a further embodiment, the Neutron Capture Agent comprises an istope of Au (Gold).
In a further embodiment, the Neutron Capture Agent comprises an isotope with a favorable neutron capture cross section.
In a further embodiment, the invention comprises methods of concentrating neutrons in a cell comprising (i) loading a MSN and/or BPM0 with a Neutron Capture Agent; (ii) administrering the loaded MSN or BPM0 to a patient, and (iii) irradiating the cell with neutrons.
In another embodiment, the present disclosure teaches methods of fabricating MSN and/or BPM0s with Neutron Capture Agents.
In another embodiment, the present disclosure teaches methods of treating cancer(s), immunological disorders and other diseases in humans.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1. Synthesis of BPM0 loaded with 10BPA and surface modified with phosphonate.
Figure 2. Characterization of BPM0 nanoparticles. Figure 2(1)(a) shows the BPM0 of the invention analyzed by SEM. Figure 2(1)(b) shows the BPM0 of the invention analyzed by TEM. Figure 2(2) shows degradation analysis performed on the BPM0 using TEM.
Figure 3. A scheme to evaluate tumor targeting of BPA-loaded phosphonate modified BPM0.
Figure 4. Tumor targeting of BPA-loaded phosphonate modified BPM0.
Figure 5. Tumor targeting of BPA-loaded phosphonate modified BPM0.
Figure 6. Flowchart of Experimental Protocol Using BNCT with BPA-loaded BPM0 in Chicken Egg Tumor Model.
DETAILED DESCRIPTION OF THE INVENTION
Outline of Sections 1) Definitions II.) Mesoporous Silica Nanoparticles (MSN) & Periodic Mesoporous Organosilica (PMO) III.) Neutron Capture Agents
3 Date Recue/Date Received 2020-11-25 IV.) PM0s loaded with Neutron Capture Agents V.) Boron Neutron Capture Therapy Vi) Methods of Delivering Neutron Capture Agents to a Cell VII.) Methods of Treating Cancer(s) and Other Immunological Disorder(s) VIII.) KITS/Articles of Manufacture I.) Definitions:
Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains unless the context clearly indicates otherwise.
In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.
When a trade name is used herein, reference to the trade name also refers to the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.
The terms "advanced cancer", "locally advanced cance, "advanced disease" and "locally advanced disease" mean cancers that have extended through the relevant tissue capsule, and are meant to include stage C disease under the American Urological Association (AUA) system, stage Cl-C2 disease under the Whitmore-Jewett system, and stage T3-T4 and N+ disease under the TNM
(tumor, node, metastasis) system. In general, surgery is not recommended for patients with locally advanced disease, and these patients have substantially less favorable outcomes compared to patients having clinically localized (organ-confined) cancer.
The terms "inhibit" or "inhibition of as used herein means to reduce by a measurable amount, or to prevent entirely.
The term "mammal" refers to any organism classified as a mammal, including mice, rats, rabbits, dogs, cats, cows, horses and humans. In one embodiment of the invention, the mammal is a mouse. In another embodiment of the invention, the mammal is a human.
The terms "metastatic cancer" and "metastatic disease" mean cancers that have spread to regional lymph nodes or to distant sites, and are meant to include stage D
disease under the AUA
system and stage TxNxM+ under the TNM system.
"molecular recognition" means a chemical event in which a host molecule is able to form a complex with a second molecule (i.e. the guest). This process occurs through non-covalent chemical bonds, including but not limited to, hydrogen bonding, hydrophobic interactions, ionic interaction.
Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this invention pertains unless the context clearly indicates otherwise.
In some cases, terms with commonly understood meanings are defined herein for clarity and/or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.
When a trade name is used herein, reference to the trade name also refers to the product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.
The terms "advanced cancer", "locally advanced cance, "advanced disease" and "locally advanced disease" mean cancers that have extended through the relevant tissue capsule, and are meant to include stage C disease under the American Urological Association (AUA) system, stage Cl-C2 disease under the Whitmore-Jewett system, and stage T3-T4 and N+ disease under the TNM
(tumor, node, metastasis) system. In general, surgery is not recommended for patients with locally advanced disease, and these patients have substantially less favorable outcomes compared to patients having clinically localized (organ-confined) cancer.
The terms "inhibit" or "inhibition of as used herein means to reduce by a measurable amount, or to prevent entirely.
The term "mammal" refers to any organism classified as a mammal, including mice, rats, rabbits, dogs, cats, cows, horses and humans. In one embodiment of the invention, the mammal is a mouse. In another embodiment of the invention, the mammal is a human.
The terms "metastatic cancer" and "metastatic disease" mean cancers that have spread to regional lymph nodes or to distant sites, and are meant to include stage D
disease under the AUA
system and stage TxNxM+ under the TNM system.
"molecular recognition" means a chemical event in which a host molecule is able to form a complex with a second molecule (i.e. the guest). This process occurs through non-covalent chemical bonds, including but not limited to, hydrogen bonding, hydrophobic interactions, ionic interaction.
4 Date Recue/Date Received 2020-11-25 "Pharmaceutically acceptable" refers to a non-toxic, inert, and/or composition that is physiologically compatible with humans or other mammals.
"Nanomaterial" means a material in any dimensional form (zero, one, two, three) and domain size in the range 40-400 nanometers.
"Nanostructure" means a structure having at least one dimension that is less than 500 nanometers. Examples, include but are not limited to nanocrystals, nanocomposites, nanograins, nanotubes, nanoceramics, and nanopowders.
"Nanofiller" (a.k.a. nanostructured filler) means a structure or particle intimately mixed with a matrix to form a nanostructured composite. At least one of the nanostructured filler and the nanostructured composite has a desired material property which differs by at least 20% from the same material property for a micron-scale filler or a micron-scale composite, respectively. The desired material property is selected from the group consisting of refractive index, transparency to light, reflection characteristics, resistivity, permittivity, permeability, coercivity, B-H product, magnetic hysteresis, breakdown voltage, skin depth, curie temperature, dissipation factor, work function, band gap, electromagnetic shielding effectiveness, radiation hardness, chemical reactivity, thermal conductivity, temperature coefficient of an electrical property, voltage coefficient of an electrical property, thermal shock resistance, biocompatibility and wear rate. The nanostructured filler may comprise one or more elements selected from the s, p, d, and f groups of the periodic table, or it may comprise a compound of one or more such elements with one or more suitable anions, such as aluminum, antimony, boron, bromine, carbon, chlorine, fluorine, germanium, hydrogen, indium, iodine, nickel, nitrogen, oxygen, phosphorus, selenium, silicon, sulfur, or tellurium.
The matrix may be a polymer (e.g., poly(methyl methacrylate), poly(vinyl alcohol), polycarbonate, polyalkene, or polyaryl), a ceramic (e.g., zinc oxide, indium-tin oxide, hafnium carbide, or ferrite), or a metal (e.g., copper, tin, zinc, or iron). Loadings of the nanofiller may be as high as 95%, although loadings of 80% or less are preferred. The invention also comprises devices which incorporate the nanofiller (e.g., electrical, magnetic, optical, biomedical, and electrochemical devices).
The term "neutron capture agent" means a stable non-reactive chemical isotope which, when activated by neutrons produces alpha-rays and gamma-rays.
The term "neutron capture therapy" means a noninvasive therapeutic modality for treating locally invasive malignant tumors such as primary brain tumors and recurrent head and neck cancer and other immunological disorders and disease by irradiating a neutron capture agent with neutrons.
As used herein "to treat" or "therapeutic" and grammatically related terms, refer to any improvement of any consequence of disease, such as prolonged survival, less morbidity, and/or a lessening of side effects which are the byproducts of an alternative therapeutic modality; as is readily Date Recue/Date Received 2020-11-25 appreciated in the art, full eradication of disease is a preferred but albeit not a requirement for a treatment act.
IL) Mesoporous Silica Nanoparticles (MSN) & Biodegradable Periodic Mesoporous Organosilica (BPMO) Mesoporous silica nanoparticles (MSNs) have emerged as a powerful drug delivery vehicle.
Generally, these silica particles have a diameter ranging from 40 to 400 nm and contain thousands of pores where anticancer drugs, among other things, can be stored. Various cellular and animal studies have been reported that point to the efficacy of MSNs to deliver anticancer drugs. See, for example, Wang, Y. et. al., Mesoporous silica nanoparticles in drug delivery and biomedical applications.
Nanomedicine. 11, 313-327 (2015). Because of the relative stability of these nanomaterials, various chemical modifications can be applied to these nanoparticles. A surface charge property can be altered to prevent the aggregation of particles in biological media and to achieve prolonged circulation.
Furthermore, various nanomachines can be engineered on the particle surface to confer the ability to release anticancer drug upon stimuli including light and magnetic field exposure.
Artisans skilled in the art have recently developed a new generation of mesoporous nanoparticles called biodegradable PM0 (Periodic Mesoporous Organosilica) nanoparticles ("BPMO") which are tuned for biodegradation by incorporating disulfide, tetrasulfide bonds, or protease sensitive bonds leading to excellent candidates for nanomedicine applications. See, for example, Croissant, J. et.
al., Biodegradable oxamide-phenylene-based mesoporous organosilica nanoparticles with unprecedented drug payloads for delivery in cells. Chem. Eur. J. 22, 14806-14811 (2016). These nanoparticles retain the advantageous features of MSNs described above and, in addition, they possess enhanced degradability. The BPM0s exhibit efficient loading capacity with Neutron Capture Agents, such as Boron, as well as other anticancer drugs, which are known in the art, and the Neutron Capture Agents can be delivered into human cancer cells.
A recently developed BPM0s contain biodegradable bonds within the framework of mesoporous silica network and thus are degradable by conditions inside the cell, such as reducing environment. For this, two (2) types of BPM0 nanoparticles containing a disulfide bond or tetrasulfide bond have been developed. In a preferred embodiment, a BPM0 of the invention is synthesized using the sol-gel synthesis method with precursors containing disulfide or tetrasulfide bond. The use of these special precursors for synthesis results in the incorporation of these biodegradable bonds into the framework of nanoparticles.
During the synthesis, surfactant CTAB (cetyltrimethylammonium bromide) was included to produce a porous structure. Generally speaking, a preferred BPM0 of the invention was synthesized by Date Recue/Date Received 2020-11-25 mixing bis(triethoxysilylpropyl)disulfide with bis(triethoxysilyl)ethylene (50-50 ratio). The resulting BPM0s have a diameter of 100-300 nm and contain pores with 2-3.5 nm diameter.
In yet another preferred embodiment, a BPM0 of the disclosure was synthesized by mixing 1,2-bis(triethoxysilyl)ethane with CTAB and NaOH, stirred vigorously and then the mixture was heated to 80 C. Next, the solution was added dropwise into the flask and bis[3(triethoxysily1) propyl] tetrasulfide was added immediately thereafter. After condensation at 80 C for 2.0 hours, BPM0 was collected by centrifugation and washed twice with ethanol. To remove CTAB from the pores, the particles was refluxed overnight in ethanolic acid of ammonium nitrate. The particles were purified by washing with ethanol (3 times) and dried completely.
In yet another preferred embodiment, a BPM0 of the present disclosure was functionalized with GOPTS (3-glycidyloxypropyl trimethoxysilane) by a post-synthesis grafting method. To open the epoxy ring of GOPTS, the functionalized BPM0 was suspended in water and heated at 70 C for two days.
This step produces diol-modified BPM0. Further modification to add phosphonate on the surface was accomplished using 3(trihydroxylsily1) propyl methyl phosphonate.10BPA (4 borono L-phenylalanine) was added to the nanoparticles so thatloBPA will be chelated onto the diol modified BPM0.
In another preferred embodiment, a BPM0 which has been surface modified with phosphonate is loaded with a Neutron Capture Agent, whereby the Neutron Capture Agent is encapsulated within the BPM0. In a further embodiment, the Neutron Capture Agent is chemically bonded to the surface of a BPM0. Exemplary embodiments of a Neutron Capture Agent of the invention is set forth herein.
One of ordinary skill in the art will appreciate and be enabled to make variations and modifications to the disclosed embodiment without altering the function and purpose of the invention disclosed herein. Such variations and modifications are intended within the scope of the present disclosure.
III.) Neutron Capture Agent(s) Another aspect of the present invention relates to improved Neutron Capture Agents. Generally speaking, Neutron Capture Agents success is predicated on selective localization in tumor cells and adequate flux of neutrons of appropriate energy to the tumor. A current drawback with neutron capture therapy is the inability of neutron capture agents to adequately concentrate in the tumor, while at the same time minimizing concentration in normal cells. As will be appreciated by one of ordinary skill in the art, several neutron capture agents of the invention posess properties which will be beneficial for the instant disclosure. For example, a high cross section of thermal neutron interactions will cause high ionization capability whereby cells enriched by neutron capture agents will be killed and the normal cells will be damaged much less. However, to date, the dimishment of damaging healthy normal cells has not been achieved. It is an object of the present invention to remedy this deficiency.
Date Recue/Date Received 2020-11-25 In a further embodiment, the Neutron Capture Agent comprises the Boron isotope 10B.
In a further embodiment, the Neutron Capture Agent comprises the Lithium isotope 6Li.
In a further embodiment, the Neutron Capture Agent comprises the He isotope 3He.
In a further embodiment, the Neutron Capture Agent comprises the Cadmium isotope 113Cd.
In a further embodiment, the Neutron Capture Agent comprises the Samarium isotope 1495m.
In a further embodiment, the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
In a further embodiment, the Neutron Capture Agent comprises an istope of Au (Gold).
In a further embodiment, the Neutron Capture Agent comprises an isotope with a favorable neutron capture cross section.
One of ordinary skill in the art will appreciate and be enabled to make variations and modifications to the disclosed embodiment without altering the function and purpose of the invention disclosed herein. Such variations and modifications are intended within the scope of the present disclosure.
IV.) BPM0s loaded with Neutron Capture Agents One apect of the present invention relates to BPM0s loaded with Neutron Capture Agents. As previously discussed, BPM0s of the disclosure have a high loading capacity at the appropriate pH. In a preferred embodiment, the pH is around 8.5. Furthermore, the once loaded, the Neutron Capture Agent is between 20% - 60% to total weight of BPM0. In a preferred embodiment, the Neutron Capture Agent constitutes between 30% - 50% of the total weight of the loaded BPM0. In a further embodiment, the Neutron Capture Agent comprises the Boron isotope 10B. In a further embodiment, the Neutron Capture Agent comprises 10BPA. In a further embodiment, the Neutron Capture Agent comprises the Lithium isotope 6Li. In a further embodiment, the Neutron Capture Agent comprises the He isotope 3He. In a further embodiment, the Neutron Capture Agent comprises the Cadmium isotope 113Cd. In a further embodiment, the Neutron Capture Agent comprises the Samarium isotope 1495m. In a further embodiment, the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
It will be appreciated by one or ordinary skill in the art that a Neutron Capture Agent may be fabricated to a PM0 by various means known in the art, such as encapsulation, or chemically bonded to the surface of the BPM0, and/or conjugated to BPM0s using methods known in the art. Such variations and modifications are intended within the scope of the present disclosure.
V.) Boron Neutron Capture Therapy using BPM0s loaded with 10B
One apect of the present disclosure is the use of BPM0s loaded with 10B as a modality for Boron Neutron Capture Therapy ("BNCT"). Briefly, BNCT is a binary treatment modality in which neither component alone is legal or highly toxic. The two components comprise (i) the infusion or Date Recue/Date Received 2020-11-25 delivery of a capture compound, which preferentially is concentrated in the tumor, and (ii) the irradiation of the tumor site by neutrons. Given the large cross-section of thermal neutron interactions with 10B, there is consequently a high probability of a splitting of Boron nucleus into He and Li. Given that the ionization capability of He and Li is high, and the runs are short, then the cells preferably enriched by Boron are killed and the healthy cells are damaged much less. Given this, the advantage of BNCT is the destruction of tumor cells without a highly traumatic surgical procedure.
However, as will be understood by one of skill in the art, success is predicated high concentration and selective localization of 10B in tumor cells.
In one embodiment, 10B is loaded to a BPM0 of the invention and is localized into a tumor cell.
The BPM0s containing 10B are concentrated into the tumor and the tumor is irradiated using epithermal neutrons. The tumor cells are destroyed.
VI. Methods of Delivering Neutron Capture Agents to a Cell As will be appreciated by one of ordinary skill in the art, the ability to efficiently deliver an improved Neutron Capture Agent of the present disclosure to a cell is an advantage of the present invention.
It is shown that the nanoparticle formulation (BPM0s of the present disclosure) enables a higher amount of Neutron Capture Agents to be administered safely to mammals.
Briefly, to investigate tumor delivery of Neutron Capture Agents, it is shown by fluorescence of Neutron Capture Agents in the tumor from one (1) to five (5) days after injection of Neutron Capture Agents loaded PM0 nanoparticles.
The fluorescence is observed in the tumor. To examine whether the fluorescence is observed predominantly in the tumor, various organs are removed, processed and examined by fluorescence microscopy or other detection methods known in the art. It is shown that fluorescence is observed predominantly in the tumor whereas little fluorescence is observed in various organs. Control tumor represents tumor sample obtained from the model that did not receive nanoparticle injection. Thus, Neutron Capture Agents can be delivered preferentially in the tumor.
Futhermore, to investigate whether the BPM0s are localized to the tumor, it is shown that synthesized BPM0 nanoparticles labeled with Rhodamine-B is prepared. Briefly, Rhodamine B labeled BPM0 nanoparticles are prepared by the co-condensation with Rhodamine B-APTES
prepared by chemically linking fluorescent Rhodamine B isothiocyanate (RBITC) dye with aminopropyltriethoxysilane (APTES) or other methods known in the art. These enable characterization of BPM0 biodistribution by following red fluorescence. Rhodamine B labeled nanoparticles are injected and the distribution of red fluorescence is examined 1-3 days after the injection. Tumor and various organs from the sample are cut out. It is shown that red fluorescence was detected predominantly in the tumor two to three days after the injection. Much less red fluorescence was detected in other organs such as liver. The control Date Recue/Date Received 2020-11-25 tumor represents tumor sample obtained from the model that did not receive BPM0 injection. Similar results are obtained when the analysis is carried out one day after the injection. Thus, BPM0 nanoparticles preferentially accumulate in the tumor. On the other hand, BPM0 surface modified to possess positive charge accumulated more in liver and kidney.
Accordingly, it is shown that BPM0s of the disclosure loaded with Neutron Capture Agents can be modified to selectively localize in high concentrations in tumor cells.
IX.) Kits/Articles of Manufacture For use in the laboratory, prognostic, prophylactic, diagnostic and therapeutic applications described herein, kits are within the scope of the invention. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in the method, along with a label or insert comprising instructions for use, such as a use described herein. For example, the container(s) can comprise a BPM0 that is or can be detectably labeled and/or is loaded with a Neutron Capture Agent. Kits can comprise a container comprising a drug unit. The kit can include all or part of the BPM0s and/or Neutron Capture Agents.
The kit of the invention will typically comprise the container described above and one or more other containers associated therewith that comprise materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
A label can be present on or with the container to indicate that the composition is used for a specific therapy or non-therapeutic application, such as a prognostic, prophylactic, diagnostic or laboratory application, and can also indicate directions for either in vivo or in vitro use, such as those described herein. Directions and or other information can also be included on an insert(s) or label(s) which is included with or on the kit. The label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. The label can indicate that the composition is used for diagnosing, treating, prophylaxing or prognosing a condition, such as a cancer or other immunological disorder.
The terms "kit" and "article of manufacture" can be used as synonyms.
In another embodiment of the invention, an article(s) of manufacture containing compositions, such as BPM0s and/or Neutron Capture Agents and/or BPM0s loaded with Neutron Capture Agents.
The article of manufacture typically comprises at least one container and at least one label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed Date Recue/Date Received 2020-11-25 from a variety of materials such as glass, metal or plastic. The container can hold BPM0s and Neutron Capture Agents.
The container can alternatively hold a composition that is effective for treating, diagnosis, prognosing or prophylaxing a condition and can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agents in the composition can be a BPMO loaded with a Neutron Capture Agent.
The article of manufacture can further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and/or dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, stirrers, needles, syringes, and/or package inserts with indications and/or instructions for use.
EXAMPLES:
Various aspects of the invention are further described and illustrated by way of the several examples that follow, none of which is intended to limit the scope of the invention.
Example 1: Synthesis of BPMO
In one embodiment, a BPMO of the disclosure was synthesized in the following manner. First, 1,2-bis(triethoxysilyl)ethane was mixed with CTAB and NaOH, stirred vigorously, and then the mixture was heated to 800C. Next, the solution was added dropwise into the flask and bis[3(triethoxysily1) propyl] tetrasulfide was added immediately thereafter. After condensation at 80 C for 2.0 hours, BPMO
was collected by centrifugation and washed twice with ethanol. Removal of the CTAB from the pores was performed by reflux overnight in ethanolic acid of ammonium nitrate. The particles were purified by washing with ethanol (3x times) and dried completely. See, Figure 1.
Example 2: Characterizaton of BPMO Nanoparticles The BPMO's set forth in Example 1 (Synthesis of BPMO) were characterized by scanning electron microscopy ("SEM") and transmission electron microscopy ("TEM") using techniques known in the art. Analysis of the BPMO using SEM shows homogeneous nanoparticles with 100-200 nm diameter. See, Figure 2(1)(a).
Analysis of the BPMO using TEM shows the presence of pore structure(s). See, Figure 2(1)(b).
Finally, degradation analysis on the BPMO was performed using TEM. Briefly, BPMO (0.1 mg/ml) was incubated in PBS (phosphate buffered saline) solution containing 10 mM glutathione (GSH) Date Recue/Date Received 2020-11-25 at 37 C for 5 days and visualized by TEM (transmission electron microscopy).
The results show that BPMO was degradable under reducing conditions. See, Figure 2(2).
Example 3: Synthesis of BPMO surface modified with Phosphonate and diol The BPMO produced according to the example entitled "Synthesis of BPMO" was surface modified. Briefly, synthesized BPMO was immersed in toluene and the mixture was sonicated for 10 minutes. Then, 3-glycidyloxypropyl trimethoxysilane (GOPTS):
was added to this mixture and refluxed overnight. Solid product was collected by centrifugation and washed 3x times with ethanol. Dried product was obtained and added into deionized water. This mixture was heated at 70 C for two (2) days. Diol-BPMO was further modified with 3(trihydroxysily1) propyl methyl phosphonate to provide a negative charge on the surface by stirring the 3(trihydroxysily1) propyl methyl phosphonate at 700C. See, Figure 1.
Example 4: Method of Loading 10BPA to Surface Modified BPMO
The BPMO functionalized with diol and phosphonate as described in the example entitled "Synthesis of BPMO surface modified with phonsphonate and diol" was loaded with neutron capture agent 10BPA. Briefly, BPMO-diol was added into 10BPA solution, pH was adjusted to approximately 8.5-8.8 and the mixture was stirred at 4 C for twenty-four (24) hr. The product was collected by centrifugation and then washed with deionized water and ethanol. Dried product was obtained after evaporation. The resulting composition P-BPMO-diol-10BPA is shown by the process described in Figure 1 and is within the scope of the invention.
Example 5: Tumor Targeting of 10BPA loaded phosphonate modified BPMO
Evaluation of the BPMO set forth in the previous examples was carried out to show the tumor targeting activity of the 10BPA loaded BPMO. Briefly, fertilized eggs were incubated for ten (10) days at which time human cancer cells were transplanted onto the CAM membrane (chorioallantoic membrane).
GFP expressing ovarian cancer cells are used. Three (3) days later, a tumor is formed on the CAM
membrane. Rhodamine-B labeled BPMO synthesized as described in Example 2 is injected intravenously and the overlap of red fluorescence (BPMO) abd green fluorescence (GFP expressing tumor) are investigated.
Date Recue/Date Received 2020-11-25 The results demonstrate that leliPA-loaded BPM0 accumulates in the tumor when injected at 0.2 mg per egg intravenously. Two (2) days after the injection, the tumor as well as various organs from chick embryo were cut out and examined under fluorescent microscopy using techniques known in the art. Note that red fluorescence of BPM0 overlaps with green fluorescence of tumor. See, Figure 3 and Figure 4.
In a subsequent analysis, the tumor and organs used and shown in Figure 4 were cut into thin sections and then were examined by confocal microscopy using techniques known in the art. The results show that red fluorescence of BPM0 is detected in the tumor with a de minimus amount in normal liver. Green fluorescence of tumor is due to GFP expressing cancer cells. See, Figure 4 and Figure 5.
Example 6: BNCT Using 1(IBPA Loaded BPMO surface modified with Phosphonate The effectiveness of loBPA loaded BPM0 that has been surface modified with phosphonate as a therapeutic modality in BNCT is shown using the following method. First, human cancer cells are transplanted on the CAM membrane inside the chicken egg. Second, the loBPA
loaded BPM0 that has been surface modified with phosphonate is injected and is allowed to set for 1-2 days. Exposure to a neutron beam is initiated. After exposure to the neutron (usually around 60 min), the chicken eggs are incubated for three (3) days. After three (3) days the tumor is analyzed with techniques known in the art and the size and weight of the tumor are measured. The tumor size and weight is examined. See, Figure 6.
It will be understood by one of ordinary skill in the art that a variety of additional neutron capture agents can be utilized using the same protocol as described herein.
Example 7: Human Clinical Trials for the Treatment of Human Carcinomas through the Use of BPM0s loaded with Neutron Capture Agents.
BPM0s loaded with Neutron Capture Agents are used in accordance with the present invention which specifically accumulate in a tumor cell, and are used in the treatment of certain tumors and other immunological disorders and/or other diseases. In connection with each of these indications, two clinical approaches are successfully pursued.
I.) Adiunctive therapy: In adjunctive therapy, patients are treated with BPM0s loaded with Neutron Capture Agents in combination with a chemotherapeutic or pharmaceutical or biopharmaceutical agent or a combination thereof. Primary cancer targets, are treated under standard protocols by the addition of BPM0s loaded with Neutron Capture Agents and then irradiated. Protocol designs address effectiveness as assessed by the following examples, including but not limited to, Date Recue/Date Received 2020-11-25 reduction in tumor mass of primary or metastatic lesions, increased progression free survival, overall survival, improvement of patients health, disease stabilization, as well as the ability to reduce usual doses of standard chemotherapy and other biologic agents. These dosage reductions allow additional and/or prolonged therapy by reducing dose-related toxicity of the chemotherapeutic or biologic agent.
II.) Monotherapy: In connection with the use of the BPM0s loaded with Neutron Capture Agenrs in monotherapy of tumors, the BPM0s loaded with Neutron Capture Agents are administered to patients without a chemotherapeutic or pharmaceutical or biologica agent. In one embodiment, monotherapy is conducted clinically in end-stage cancer patients with extensive metastatic disease. Protocol designs address effectiveness as assessed by the following examples, including but not limited to, reduction in tumor mass of primary or metastatic lesions, increased progression free survival, overall survival, improvement of patients health, disease stabilization, as well as the ability to reduce usual doses of standard chemotherapy and other biologic agents.
Dosage Dosage regimens may be adjusted to provide the optimum desired response. For example, a single injection of loaded BPM0s may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. "Dosage Unit Form" as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the BPM0 loaded with the Neutron Capture Agent, the individual mechanics of the irradiation mechanism (reactor) and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an compound for the treatment of sensitivity in individuals.
Clinical Development Plan (CDP) The CDP follows and develops treatments of using BPM0s loaded with Neutron Capture Agents which are then irradiated using Neutron Capture Therapy in connection with adjunctive therapy or monotherapy. Trials initially demonstrate safety and thereafter confirm efficacy in repeat doses. Trials are open label comparing standard chemotherapy with standard therapy plus BPM0s loaded with Neutron Capture Agents which are then irradiated using Neutron Capture Therapy. As will be appreciated, one non-limiting criteria that can be utilized in connection with enrollment of patients is concentration of Neutron Capture Agents in a tumor as determined by standard detection methods known in the art.
Date Recue/Date Received 2020-11-25 The present invention is not to be limited in scope by the embodiments disclosed herein, which are intended as single illustrations of individual aspects of the invention, and any that are functionally equivalent are within the scope of the invention. Various modifications to the models, methods, and life cycle methodology of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and teachings, and are similarly intended to fall within the scope of the invention. Such modifications or other embodiments can be practiced without departing from the true scope and spirit of the invention.
Date Recue/Date Received 2020-11-25
"Nanomaterial" means a material in any dimensional form (zero, one, two, three) and domain size in the range 40-400 nanometers.
"Nanostructure" means a structure having at least one dimension that is less than 500 nanometers. Examples, include but are not limited to nanocrystals, nanocomposites, nanograins, nanotubes, nanoceramics, and nanopowders.
"Nanofiller" (a.k.a. nanostructured filler) means a structure or particle intimately mixed with a matrix to form a nanostructured composite. At least one of the nanostructured filler and the nanostructured composite has a desired material property which differs by at least 20% from the same material property for a micron-scale filler or a micron-scale composite, respectively. The desired material property is selected from the group consisting of refractive index, transparency to light, reflection characteristics, resistivity, permittivity, permeability, coercivity, B-H product, magnetic hysteresis, breakdown voltage, skin depth, curie temperature, dissipation factor, work function, band gap, electromagnetic shielding effectiveness, radiation hardness, chemical reactivity, thermal conductivity, temperature coefficient of an electrical property, voltage coefficient of an electrical property, thermal shock resistance, biocompatibility and wear rate. The nanostructured filler may comprise one or more elements selected from the s, p, d, and f groups of the periodic table, or it may comprise a compound of one or more such elements with one or more suitable anions, such as aluminum, antimony, boron, bromine, carbon, chlorine, fluorine, germanium, hydrogen, indium, iodine, nickel, nitrogen, oxygen, phosphorus, selenium, silicon, sulfur, or tellurium.
The matrix may be a polymer (e.g., poly(methyl methacrylate), poly(vinyl alcohol), polycarbonate, polyalkene, or polyaryl), a ceramic (e.g., zinc oxide, indium-tin oxide, hafnium carbide, or ferrite), or a metal (e.g., copper, tin, zinc, or iron). Loadings of the nanofiller may be as high as 95%, although loadings of 80% or less are preferred. The invention also comprises devices which incorporate the nanofiller (e.g., electrical, magnetic, optical, biomedical, and electrochemical devices).
The term "neutron capture agent" means a stable non-reactive chemical isotope which, when activated by neutrons produces alpha-rays and gamma-rays.
The term "neutron capture therapy" means a noninvasive therapeutic modality for treating locally invasive malignant tumors such as primary brain tumors and recurrent head and neck cancer and other immunological disorders and disease by irradiating a neutron capture agent with neutrons.
As used herein "to treat" or "therapeutic" and grammatically related terms, refer to any improvement of any consequence of disease, such as prolonged survival, less morbidity, and/or a lessening of side effects which are the byproducts of an alternative therapeutic modality; as is readily Date Recue/Date Received 2020-11-25 appreciated in the art, full eradication of disease is a preferred but albeit not a requirement for a treatment act.
IL) Mesoporous Silica Nanoparticles (MSN) & Biodegradable Periodic Mesoporous Organosilica (BPMO) Mesoporous silica nanoparticles (MSNs) have emerged as a powerful drug delivery vehicle.
Generally, these silica particles have a diameter ranging from 40 to 400 nm and contain thousands of pores where anticancer drugs, among other things, can be stored. Various cellular and animal studies have been reported that point to the efficacy of MSNs to deliver anticancer drugs. See, for example, Wang, Y. et. al., Mesoporous silica nanoparticles in drug delivery and biomedical applications.
Nanomedicine. 11, 313-327 (2015). Because of the relative stability of these nanomaterials, various chemical modifications can be applied to these nanoparticles. A surface charge property can be altered to prevent the aggregation of particles in biological media and to achieve prolonged circulation.
Furthermore, various nanomachines can be engineered on the particle surface to confer the ability to release anticancer drug upon stimuli including light and magnetic field exposure.
Artisans skilled in the art have recently developed a new generation of mesoporous nanoparticles called biodegradable PM0 (Periodic Mesoporous Organosilica) nanoparticles ("BPMO") which are tuned for biodegradation by incorporating disulfide, tetrasulfide bonds, or protease sensitive bonds leading to excellent candidates for nanomedicine applications. See, for example, Croissant, J. et.
al., Biodegradable oxamide-phenylene-based mesoporous organosilica nanoparticles with unprecedented drug payloads for delivery in cells. Chem. Eur. J. 22, 14806-14811 (2016). These nanoparticles retain the advantageous features of MSNs described above and, in addition, they possess enhanced degradability. The BPM0s exhibit efficient loading capacity with Neutron Capture Agents, such as Boron, as well as other anticancer drugs, which are known in the art, and the Neutron Capture Agents can be delivered into human cancer cells.
A recently developed BPM0s contain biodegradable bonds within the framework of mesoporous silica network and thus are degradable by conditions inside the cell, such as reducing environment. For this, two (2) types of BPM0 nanoparticles containing a disulfide bond or tetrasulfide bond have been developed. In a preferred embodiment, a BPM0 of the invention is synthesized using the sol-gel synthesis method with precursors containing disulfide or tetrasulfide bond. The use of these special precursors for synthesis results in the incorporation of these biodegradable bonds into the framework of nanoparticles.
During the synthesis, surfactant CTAB (cetyltrimethylammonium bromide) was included to produce a porous structure. Generally speaking, a preferred BPM0 of the invention was synthesized by Date Recue/Date Received 2020-11-25 mixing bis(triethoxysilylpropyl)disulfide with bis(triethoxysilyl)ethylene (50-50 ratio). The resulting BPM0s have a diameter of 100-300 nm and contain pores with 2-3.5 nm diameter.
In yet another preferred embodiment, a BPM0 of the disclosure was synthesized by mixing 1,2-bis(triethoxysilyl)ethane with CTAB and NaOH, stirred vigorously and then the mixture was heated to 80 C. Next, the solution was added dropwise into the flask and bis[3(triethoxysily1) propyl] tetrasulfide was added immediately thereafter. After condensation at 80 C for 2.0 hours, BPM0 was collected by centrifugation and washed twice with ethanol. To remove CTAB from the pores, the particles was refluxed overnight in ethanolic acid of ammonium nitrate. The particles were purified by washing with ethanol (3 times) and dried completely.
In yet another preferred embodiment, a BPM0 of the present disclosure was functionalized with GOPTS (3-glycidyloxypropyl trimethoxysilane) by a post-synthesis grafting method. To open the epoxy ring of GOPTS, the functionalized BPM0 was suspended in water and heated at 70 C for two days.
This step produces diol-modified BPM0. Further modification to add phosphonate on the surface was accomplished using 3(trihydroxylsily1) propyl methyl phosphonate.10BPA (4 borono L-phenylalanine) was added to the nanoparticles so thatloBPA will be chelated onto the diol modified BPM0.
In another preferred embodiment, a BPM0 which has been surface modified with phosphonate is loaded with a Neutron Capture Agent, whereby the Neutron Capture Agent is encapsulated within the BPM0. In a further embodiment, the Neutron Capture Agent is chemically bonded to the surface of a BPM0. Exemplary embodiments of a Neutron Capture Agent of the invention is set forth herein.
One of ordinary skill in the art will appreciate and be enabled to make variations and modifications to the disclosed embodiment without altering the function and purpose of the invention disclosed herein. Such variations and modifications are intended within the scope of the present disclosure.
III.) Neutron Capture Agent(s) Another aspect of the present invention relates to improved Neutron Capture Agents. Generally speaking, Neutron Capture Agents success is predicated on selective localization in tumor cells and adequate flux of neutrons of appropriate energy to the tumor. A current drawback with neutron capture therapy is the inability of neutron capture agents to adequately concentrate in the tumor, while at the same time minimizing concentration in normal cells. As will be appreciated by one of ordinary skill in the art, several neutron capture agents of the invention posess properties which will be beneficial for the instant disclosure. For example, a high cross section of thermal neutron interactions will cause high ionization capability whereby cells enriched by neutron capture agents will be killed and the normal cells will be damaged much less. However, to date, the dimishment of damaging healthy normal cells has not been achieved. It is an object of the present invention to remedy this deficiency.
Date Recue/Date Received 2020-11-25 In a further embodiment, the Neutron Capture Agent comprises the Boron isotope 10B.
In a further embodiment, the Neutron Capture Agent comprises the Lithium isotope 6Li.
In a further embodiment, the Neutron Capture Agent comprises the He isotope 3He.
In a further embodiment, the Neutron Capture Agent comprises the Cadmium isotope 113Cd.
In a further embodiment, the Neutron Capture Agent comprises the Samarium isotope 1495m.
In a further embodiment, the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
In a further embodiment, the Neutron Capture Agent comprises an istope of Au (Gold).
In a further embodiment, the Neutron Capture Agent comprises an isotope with a favorable neutron capture cross section.
One of ordinary skill in the art will appreciate and be enabled to make variations and modifications to the disclosed embodiment without altering the function and purpose of the invention disclosed herein. Such variations and modifications are intended within the scope of the present disclosure.
IV.) BPM0s loaded with Neutron Capture Agents One apect of the present invention relates to BPM0s loaded with Neutron Capture Agents. As previously discussed, BPM0s of the disclosure have a high loading capacity at the appropriate pH. In a preferred embodiment, the pH is around 8.5. Furthermore, the once loaded, the Neutron Capture Agent is between 20% - 60% to total weight of BPM0. In a preferred embodiment, the Neutron Capture Agent constitutes between 30% - 50% of the total weight of the loaded BPM0. In a further embodiment, the Neutron Capture Agent comprises the Boron isotope 10B. In a further embodiment, the Neutron Capture Agent comprises 10BPA. In a further embodiment, the Neutron Capture Agent comprises the Lithium isotope 6Li. In a further embodiment, the Neutron Capture Agent comprises the He isotope 3He. In a further embodiment, the Neutron Capture Agent comprises the Cadmium isotope 113Cd. In a further embodiment, the Neutron Capture Agent comprises the Samarium isotope 1495m. In a further embodiment, the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
It will be appreciated by one or ordinary skill in the art that a Neutron Capture Agent may be fabricated to a PM0 by various means known in the art, such as encapsulation, or chemically bonded to the surface of the BPM0, and/or conjugated to BPM0s using methods known in the art. Such variations and modifications are intended within the scope of the present disclosure.
V.) Boron Neutron Capture Therapy using BPM0s loaded with 10B
One apect of the present disclosure is the use of BPM0s loaded with 10B as a modality for Boron Neutron Capture Therapy ("BNCT"). Briefly, BNCT is a binary treatment modality in which neither component alone is legal or highly toxic. The two components comprise (i) the infusion or Date Recue/Date Received 2020-11-25 delivery of a capture compound, which preferentially is concentrated in the tumor, and (ii) the irradiation of the tumor site by neutrons. Given the large cross-section of thermal neutron interactions with 10B, there is consequently a high probability of a splitting of Boron nucleus into He and Li. Given that the ionization capability of He and Li is high, and the runs are short, then the cells preferably enriched by Boron are killed and the healthy cells are damaged much less. Given this, the advantage of BNCT is the destruction of tumor cells without a highly traumatic surgical procedure.
However, as will be understood by one of skill in the art, success is predicated high concentration and selective localization of 10B in tumor cells.
In one embodiment, 10B is loaded to a BPM0 of the invention and is localized into a tumor cell.
The BPM0s containing 10B are concentrated into the tumor and the tumor is irradiated using epithermal neutrons. The tumor cells are destroyed.
VI. Methods of Delivering Neutron Capture Agents to a Cell As will be appreciated by one of ordinary skill in the art, the ability to efficiently deliver an improved Neutron Capture Agent of the present disclosure to a cell is an advantage of the present invention.
It is shown that the nanoparticle formulation (BPM0s of the present disclosure) enables a higher amount of Neutron Capture Agents to be administered safely to mammals.
Briefly, to investigate tumor delivery of Neutron Capture Agents, it is shown by fluorescence of Neutron Capture Agents in the tumor from one (1) to five (5) days after injection of Neutron Capture Agents loaded PM0 nanoparticles.
The fluorescence is observed in the tumor. To examine whether the fluorescence is observed predominantly in the tumor, various organs are removed, processed and examined by fluorescence microscopy or other detection methods known in the art. It is shown that fluorescence is observed predominantly in the tumor whereas little fluorescence is observed in various organs. Control tumor represents tumor sample obtained from the model that did not receive nanoparticle injection. Thus, Neutron Capture Agents can be delivered preferentially in the tumor.
Futhermore, to investigate whether the BPM0s are localized to the tumor, it is shown that synthesized BPM0 nanoparticles labeled with Rhodamine-B is prepared. Briefly, Rhodamine B labeled BPM0 nanoparticles are prepared by the co-condensation with Rhodamine B-APTES
prepared by chemically linking fluorescent Rhodamine B isothiocyanate (RBITC) dye with aminopropyltriethoxysilane (APTES) or other methods known in the art. These enable characterization of BPM0 biodistribution by following red fluorescence. Rhodamine B labeled nanoparticles are injected and the distribution of red fluorescence is examined 1-3 days after the injection. Tumor and various organs from the sample are cut out. It is shown that red fluorescence was detected predominantly in the tumor two to three days after the injection. Much less red fluorescence was detected in other organs such as liver. The control Date Recue/Date Received 2020-11-25 tumor represents tumor sample obtained from the model that did not receive BPM0 injection. Similar results are obtained when the analysis is carried out one day after the injection. Thus, BPM0 nanoparticles preferentially accumulate in the tumor. On the other hand, BPM0 surface modified to possess positive charge accumulated more in liver and kidney.
Accordingly, it is shown that BPM0s of the disclosure loaded with Neutron Capture Agents can be modified to selectively localize in high concentrations in tumor cells.
IX.) Kits/Articles of Manufacture For use in the laboratory, prognostic, prophylactic, diagnostic and therapeutic applications described herein, kits are within the scope of the invention. Such kits can comprise a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in the method, along with a label or insert comprising instructions for use, such as a use described herein. For example, the container(s) can comprise a BPM0 that is or can be detectably labeled and/or is loaded with a Neutron Capture Agent. Kits can comprise a container comprising a drug unit. The kit can include all or part of the BPM0s and/or Neutron Capture Agents.
The kit of the invention will typically comprise the container described above and one or more other containers associated therewith that comprise materials desirable from a commercial and user standpoint, including buffers, diluents, filters, needles, syringes; carrier, package, container, vial and/or tube labels listing contents and/or instructions for use, and package inserts with instructions for use.
A label can be present on or with the container to indicate that the composition is used for a specific therapy or non-therapeutic application, such as a prognostic, prophylactic, diagnostic or laboratory application, and can also indicate directions for either in vivo or in vitro use, such as those described herein. Directions and or other information can also be included on an insert(s) or label(s) which is included with or on the kit. The label can be on or associated with the container. A label can be on a container when letters, numbers or other characters forming the label are molded or etched into the container itself; a label can be associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert. The label can indicate that the composition is used for diagnosing, treating, prophylaxing or prognosing a condition, such as a cancer or other immunological disorder.
The terms "kit" and "article of manufacture" can be used as synonyms.
In another embodiment of the invention, an article(s) of manufacture containing compositions, such as BPM0s and/or Neutron Capture Agents and/or BPM0s loaded with Neutron Capture Agents.
The article of manufacture typically comprises at least one container and at least one label. Suitable containers include, for example, bottles, vials, syringes, and test tubes. The containers can be formed Date Recue/Date Received 2020-11-25 from a variety of materials such as glass, metal or plastic. The container can hold BPM0s and Neutron Capture Agents.
The container can alternatively hold a composition that is effective for treating, diagnosis, prognosing or prophylaxing a condition and can have a sterile access port (for example the container can be an intravenous solution bag or a vial having a stopper pierceable by a hypodermic injection needle). The active agents in the composition can be a BPMO loaded with a Neutron Capture Agent.
The article of manufacture can further comprise a second container comprising a pharmaceutically-acceptable buffer, such as phosphate-buffered saline, Ringer's solution and/or dextrose solution. It can further include other materials desirable from a commercial and user standpoint, including other buffers, diluents, filters, stirrers, needles, syringes, and/or package inserts with indications and/or instructions for use.
EXAMPLES:
Various aspects of the invention are further described and illustrated by way of the several examples that follow, none of which is intended to limit the scope of the invention.
Example 1: Synthesis of BPMO
In one embodiment, a BPMO of the disclosure was synthesized in the following manner. First, 1,2-bis(triethoxysilyl)ethane was mixed with CTAB and NaOH, stirred vigorously, and then the mixture was heated to 800C. Next, the solution was added dropwise into the flask and bis[3(triethoxysily1) propyl] tetrasulfide was added immediately thereafter. After condensation at 80 C for 2.0 hours, BPMO
was collected by centrifugation and washed twice with ethanol. Removal of the CTAB from the pores was performed by reflux overnight in ethanolic acid of ammonium nitrate. The particles were purified by washing with ethanol (3x times) and dried completely. See, Figure 1.
Example 2: Characterizaton of BPMO Nanoparticles The BPMO's set forth in Example 1 (Synthesis of BPMO) were characterized by scanning electron microscopy ("SEM") and transmission electron microscopy ("TEM") using techniques known in the art. Analysis of the BPMO using SEM shows homogeneous nanoparticles with 100-200 nm diameter. See, Figure 2(1)(a).
Analysis of the BPMO using TEM shows the presence of pore structure(s). See, Figure 2(1)(b).
Finally, degradation analysis on the BPMO was performed using TEM. Briefly, BPMO (0.1 mg/ml) was incubated in PBS (phosphate buffered saline) solution containing 10 mM glutathione (GSH) Date Recue/Date Received 2020-11-25 at 37 C for 5 days and visualized by TEM (transmission electron microscopy).
The results show that BPMO was degradable under reducing conditions. See, Figure 2(2).
Example 3: Synthesis of BPMO surface modified with Phosphonate and diol The BPMO produced according to the example entitled "Synthesis of BPMO" was surface modified. Briefly, synthesized BPMO was immersed in toluene and the mixture was sonicated for 10 minutes. Then, 3-glycidyloxypropyl trimethoxysilane (GOPTS):
was added to this mixture and refluxed overnight. Solid product was collected by centrifugation and washed 3x times with ethanol. Dried product was obtained and added into deionized water. This mixture was heated at 70 C for two (2) days. Diol-BPMO was further modified with 3(trihydroxysily1) propyl methyl phosphonate to provide a negative charge on the surface by stirring the 3(trihydroxysily1) propyl methyl phosphonate at 700C. See, Figure 1.
Example 4: Method of Loading 10BPA to Surface Modified BPMO
The BPMO functionalized with diol and phosphonate as described in the example entitled "Synthesis of BPMO surface modified with phonsphonate and diol" was loaded with neutron capture agent 10BPA. Briefly, BPMO-diol was added into 10BPA solution, pH was adjusted to approximately 8.5-8.8 and the mixture was stirred at 4 C for twenty-four (24) hr. The product was collected by centrifugation and then washed with deionized water and ethanol. Dried product was obtained after evaporation. The resulting composition P-BPMO-diol-10BPA is shown by the process described in Figure 1 and is within the scope of the invention.
Example 5: Tumor Targeting of 10BPA loaded phosphonate modified BPMO
Evaluation of the BPMO set forth in the previous examples was carried out to show the tumor targeting activity of the 10BPA loaded BPMO. Briefly, fertilized eggs were incubated for ten (10) days at which time human cancer cells were transplanted onto the CAM membrane (chorioallantoic membrane).
GFP expressing ovarian cancer cells are used. Three (3) days later, a tumor is formed on the CAM
membrane. Rhodamine-B labeled BPMO synthesized as described in Example 2 is injected intravenously and the overlap of red fluorescence (BPMO) abd green fluorescence (GFP expressing tumor) are investigated.
Date Recue/Date Received 2020-11-25 The results demonstrate that leliPA-loaded BPM0 accumulates in the tumor when injected at 0.2 mg per egg intravenously. Two (2) days after the injection, the tumor as well as various organs from chick embryo were cut out and examined under fluorescent microscopy using techniques known in the art. Note that red fluorescence of BPM0 overlaps with green fluorescence of tumor. See, Figure 3 and Figure 4.
In a subsequent analysis, the tumor and organs used and shown in Figure 4 were cut into thin sections and then were examined by confocal microscopy using techniques known in the art. The results show that red fluorescence of BPM0 is detected in the tumor with a de minimus amount in normal liver. Green fluorescence of tumor is due to GFP expressing cancer cells. See, Figure 4 and Figure 5.
Example 6: BNCT Using 1(IBPA Loaded BPMO surface modified with Phosphonate The effectiveness of loBPA loaded BPM0 that has been surface modified with phosphonate as a therapeutic modality in BNCT is shown using the following method. First, human cancer cells are transplanted on the CAM membrane inside the chicken egg. Second, the loBPA
loaded BPM0 that has been surface modified with phosphonate is injected and is allowed to set for 1-2 days. Exposure to a neutron beam is initiated. After exposure to the neutron (usually around 60 min), the chicken eggs are incubated for three (3) days. After three (3) days the tumor is analyzed with techniques known in the art and the size and weight of the tumor are measured. The tumor size and weight is examined. See, Figure 6.
It will be understood by one of ordinary skill in the art that a variety of additional neutron capture agents can be utilized using the same protocol as described herein.
Example 7: Human Clinical Trials for the Treatment of Human Carcinomas through the Use of BPM0s loaded with Neutron Capture Agents.
BPM0s loaded with Neutron Capture Agents are used in accordance with the present invention which specifically accumulate in a tumor cell, and are used in the treatment of certain tumors and other immunological disorders and/or other diseases. In connection with each of these indications, two clinical approaches are successfully pursued.
I.) Adiunctive therapy: In adjunctive therapy, patients are treated with BPM0s loaded with Neutron Capture Agents in combination with a chemotherapeutic or pharmaceutical or biopharmaceutical agent or a combination thereof. Primary cancer targets, are treated under standard protocols by the addition of BPM0s loaded with Neutron Capture Agents and then irradiated. Protocol designs address effectiveness as assessed by the following examples, including but not limited to, Date Recue/Date Received 2020-11-25 reduction in tumor mass of primary or metastatic lesions, increased progression free survival, overall survival, improvement of patients health, disease stabilization, as well as the ability to reduce usual doses of standard chemotherapy and other biologic agents. These dosage reductions allow additional and/or prolonged therapy by reducing dose-related toxicity of the chemotherapeutic or biologic agent.
II.) Monotherapy: In connection with the use of the BPM0s loaded with Neutron Capture Agenrs in monotherapy of tumors, the BPM0s loaded with Neutron Capture Agents are administered to patients without a chemotherapeutic or pharmaceutical or biologica agent. In one embodiment, monotherapy is conducted clinically in end-stage cancer patients with extensive metastatic disease. Protocol designs address effectiveness as assessed by the following examples, including but not limited to, reduction in tumor mass of primary or metastatic lesions, increased progression free survival, overall survival, improvement of patients health, disease stabilization, as well as the ability to reduce usual doses of standard chemotherapy and other biologic agents.
Dosage Dosage regimens may be adjusted to provide the optimum desired response. For example, a single injection of loaded BPM0s may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation. "Dosage Unit Form" as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the BPM0 loaded with the Neutron Capture Agent, the individual mechanics of the irradiation mechanism (reactor) and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an compound for the treatment of sensitivity in individuals.
Clinical Development Plan (CDP) The CDP follows and develops treatments of using BPM0s loaded with Neutron Capture Agents which are then irradiated using Neutron Capture Therapy in connection with adjunctive therapy or monotherapy. Trials initially demonstrate safety and thereafter confirm efficacy in repeat doses. Trials are open label comparing standard chemotherapy with standard therapy plus BPM0s loaded with Neutron Capture Agents which are then irradiated using Neutron Capture Therapy. As will be appreciated, one non-limiting criteria that can be utilized in connection with enrollment of patients is concentration of Neutron Capture Agents in a tumor as determined by standard detection methods known in the art.
Date Recue/Date Received 2020-11-25 The present invention is not to be limited in scope by the embodiments disclosed herein, which are intended as single illustrations of individual aspects of the invention, and any that are functionally equivalent are within the scope of the invention. Various modifications to the models, methods, and life cycle methodology of the invention, in addition to those described herein, will become apparent to those skilled in the art from the foregoing description and teachings, and are similarly intended to fall within the scope of the invention. Such modifications or other embodiments can be practiced without departing from the true scope and spirit of the invention.
Date Recue/Date Received 2020-11-25
Claims (20)
1) A composition comprising, a) A biodegradable periodic mesoporous organosilica (BPMO) nanomaterial; and b) a neutron capture agent;
2) The composition of claim 1, whereby the BPMO is modified by incorporating a disulfide bond, a tetrasulfide bond, or a protease sensitive bond.
3) The composition of claim 1, whereby the surface is modified.
4) The composition of claim 1, whereby the loaded neutron capture agent constitutes between 15% - 85% of the total weight of the loaded BPMO.
5) The composition of Claim 1, whereby the Neutron Capture Agent comprises the Boron isotope 10B.
6) The composition of Claim 1, whereby the Neutron Capture Agent comprises the Lithium isotope 6Li.
7) The composition of claim 3, wherein the surface charge modification comprises a post-synthesis grafting step using phosphonate and diol.
8) The composition of Claim 1, whereby the Neutron Capture Agent comprises the Cadmium isotope 113Cd.
9) The composition of Claim 1, whereby the Neutron Capture Agent comprises the Samarium isotope 149Sm.
10) The composition of Claim 1, whereby the Neutron Capture Agent comprises the Gadolinium isotope 167Gd.
1 1) A method of fabricating a Neutron Capture Agent to a biodegradable periodic mesoporous organosilica (BPMO) nanomaterial, comprising:
12) A method of performing Neutron Capture Therapy in the treatment of human cancer comprising:
a) loading a biodegradable periodic mesoporous organosilica (BPMO) nanomaterial with Neutron Capture Agent;
b) injecting the loaded BPMO into a tumor, whereby said loaded BPMO
accumulates into a tumor cell; and c) irradiating the loaded BPMO with neutrons.
a) loading a biodegradable periodic mesoporous organosilica (BPMO) nanomaterial with Neutron Capture Agent;
b) injecting the loaded BPMO into a tumor, whereby said loaded BPMO
accumulates into a tumor cell; and c) irradiating the loaded BPMO with neutrons.
13) The method of claim 13, wherein the irradiation comprises epithermal neutrons.
14) The methods of Claim 13, wherein the irradiation triggers neutron activation.
15) The method of Claim 13, wherein the Neutron Capture Agent is selected from the group consisting of the Boron isotope 10B, the Lithium isotope 6Li, the Cadmium isotope 113Cd, the Samarium isotope 1495m, or the Gadolinium isotope 167Gd.
Date Recue/Date Received 2020-11-25
Date Recue/Date Received 2020-11-25
16) A kit comprising the composition of Claim 1.
17) A kit comprising the composition of Claim 1, which is specifically adapted to perform the method of Claim 13.
18) A Dosage Unit Form comprising the composition of Claim 1.
19) The composition of claim 1, whereby the BPMO is surface modified with a phosphonate.
20) The composition of Claim 1, whereby the Neutron Capture Agent comprises 10BPA.
Date Recue/Date Received 2020-11-25
Date Recue/Date Received 2020-11-25
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