# US 11,305,131 B2 · X-ray psoralen activated cancer therapy (X-PACT)

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- Number: US 11,305,131 B2
- Document ID: US11305131B2
- Status: Granted
- Kind: B2
- Application number: 16/554,831
- Filed: 2019-08-29
- Published: 2020-01-09
- Granted: 2022-04-19
- Earliest claimed: 2015-10-19
- Assignees: Immunolight, LLC; Duke University
- Applicants: Immunolight, LLC; Duke University
- Inventors: Mark Oldham; Zakaryae Fathi; Wayne F. Beyer; Frederic A. Bourke, Jr.; Harold Walder; Mark DeWhirst; Neil L. Spector; Paul Yoon; Justus Adamson; David Alcorta; Kim Lyerly; Leihua Liu; Takuya Osada
- Web page: https://patentgrep.com/patent/US11305131B2

## CPC

- A61K 41/0057: {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}
- A61N 5/062: {Photodynamic therapy, i.e. excitation of an agent}
- A61K 31/352: condensed with carbocyclic rings, e.g. methantheline {(cannabinoids A61K31/658)}
- A61K 33/42: Phosphorus; Compounds thereof
- A61K 41/0066: {Psoralene-activated UV-A photochemotherapy (PUVA-therapy), e.g. for treatment of psoriasis or eczema, extracorporeal photopheresis with psoralens or fucocoumarins}
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence)
- A61N 2005/0661: {ultraviolet}
- A61N 2005/0662: {Visible light}
- A61N 2005/1089: {Electrons}
- A61N 2005/1091: {Kilovoltage or orthovoltage range photons}
- A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A system for treating a diseased site in a human or animal body. The system includes a pharmaceutical carrier including one or more phosphors which are capable of emitting light into the diseased site upon interaction, a photoactivatable drug for intercalating into DNA of cells at the diseased site, one or more devices which infuse the diseased sited with the photoactivatable drug and the pharmaceutical carrier, an x-ray or high energy electron source, and a processor programmed to control a dose of x-rays or electrons to the diseased site for production of light inside the tumor to activate the photoactivatable drug.

## Claims

### Claim 1

A system for treating a diseased site in a human or animal body, comprising:
a pharmaceutical carrier including one or more phosphors which are capable of emitting ultraviolet or visible light into the body;
a photoactivatable drug for intercalating into DNA of cells at the diseased site;
one or more devices which are configured to infuse the diseased site with the photoactivatable drug and the pharmaceutical carrier;
an initiation energy source comprising an x-ray source which is configured to irradiate the diseased site with x-rays to thereby initiate emission of said ultraviolet or visible light into the body; and
a processor programmed to control a dose of said x-rays to the diseased site for production of said ultraviolet or visible light at the diseased site to activate the photoactivatable drug, wherein the infusion of the photoactivatable drug and the phosphors into the diseased site and the dose of x-rays produces a cytotoxicity inside the diseased site of greater than 20%,
wherein an amount of the phosphors in the pharmaceutical carrier ranges from 0.1 to 0.66 milligrams of phosphor per cm3 of the volume of the diseased site, and a concentration of the photoactivatable drug in the pharmaceutical carrier ranges from 10 μg/mL to 50 μg/mL; and
wherein the processor is programmed to apply the x-rays to the diseased site in a pulsed manner, wherein the x-rays are delivered in either (i) a radiograph mode where multiple pulses of a set mA and ms are delivered every 5-15 seconds, or (ii) a pulsed fluoroscopy mode at a maximum mA setting.

### Claim 2 (depends on 1)

The system of claim 1, wherein the initiation energy source comprises an x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 300 kVp.

### Claim 3 (depends on 2)

The system of claim 2, wherein the initiation energy source comprises an x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 200 kVp.

### Claim 4 (depends on 2)

The system of claim 2, wherein the initiation energy source comprises an x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 120 kVp.

### Claim 5 (depends on 2)

The system of claim 2, wherein the initiation energy source comprises an x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 105 kVp.

### Claim 6 (depends on 2)

The system of claim 2, wherein the initiation energy source comprises an x-ray source configured to generate x-rays from a peak applied cathode voltage at or below 80 kVp.

### Claim 7 (depends on 1)

The system of claim 1, wherein the phosphors are configured to be injected nearby the diseased site for illumination of the photoactivatable drug to treat the diseased site.

### Claim 8 (depends on 7)

The system of claim 7, wherein the phosphors comprise a mixture of micron-size and nanometer-size particles.

### Claim 9 (depends on 1)

The system of claim 1, wherein the phosphors comprise at least one of:
phosphor particles;
ionic doped phosphor particles;
single crystal or poly-crystalline powders;
single crystal or poly-crystalline monoliths;
scintillator particles;
a metallic shell encapsulating at least a fraction of a surface of the phosphors;
a semiconductor shell encapsulating at least a fraction of a surface of the phosphors;
an insulator shell encapsulating at least a fraction of a surface of the phosphors; and
phosphors of a distributed particle size.

### Claim 10 (depends on 1)

The system of claim 1, wherein the phosphors comprise at least one of Y2O3; ZnS; ZnSe; MgS; CaS; Mn, Er ZnSe; Mn, Er MgS; Mn, Er CaS; Mn, Er ZnS; Mn, Yb ZnSe; Mn, Yb MgS; Mn, Yb CaS; Mn, Yb ZnS:Tb3+, Er3+; ZnS:Tb3+; Y2O3:Tb3+; Y2O3:Tb3+, Er3+; ZnS:Mn2+; ZnS:Mn, Er3+; CaWO4, YaTO4, YaTO4:Nb, BaSO4:Eu, La2O2S:Tb, BaSi2O5:Pb, NaI(Tl), CsI(Tl), CsI(Na), CsI(pure), CsF, KI(Tl), LiI(Eu), BaF2, CaF, CaF2(Eu), ZnS(Ag), CaWO4, CdWO4, YAG(Ce) (Y3Al5O12(Ce)), BGO bismuth germanate, GSO gadolinium oxyorthosilicate, LSO lutetium oxyorthosilicate, LaCl3(Ce), LaBr3(Ce), LaPO4; Ce, Tb (doped), Zn2SiO4:Mn with Mn doped between 0.05-10%, and YTaO4.

### Claim 11 (depends on 1)

The system of claim 1, wherein the phosphors comprise down conversion media, and agglomerations thereof with or without plasmonic agents.

### Claim 12 (depends on 1)

The system of claim 1, wherein the photoactivatable drug comprises a psoralen compound mixed with the phosphors.

### Claim 13 (depends on 1)

The system of claim 1, wherein the photoactivatable drug is selected from psoralens, pyrene cholesteryloleate, acridine, porphyrin, fluorescein, rhodamine, 16-diazorcortisone, ethidium, transition metal complexes of bleomycin, transition metal complexes of deglycobleomycin organoplatinum complexes, alloxazines, vitamin Ks, vitamin L, vitamin metabolites, vitamin precursors, naphthoquinones, naphthalenes, naphthols and derivatives thereof having planar molecular conformations, porphorinporphyrins, dyes and phenothiazine derivatives, coumarins, quinolones, quinones, and anthroquinones.

### Claim 14 (depends on 1)

The system of claim 1, wherein the photoactivatable drug comprises a psoralen, a coumarin, a porphyrin or a derivative thereof.

### Claim 15 (depends on 1)

The system of claim 1, wherein the photoactivatable drug comprises 8-MOP, TMP, or AMT.

### Claim 16 (depends on 1)

The system of claim 1, wherein the photoactivatable drug comprises one selected from 7,8-dimethyl-10-ribityl, isoalloxazine, 7,8,10-trimethylisoalloxazine, 7,8-dimethylalloxazine, isoalloxazine-adenine dinucleotide, alloxazine mononucleotide, aluminum (III) phthalocyanine tetrasulonate, hematoporphyrin, and phthadocyanine.

### Claim 17 (depends on 1)

The system of claim 1, wherein the photoactivatable drug is coupled to a carrier that is capable of binding to a receptor at the diseased site.

### Claim 18 (depends on 17)

The system of claim 17, wherein the carrier is one selected from insulin, interleukin, thymopoietin or transferrin.

### Claim 19 (depends on 17)

The system of claim 17, wherein the receptor is one selected from nucleic acids of nucleated cells, antigenic sites on nucleated cells, or epitopes.

### Claim 20 (depends on 1)

The system of claim 1, wherein the photoactivatable drug has an affinity for a tumor at the diseased site.

### Claim 21 (depends on 20)

The system of claim 20, wherein the photoactivatable drug is capable of being absorbed by a tumor at the diseased site.

### Claim 22 (depends on 21)

The system of claim 21, wherein the photoactivatable drug is a DNA intercalator or a halogenated derivative thereof.

### Claim 23 (depends on 1)

The system of claim 1, wherein the initiation energy source is configured to deliver a controlled radiation dose to the phosphors for activation of the photoactivatable drug.

### Claim 24 (depends on 23)

The system of claim 23, wherein the controlled radiation dose causes an auto-vaccine effect in the human or animal body.

### Claim 25 (depends on 1)

The system of claim 1, wherein the processor is configured to control the x-ray or source during a booster treatment repeated on a periodic basis after an initial treatment of the diseased site.

### Claim 26 (depends on 1)

The system of claim 1, wherein the initiation energy source is configured to direct radiation to at least one of a tumor or a malignancy.

### Claim 27 (depends on 1)

The system of claim 1, wherein the initiation energy source is configured to direct radiation to at least one of a eukaryotic cell, a prokaryotic cell, a subcellular structure, an extracellular structure, a virus or prion, a cellular tissue, a cell membrane, a nuclear membrane, cell nucleus, nucleic acid, mitochondria, ribosome, or other cellular organelle.

### Claim 28 (depends on 1)

The system of claim 1, wherein the initiation energy source is configured to direct said x-rays to the diseased site in a pulsed manner having an on and off time such that the on time activates the phosphors and the off time is long enough for decay of phosphor light emission.

### Claim 29 (depends on 1)

The system of claim 1, wherein the initiation energy source is configured to direct said x-rays to the diseased site according to a predetermined radiation protocol such that a predetermined change occurs in the diseased site.

### Claim 30 (depends on 29)

The system of claim 29, wherein
said predetermined change at least one of 1) affects a prion, viral, bacterial, fungal, or parasitic infection, 2) comprises at least one of one of tissue regeneration, inflammation relief, pain relief, immune system fortification, or 3) comprises at least changes in cell membrane permeability, up-regulation and down-regulation of adenosine triphosphate and nitric oxide.

### Claim 31

A system for treating a diseased sited site in a human or animal body, comprising:
a pharmaceutical carrier including one or more phosphors which are capable of emitting ultraviolet or visible light into the body;
a photoactivatable drug for intercalating into DNA of cells at the diseased site;
one or more devices which are configured to infuse the diseased site with the photoactivatable drug and the pharmaceutical carrier;
an initiation energy source comprising an x-ray source which is configured to irradiate the diseased site with x-rays to thereby initiate emission of said ultraviolet or visible light into the body; and a processor programmed to control a dose of said to the diseased site for production of said ultraviolet or visible light at the diseased site to activate the photoactivatable drug, wherein the infusion of the photoactivatable drug and the phosphors into the diseased site and the dose of x-rays produces a day-25 stable tumor volume,
wherein an amount of the phosphors in the pharmaceutical carrier ranges from 0.1 to 0.66 milligrams of phosphor per cm3 of the volume of the diseased site, and a concentration of the photoactivatable drug in the pharmaceutical carrier ranges from 10 μg/mL to 50 μg/mL; and
wherein the processor is programmed to apply the x-rays to the diseased site in a pulsed manner, wherein the x-rays are delivered in either (i) a radiograph mode where multiple pulses of a set mA and ms are delivered every 5-15 seconds, or (ii) a pulsed fluoroscopy mode at a maximum mA setting.

### Claim 32 (depends on 31)

The system of claim 31, wherein the infusion of the photoactivatable drug and the phosphors and the dose of x-rays or electrons produces a day-25 tumor volume reduction of at least 10%.

### Claim 33 (depends on 31)

The system of claim 31, wherein the infusion of the photoactivatable drug and the phosphors and the dose of x-rays or electrons produces a day-25 complete tumor remission.

### Claim 34 (depends on 31)

The system of claim 31, wherein the infusion of the photoactivatable drug and the phosphors and the dose of x-rays or electrons produces a day-25 tumor volume reduction of at least 20%.

### Claim 35 (depends on 31)

The system of claim 31, wherein the infusion of the photoactivatable drug and the phosphors and the dose of x-rays or electrons produces a day-25 tumor volume reduction of at least 30%.

### Claim 36 (depends on 31)

The system of claim 31, wherein the infusion of the photoactivatable drug and the phosphors and the dose of x-rays or electrons produces a day-25 tumor volume reduction of at least 40%.

### Claim 37 (depends on 31)

The system of claim 31, wherein the infusion of the photoactivatable drug and the phosphors and the dose of x-rays or electrons produces a day-25 tumor volume reduction of at least 50%.