# US 2019/0167822 A1 · Non-iodinated radiolabeled radiopaque microbeads with mri contrast for radioembolization

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- Number: US 2019/0167822 A1
- Document ID: US20190167822A1
- Status: Published application
- Kind: A1
- Application number: 16/302,565
- Filed: 2017-05-19
- Published: 2019-06-06
- Earliest claimed: 2016-05-19
- Assignees: Amrita Vishwa Vidyapeetham
- Applicants: Amrita Vishwa Vidyapeetham
- Inventors: Manzoor KOYAKUTTY; Vijay Harish SOMASUNDARAM; Anusha ASHOKAN; Shantikumar NAIR
- Web page: https://patentgrep.com/patent/US20190167822A1

## CPC

- A61K 51/1251: {micro- or nanospheres, micro- or nanobeads, micro- or nanocapsules}
- A61K 49/0002: {General or multifunctional contrast agents, e.g. chelated agents}
- A61K 49/0419: {Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer}
- A61K 49/1821: {coated or functionalised microparticles or nanoparticles}
- A61K 51/0474: {complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group}
- A61P 35/00: Antineoplastic agents
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention discloses non-iodinated radiopaque microbeads that may be used in image guided embolization in a subject ailing with tumor. The non-iodinated radiopaque microbeads include a ceramic material doped with a CT contrast agent or a MRI contrast agent or both. The doped ceramic is blended with a polymer and the blend is electrosprayed to form the radiopaque microbeads. Further the radiopaque microbeads are radiolabeled with a radioactive isotope. Methods of synthesis of the radiopaque microspheres are also disclosed. The non-iodinated radiopaque microbeads with radiolabeling are capable of rendering an imageable computed tomography (CT) contrast or magnetic resonance imaging (MRI) contrast when administered in a subject. Also the microspheres are biodegradable and hence the treatment could be repeated in case of recurrence of the tumor in the subject.

## Claims

### Claim 1

A non-iodinated, radiopaque microbead or microsphere composition for use in image-guided embolization or radioembolization in a subject, comprising:
a ceramic material (C), comprising an impurity dopant (X), wherein the impurity dopant X is present at a concentration of 0-30% (w/w) and is selected from molybdenum, tungsten, zirconium or gold or a combination thereof;
a polymer binder blended to the ceramic material; and
a radioisotope conjugated to the ceramic material or the microbeads,
wherein the composition renders imageable computed tomography (CT) contrast or magnetic resonance imaging (MRI) contrast, or both, when administered to the subject.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the image-guided embolization is selected from transarterial embolization (TE), transarterial radioembolization (TARE) or Selective Internal Radiation Therapy (SIRT) of tumors.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the size of the microsphere is 1-1500 μm.

### Claim 4 (depends on 1)

The composition of claim 1, further comprising a magnetic resonance imaging (MRI) contrast agent or dopant, doped or loaded in the ceramic material.

### Claim 5 (depends on 4)

The composition of claim 4, wherein the MRI contrast agent is selected from iron, manganese, terbium, erbium, dysprosium, holmium, thulium, bismuth, barium, strontium, iodine, zirconium, lanthanides, hafnium or aluminium.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the ceramic is selected from the group consisting of alumina, zirconia, silica, hydroxyapatite, calcium aluminate, bioactive glass, cerium oxide, calcium sulphate, calcium molybdate, calcium silicates, calcium carbonate, α-tricalcium phosphate, β-tricalcium phosphate, octocalcium phosphate, dicalcium phosphates, tetracalcium phosphate monoxide, ferric-calcium-phosphorus oxides, biocorals or any combination thereof.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the polymer is selected from the group comprising of polyvinyl alcohols, polyacrylic acids, polymethacrylic acids, polyethylenimines, poly vinyl sulphonates, carboxymethyl celluloses, hydroxymethyl celluloses, oxidized cellulose, gellan, gum arabic, substituted celluloses, polyanhydrides, poly (ortho)esters, polyacrylamides, polyethylene glycols, polyamides, polyvinylpyrrolidones, polyureas, polyurethanes, polyesters, polyethers, polystyrenes, polysaccharides, polylactic acids, polyethylenes, polymethyl methacrylates, polycaprolactones, polyvinyl acetate, polyglycolic acids, poly(lactic-co-glycolic) acids, albumin, transferrin, caseins, gelatin, mannose, sucrose, starch, galactose, galactomannans, or a combination thereof.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the polymer is a biopolymer selected from alginate, gelatin, collagen, chitosan, carboxymethyl chitosan, chitin, cellulose, carboxymethyl cellulose, dextran, fibrin, hyaluronic acid, chondroitin sulphate, agarose, starch, poly[lactic-co-glycolic] acid, poly-L-lactic acid, polylactic acid, polycaprolactone, polyvinyl alcohol, polyhydroxy butyrate, polyhydroxy butyrate co hydroxyvalerate, polyphosphazenes, polyurethane, or polyanhydrides.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the polymer is present at a concentration of 0-30% (w/w) of the ceramic.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the microspheres are biodegradable and undergo degradation in at least two months.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the composition is administered by intra-arterial, transarterial, intra-articular or local route.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the microspheres are non-iodinated and show combinatorial CT and MRI contrast in T2 mode with relaxivity of at least R2=17 mM−1s−1.

### Claim 13 (depends on 1)

The composition of claim 1, the radioisotope is selected from 99mTc, 111In, 123I, 131I, 188Re, 186Re, 166Ho, 32P, 18F, 68Ga, 177Lu, 90Y, 166Dy, 103Pd, 169Yb, 212Bi, 213Bi, 212Po, 225Ac, 211At, 89Sr, 192Ir, 194Ir or 223Ra conjugated to the microspheres.

### Claim 14

A method of synthesis of radiopaque microsphere or microbeads capable of rendering an imageable computed tomography (CT) contrast when administered in a subject comprising:
doping or co-loading an impurity dopant in a ceramic to obtain a ceramic material, wherein the impurity dopant is present at a concentration of 0-30% (w/w) and is selected from molybdenum, tungsten or zirconium or a combination thereof, for X ray contrast and from iron, manganese, terbium, erbium, dysprosium, holmium, thulium, bismuth, barium, strontium, iodine, zirconium, lanthanides, hafnium or aluminium or thereof, for MRI contrast;
blending the ceramic material with a polymer solution;
electrospraying the blend with or without a crosslinker to form microbeads;
incubating the formed microbeads at an optimum temperature for 48 hours and
radiolabeling the microbeads with a radioisotope to produce the radiolabeled radiopaque microbeads.

### Claim 15 (depends on 14)

The method of claim 14 wherein the crosslinker is selected from one of bivalent cationic solutions comprising calcium chloride, stannous chloride, barium chloride or ferric chloride, carbodiamides, EDC, trivinyl sulphones, acrylamides, epoxides, polyamides, maleimide, iminoesters, or combinations thereof.

### Claim 16 (depends on 14)

The method of claim 14 further comprising the step of calcining the beads in the temperature range 100-1000° C. to produce the radiopaque beads.

### Claim 17 (depends on 14)

The method of claim 14 wherein the beads are further subjected to lyophilization to produce the radiopaque beads.

### Claim 18 (depends on 14)

The method of claim 14, wherein the synthesized microbeads are non-iodinated

### Claim 19 (depends on 14)

The method of claim 14, wherein the radiolabeling of microbeads is done either by direct interaction or by using an appropriate ligand or chelating agent.

### Claim 20 (depends on 19)

The method of claim 19 wherein, the ligand or chelating agent is selected from bisphosphonates, DMSA, DMDTPA, ethylene dicysteine, mercaptoacetyltriglycine, hydrazinonicotinamide, iminodiacetic acid, a crown ether, DTPA monoamide, EDTA, DOTA, EGTA, BAPTA, DO3A, NOTA-Bn, styrene, butyl acrylate, glycidil methacrylate, aminocarboxylic acids, NODASA, NODAGA, peptides, oligomers, amino acids, 10-decanedithiol (HDD), ethyl cysteinate dimer complexes, DEDC, methoxyisobutylisonitrile, or derivatives or combinations thereof.

### Claim 21 (depends on 19)

The method of claim 19, wherein the ligand or chelating agent, with or without radiolabeling, is either covalently or electrostatically bound to the microbeads.

### Claim 22 (depends on 14)

The method of claim 14, further comprising conjugating the microsphere with a chemotherapeutic agent.

### Claim 23

A method of medical treatment of a tumor in a mammal comprising:
administering a therapeutically effective amount of a non-iodinated, radiopaque microbead or microsphere composition for use in image-guided embolization or radioembolization of the tumor, comprising:
a ceramic material (C), comprising an impurity dopant (X), wherein the impurity dopant is present at a concentration of 0-30% (w/w) and is selected from molybdenum, tungsten, zirconium or gold or a combination thereof;
a polymer binder blended to the ceramic material, and
a radioisotope conjugated to the ceramic material or the prepared microbeads, wherein the composition renders imageable computed tomography (CT) contrast or magnetic resonance imaging (MRI) contrast, or both, when administered to the subject.

### Claim 24 (depends on 23)

The method of claim 23 wherein the non-iodinated radiopaque microbeads are used in combination with radiofrequency ablation, chemotherapy or immunotherapy.

### Claim 25 (depends on 23)

The method of claim 23 wherein the non-iodinated radiopaque microbeads are biodegradable.

### Claim 26 (depends on 23)

The method of claim 23 wherein the method is repeated on re-occurrence of the tumor.