WO2007002332A2 - Optical imaging contrast agents - Google Patents
Optical imaging contrast agents Download PDFInfo
- Publication number
- WO2007002332A2 WO2007002332A2 PCT/US2006/024373 US2006024373W WO2007002332A2 WO 2007002332 A2 WO2007002332 A2 WO 2007002332A2 US 2006024373 W US2006024373 W US 2006024373W WO 2007002332 A2 WO2007002332 A2 WO 2007002332A2
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- WO
- WIPO (PCT)
- Prior art keywords
- optical
- composition
- group
- saccharide
- optical dye
- Prior art date
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- UQZIYBXSHAGNOE-XNSRJBNMSA-N stachyose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@@H]2[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO[C@@H]3[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O3)O)O2)O)O1 UQZIYBXSHAGNOE-XNSRJBNMSA-N 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
- A61K49/0052—Small organic molecules
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
- A61K49/0065—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle
- A61K49/0067—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the luminescent/fluorescent agent having itself a special physical form, e.g. gold nanoparticle quantum dots, fluorescent nanocrystals
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y10/00—Nanotechnology for information processing, storage or transmission, e.g. quantum computing or single electron logic
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Definitions
- the present invention generally relates to compositions and methods for the selective identification of diseased or damaged sites in the gastrointestinal tract. More particularly, the present invention relates to sulfated and/or phosphated saccharides or physiologically acceptable salts thereof, more specifically polysulfated and/or polyphosphated saccharide metal salts, such as sucralfate, labeled with or containing at least one optical molecule, and the use of these sulfated and/or phosphated saccharides containing an optical molecule for the identification of ulcers in the gastrointestinal tract.
- An upper endoscopy also called esophagogastroduodenoscopy (EGD)
- EGD esophagogastroduodenoscopy
- a thin, flexible, lighted tube typically also comprising a small camera, is inserted through the mouth and down the throat.
- the endoscope transmits images of the inside of the esophagus, stomach, and duodenum, allowing the physician to see abnormalities such as inflammation or bleeding that may not otherwise be easily identified.
- endoscopy is typically more accurate than some other imaging techniques, such as x-ray imaging
- endoscopy has several drawbacks, including patient discomfort due to the invasive nature of the procedure, and the necessity of using a sedative and analgesic.
- Patients receiving an EGD may also suffer a sore throat, and risk possible bleeding and puncture of the stomach lining.
- X-rays may also be used to diagnose gastric ulcerations.
- an x-ray contrast agent such as a radiopaque agent
- the x-ray contrast agent is commonly a water-soluble iodinated compound. Since the iodine in these compounds blocks x-rays, the buildup or localization of the iodine in the area to be x-rayed, such as the stomach, provides the needed contrast between the stomach and other tissues for the formation of an x-ray picture. This contrast allows a physician to visualize problems and abnormalities in the stomach.
- barium sulfate is frequently used for x-ray examination of the gastrointestinal system. Like other x-ray contrast agents, barium sulfate may be administered orally, and coats the upper gastrointestinal tract, rendering it opaque to x-rays. The esophagus, stomach, and/or duodenum may then be evaluated.
- barium sulfate and other x-ray contrast agents has several drawbacks.
- barium sulfate when administered orally, barium sulfate does not always coat the entire gastrointestinal mucosa, which may result in a failure to properly diagnosis gastric ulcers.
- the chalkiness of the barium sulfate may make ingestion unpalatable and unpleasant for the patient, and ingestion of the barium sulfate may cause constipation, diarrhea, or cramping.
- sucralfate and potassium sucrose sulfate molecules labeled with a paramagnetic, superparamagnetic, or ferromagnetic ion or particle The labeled sucralfate may be used in magnetic resonance imaging (MRI) of the gastrointestinal area.
- MRI magnetic resonance imaging
- biomedical optics Another method for evaluating the gastrointestinal tract is biomedical optics, which is a relatively new technology that has a large number of potential diagnostic and therapeutic applications.
- imaging biomedical optics may have some favorable features as compared to current imaging techniques such as commuted tomography, magnetic resonance imaging, and nuclear medicine.
- Some benefits include: (1) the need for only a small amount of contrast agent; (2) the use of a non-radioactive energy source; and (3) the use of relatively inexpensive instruments.
- the present invention relates to compositions and methods for the selective identification of diseased or damaged sites in the gastrointestinal tract. More particularly, the present invention relates to sulfated and/or phosphated saccharides or physiologically acceptable salts thereof, more specifically polysulfated and/or polyphosphated saccharide metal salts, such as sucralfate, comprising at least one optical molecule, and the use of the sulfated and/or phosphated saccharides or physiologically acceptable salts thereof comprising at least one optical molecule for the identification of gastric ulcers in the gastrointestinal tract.
- optical molecule- containing saccharide class of compounds and derivatives thereof to selectively bind to gastric ulcers and lesions in the gastrointestinal tract enables visualization of the ulcers and lesions using a variety of optical detection techniques.
- optical molecule(s) means optical dyes, nanoparticles, and optical dye encapsulated in a physiologically acceptable particulate material that are suitable for optical detection in the gastrointestinal tract.
- suitable optical dye chemically introduced into the sulfated and/or phosphated saccharides
- suitable nanoparticles including quantum dots
- optical dyes encapsulated in a physiologically acceptable particulate material which are physically introduced into the sulfated and/or phosphated saccharides and which can be optically detected in the gastrointestinal tract
- substituted means the chemical introduction of a compound or molecule onto a saccharide molecule.
- saccharides of the invention the terms "molecule(s)” and “compound(s)” are used interchangeably.
- the optical imaging agents of the present invention comprise saccharide molecules containing at least one optical molecule, e.g., substituted with at least one optical dye, capable of being optically detected in the gastrointestinal tract.
- the saccharide molecule may be any physiologically acceptable substituted saccharide, or physiologically acceptable salt thereof, that selectively binds to ulcerated and/or inflamed sites of the gastrointestinal tract.
- the saccharide molecules are sulfated and/or phosphated saccharides or physiologically acceptable salts thereof.
- sulfated saccharide or “saccharide sulfate,” used interchangeably, refer to a saccharide molecule comprising one or more sulfate groups.
- phosphated saccharide or “saccharide phosphate,” used interchangeably, refer to a saccharide molecule comprising one or more phosphate groups.
- the sulfated and/or phosphated saccharide is polysulfated and/or polyphosphated, i.e., has two or more sulfate and/or phosphate groups.
- the saccharide itself that may be used in the optical imaging agents of the present invention includes monosaccharides and polysaccharides.
- polysaccharides is meant to encompass disaccharides as well as tri-, tetra-, and oligosaccharides.
- suitable saccharides include fructose, glucose, ribose, mannose, lactose, maltose, sucrose, erythrose, threose, arabinose, deoxyribose, cellobiose, trehalose, melezitose, and stachyose, among others, or any combination thereof.
- the saccharide is a disaccharide.
- the currently preferred disaccharides are sucrose, lactose, or maltose. More preferably, the disaccharide is sucrose.
- the optical imaging compositions of the present invention may thus include substituted monosaccharides, substituted polysaccharides, or combinations thereof. Any substituted saccharide that selectively binds to damaged and/or inflamed sites of the gastrointestinal tract may be suitable for use in the present invention.
- the saccharides of the present invention may thus comprise: (1) mono- or polysulfated saccharides; (2) mono- or poly- phosphated saccharides; (3) saccharides that have been both phosphated and sulfated (i.e., sulfated-phosphated saccharides), (4) any other physiologically acceptable substituted saccharide that selectively binds to ulcerated and/or inflamed sites of the gastrointestinal tract; and (5) mixtures thereof.
- the sulfated and/or phosphated saccharide molecules used herein will bind with greater affinity to damaged sites of the gastrointestinal tract, such as inflamed and ulcerated sites, than to healthy sites.
- physiologically acceptable salts of the saccharides may be used herein.
- Physiologically acceptable salts include salts formed with suitable bases. Examples of such suitable salts are salts of alkali metals (e.g., sodium and potassium), alkaline earth metals (e.g., calcium, magnesium and barium), aluminum, ammonium (NH 4 + ), and combinations thereof.
- alkali metals e.g., sodium and potassium
- alkaline earth metals e.g., calcium, magnesium and barium
- aluminum ammonium
- saccharide metal salts such as aluminum, calcium, magnesium, sodium, potassium, barium, or any other physiologically acceptable salt, and combinations thereof may be used.
- the salt is aluminum salt.
- the saccharide is a polysulfated disaccharide aluminum salt.
- a saccharide is sucralfate ( ⁇ -D-glucopyranoside, ⁇ -D-fractofuranosyl-, octakis- (hydrogen sulfate), aluminum complex).
- Sucralfate (commercially available as CARAFATE , Hoechst Marion Roussel) is a basic aluminum complex of sulfated sucrose, having general fo ⁇ nula (1):
- R is -SO 3 Al(OH) 2 ; x is 8 to 10; and y is 22 to 31.
- sucralfate is used in the treatment of peptic, duodenal, and prepyloric ulcers, gastritis, reflux esophagitis, and other gastrointestinal irritations.
- sucralfate binds selectively to ulcerated, rather than cartilageated, areas in the gastrointestinal tract. Specifically, it has been shown that approximately six to seven times more sucralfate binds to ulcerated gastric mucosa than to prunecerated mucosa in humans.
- Sucralfate coats gastric and peptic ulcerated tissue by adhering to the proteinaceous exudate at the ulcer site and forming a protective barrier to acid, pepsin, or bile salts. It is believed that this protective barrier facilitates healing of the ulcerated gastric tissue by blocking the damaged site from further attack. Sucralfate may also exert an anti-ulcer effect by depletion of acid, pepsin, and bile salts from the gastric secretion, and by promoting revascularization and regeneration of ulcerated mucosal tissue.
- the present invention combines a sulfated and/or phosphated saccharide with a suitable optical molecule to produce an optical imaging agent that can be used to specifically target and image inflamed or ulcerated sites of the gastrointestinal tract.
- an optical imaging agent that can be used to specifically target and image inflamed or ulcerated sites of the gastrointestinal tract.
- any saccharide composition that has binding specificity for gastrointestinal ulcerated mucosa or other gastrointestinal diseases can be chemically modified in accordance with the present invention to produce a suitable optical imaging contrast agent.
- Other suitable compounds may include, in addition to those discussed above, for example, other physiologically acceptable polysulfated and/or polyphosphated saccharide metal salts, and derivatives of sucralfate, among others.
- Suitable dyes for substitution into or attachment onto a sulfated and/or phosphated saccharide molecule are optical dyes.
- optical dye means a dye that transmits, reflects, or fluoresces light in the wavelength range of about 350 nanometers to about 1300 nanometers, and is sufficiently stable under the conditions found in the gastrointestinal tract, e.g., in aqueous systems under acidic conditions.
- "sufficiently stable” means stable for a time sufficient to permit administration of the optical imaging agent of the present invention to the patient and obtaining the optical image.
- the sufficiently stable optical dyes are stable under the pH conditions in the upper gastrointestinal tract (e.g., stable at pH ⁇ 5, preferably pH ⁇ 3) for up to about 30 minutes to 4 hours, more particularly up to about 30 minutes to 2 hours.
- the optical dyes of the present invention preferably do not contain aliphatic chains or groups substituted with primary amine, secondary amine, aldehyde or ketone groups.
- optical dyes described herein and attached to a sulfated and/or phosphated saccharide molecule allow ulcerated and inflamed sites of the gastrointestinal tact to be detected using various optical imaging techniques, such as, for example, various optical tomographic, endoscopic, photoacoustic, and sonofluorescence applications.
- any suitable optical dye, or derivative thereof, known in the art may be used in combination with sulfated and/or phosphated saccharide in accordance with the present invention.
- suitable optical dye molecules in accordance with the present invention comprise at least one substituent selected from -SO 3 H (sulfonic acid), -PO 4 H 2 (phosphoric acid), - COOH (carboxylic acid), and combinations thereof.
- the optical dye molecule comprises at least two of the acid substituents. If the optical dye molecule comprises at least two acid substituents, at least two of the acid substituents are optionally in close proximity to one another in the optical dye structure.
- optical dye molecules of the present invention are believed to have low toxicity.
- optical dye molecules containing two or more sulfonic acid groups or their salts are described in U.S. Pat. No. 6,329,531, herein incorporated by reference in its entirety.
- optical dye molecules containing three or more sulfonic acid groups are described in WO 01/43781, herein incorporated by reference in its entirety.
- Food dyes containing one or more -SO 3 H or -PO 4 H 2 groups and meeting the other requirement of optical dyes according to the present invention may also be suitable for use in the present invention.
- suitable optical dyes include: cyanines, indocyanines (such as indocyanine green), phthalocyanines, squaraines, polymethines, pyrazines, rhodamines, fluoresceins, and derivatives and analogues thereof.
- suitable optical dyes are known in the art.
- suitable cyanine and/or indocyanine dyes are described in U.S. Pat. No. 6,180,085; U.S. Pat. No. 6,180,087; U.S. Pat. No. 5,453,505; U.S. Pat. No. 6,258,340; U.S. Pat. App. Pub. No. 2003/0180221; WO 00/16810; and WO 01/43781, all herein incorporated by reference in their entirety.
- Other suitable optical dyes are described in U.S. Pat. No. 6,277,841; and U.S. Pat. No. 6,540,981, all herein incorporated by reference in their entirety. Based on the description of the present invention, it will be readily apparent to one skilled in the art which of the dyes disclosed in each of the above-listed patents and published patent applications will be suitable optical dyes of the present invention.
- Preparation of the optical dyes of the present invention can be done using conventional processes well known to those of ordinary skill in the art. For example, see the above patents and published applications, such as WO 01/43781, for descriptions of how to prepare the optical dyes taught therein.
- the optical dye for incorporation into the sulfated and/or phosphated saccharide is a cyanine dye, indocyanine dye, or a derivative thereof, such as those described in U.S. Patent Nos. 6,180,087 and 6,180,085.
- the cyanine dye is a dye of general formula (2):
- W 1 and X 1 may be the same or different and are selected from the group consisting Of-CR 10 R 11 , -O-, -NR 12 , -S-, and -Se;
- Q 1 is a single bond or is selected from the group consisting of -O-, -S-, -Se-, and -NR 13 ;
- Y 1 and Z 1 may be the same or different and are selected from the group consisting of -(CH 2 ) C -CO 2 H, -(CH 2 ) C -SO 3 H, -(CH 2 ) C -PO 4 H 2 , -CH 2 -(CH 2 -O-CH 2 ) rf -CH 2 -CO 2 H, -CH 2 -(CH 2 -O-CH 2 ) ⁇ -CH 2 -SO 3 H, -CH 2 -(CH 2 -O-CH 2 ) ⁇ CH 2 -PO 4 H
- R 1 and R 10 to R 15 may be the same or different and are selected from the group consisting of hydrogen, Cl-ClO alkyl, Cl-ClO aryl, Cl-ClO alkoxyl, Cl-ClO polyalkoxyalkyl, -CH 2 (CH 2 -O-CH 2 ) C -CH 2 -OH, C1-C20 polyhydroxyalkyl, Cl- ClO polyhydroxyaryl, -(CH 2 ) ⁇ -CO 2 H, -(CH 2 ) ⁇ -SO 3 H, -(CH 2 ) ⁇ -PO 4 H 2 , -CH 2 -(CH 2 -O-CH 2 VCH 2 -CO 2 H, -CH 2 -(CH 2 -O-CH 2 ) ⁇ CH 2 -SO 3 H, and
- R 2 to R 9 may be the same or different and are selected from the group consisting of hydrogen, Cl-ClO alkyl, Cl-ClO aryl, hydroxyl, Cl-ClO polyhydroxyalkyl, Cl-ClO alkoxyl, cyano, nitro, -COOH, -SO 3 H, -PO 4 H 2 , and halogen.
- the cyanine dye is a dye of general formula (3):
- a 3 and b 3 are defined in the same manner as ai and t>i; W 3 and X 3 are defined in the same manner as W 1 and X 1 ; Y 3 is defined in the same manner as Y 1 ; Z 3 is defined in the same manner as Z 1 ;
- R 43 and R 44 may be the same or different and are selected from the group consisting of hydrogen, Cl-ClO alkyl, and Cl-ClO aryl, or together form a 5, 6, or 7 membered heterocyclic ring optionally containing one or more oxygen, nitrogen, or a sulfur atom.
- the cyanine dye is a dye of general formula (4):
- a 5 is defined in the same manner as a ⁇ W 5 and X 5 are defined in the same manner as W 1 and X 1 ; Y 5 is defined in the same manner as Y 1 ; Z 5 is defined in the same manner as Z 1 ; A 3 is defined in the same manner as A 1 ; B 3 , C 3 , and D 3 are defined in the same manner as Bi, C 1 , and Di; and R 5S to R 66 are defined in the same manner as R 29 to R 37 .
- the optical dye used herein may also be an indocyanine dye, for example, indocyanine green.
- the indocyanine dye may be an indocyanine dye such as those described in U.S. Patent Nos. 6,180,087 and 6,180,085.
- the indocyanine dye is a dye of general formula (5):
- a 2 and b 2 are defined in the same manner as ai and bi; W 2 and X 2 are defined in the same manner as W 1 and X 1 ; Q 2 is defined in the same manner as Q 1 ; R l ⁇ and R 10 to R 15 are defined in the same manner as R 1 and R 10 to R 15 ; Y 2 is defined in the same manner as Y 1 ; Z is defined in the same manner as Z ; and R to R" are defined in the same manner as R to R .
- the sulfated and/or phosphated saccharide molecules described herein may be substituted with more than one optical dye. Because of the specificity of the sulfated and/or phosphated saccharide molecule (such as sucralfate and its precursors and derivatives) for damaged areas of the gastrointestinal tract, only a small amount of optical dye is required for detection. This is particularly advantageous because the use of small amounts of dye reduces the risk of dye toxicity to the patient.
- optical dye substituted saccharide sulfate composition or "optical dye substituted sulfated saccharide composition”, used interchangeably herein, refers to a composition comprising at least one sulfated saccharide molecule that is substituted at one or more position on the sulfated saccharide with at least one optical dye.
- optical dye substituted saccharide phosphate composition or “optical dye substituted phosphated saccharide composition”, used interchangeably herein, refers to a composition comprising at least one phosphated saccharide molecule that is substituted at one or more position on the phosphated saccharide with at least one optical dye.
- sulfated and/or phosphated saccharide molecule in the composition needs to be substituted with an optical dye, so long as a sufficient amount of the sulfated and/or phosphated saccharide molecules are substituted to enable detection of damaged areas of the gastrointestinal tract.
- the amount of optical molecule, and particularly optical dye, required for detection will vary depending on the optical molecule selected and optical detection technique used, and mav readilv be determined bv one skilled in the art.
- the amount of ODtical dye in an optical dye substituted sulfated and/or phosphated saccharide composition may be specified as the mole ratio of total optical dye to total sulfated and/or phosphated saccharide and may be in the ranges of about 0.0001:1 to about 3:1, 0.001:1 to about 1:1, about 0.002:1 to about 1:1, and about 0.005:1 to about 0.5:1.
- optical dye substituted sucralfate may be reacted with 1 mole of sucralfate to produce a composition comprising optical dye substituted sucralfate with a mole ratio of optical dye to sucralfate of about 0.01:1.
- the composition of the present invention may comprise sulfated and/or phosphated saccharide molecules substituted at one position with the optical dye, sulfated and/or phosphated saccharide molecules substituted at multiple positions with the optical dye, unsubstituted sulfated and/or phosphated saccharide molecules, and combinations thereof.
- optical dye substituted sulfated and/or phosphated saccharide compositions of the present invention may optionally comprise more than one type of optical dye. Such compositions may advantageously enable the detection of damaged areas of the gastrointestinal tract using multiple detection methods.
- the optical dyes are selected from the group consisting of cyanine dyes and indocyanine dyes.
- an optical dye substituted sulfated and/or phosphated saccharide composition comprising two or more types of optical dye may be prepared by reacting two or more types of optical dye with the sulfated and/or phosphated saccharide.
- the resulting composition may comprise sulfated and/or phosphated saccharide molecules substituted with only one of the optical dyes, sulfated and/or phosphated saccharide molecules substituted with two or more of the optical dyes, unsubstituted sulfated and/or phosphated saccharide molecules, and combinations thereof.
- an optical dye substituted sulfated and/or phosphated saccharide composition comprising two or more types of optical dye may be prepared by separately reacting each optical dye with sulfated and/or phosphated saccharide molecules to produce optical dye substituted sulfated and/or phosphated saccharide compositions comprising each dye, and combining the resulting compositions to produce an optical dye substituted sulfated and/or phosphated saccharide composition comprising two or more optical dyes.
- the optical dye substituted sulfated and/or phosphated saccharide composition comprises a mole ratio of total optical dye to total sulfated and/or phosphated saccharide within the ranges of about 0.0001 : 1 to about 3:1, 0.001: 1 to about 1:1, about 0.002:1 to about 1:1, and about 0.005: 1 to about 0.5:1.
- optical dyes described above may be introduced or substituted into the sulfated and/or phosphated saccharide molecule at one or more positions on the molecule in accordance with the present invention.
- the optical dye is introduced into a saccharide having general formula (6):
- R is selected from the group consisting of -SO 3 M(OH) b , -PO 3 M(OH) b , hydrogen, and any combination thereof, so long as at least one — R group is -S ⁇ 3 M(OH) b , or — PO 3 M(OH) 1 ,;
- M is independently selected from the group consisting of Al, Ca, Mg, Na, K, Ba and NH 4 ;
- b is the valence of M minus 1 (b is 0 to 2), x is 1 to 15; and
- y is 0 to 35.
- all the R groups may be -SO 3 M(OH) b , all the R groups may be -PO 3 M(OH) b , or the R groups may be some combination of -SO 3 M(OH) b and/or -PO 3 M(OH) b and/or hydrogen, so long as at least one R group is -SO 3 M(OH) b , or -P0 3 M(0H) b .
- the optical dye may be substituted into the saccharide at various positions, as illustrated below. It is noted that formula 6 only encompasses sucrose-based sulfated and/or phosphated disaccharides. However, as previously discussed, the sulfated and/or phosphated saccharide may be any saccharide that selectively binds to damaged and/or inflamed areas of the gastrointestinal tract, and may include phosphated and/or sulfated monosaccharides and other polysaccharides. Consequently, the following discussion of optical dye substitution is intended to be exemplary, and not limiting, as similar substitutions may be made on other suitable saccharides.
- the optical dye is substituted into the saccharide molecule at any one or more of the eight -OR positions; that is, at least one (and up to all eight) of the -OR groups is eliminated and replaced with an optical dye, such that at least one optical dye replaces an -OR group and is bound, either directly or indirectly, to the ring structure or to a carbon atom that is bound to the ring structure.
- the optical dye substituted saccharide resulting from this type of substitution may have general formula (7):
- Z 1 is selected from the group consisting of an optical dye, -OR, and any combination thereof, so long as at least one Z 1 group is an optical dye
- R is selected from the group consisting of -SO 3 M(OH) b , -PO 3 M(OH) b , hydrogen, and any combination thereof, so long as at least one -R group is -SO 3 M(OH) b or -PO 3 M(OH) b
- M is independently selected from the group consisting of Al, Ca, Mg, Na, K, Ba and NH 4
- b is the valence of M minus 1 (b is 0 to 2), x is 1 to 15; and y is 0 to 35.
- the Z 1 groups may be any combination of optical dye, and/or -OR groups, so long as at least one Z 1 group is an optical dye and at least one Z 1 group is -OR.
- all the R groups may be -SO 3 M(OH) b
- all the R groups may be -PO 3 M(OH) b
- the R groups may be any combination of -SO 3 M(OH) b , and/or -PO 3 M(OH) b , and/or hydrogen, so long as at least one -R group is -SO 3 M(OH) 1 , or -P0 3 M(0H) b .
- the optical dye is substituted into the saccharide molecule at any one or more of the eight -R positions; that is, at least one (and up to all eight) of the -R groups is eliminated and replaced with an optical dye, such that at least one hydroxyl oxygen will be bonded, either directly or indirectly, to the optical dye.
- the optical dye substituted saccharide molecule resulting from this type of substitution may have general formula (8):
- M is independently selected from the group consisting of Al, Ca, Mg, Na, K, Ba, and NH 4 ;
- a is the valence of M (e.g.
- the Z 2 groups may be some combination of optical dye, and/or -R groups, and/or hydrogen, so long as at least one Z 2 group is an optical dye, and at least one Z 2 group is -R.
- R is independently selected from -SO 3 M(OH) b and --P ⁇ 3 M(OH) b " it is meant that in one molecule, all the R groups may be -S0 3 M(0H) b , all the R groups may be -P0 3 M(0H) b , or the R groups may be some combination of -S0 3 M(0H) b and -P0 3 M(0H) b .
- the optical dye is bonded to one or more of the metal atoms present in the saccharide molecule.
- the optical dye is bonded either directly or indirectly to a metal atom located in the -R group, or to a metal atom located in the complexed group.
- the optical dye substituted saccharide resulting from this type of substitution may have general formula (9):
- R is selected from the group consisting of -SO 3 M(Z 3 ) b , -PO 3 M(Z 3 ) b , hydrogen, and any combination thereof, so long as at least one -R group is -SO 3 M(Z 3 ) b or -PO 3 M(Z 3 ) b ;
- M is independently selected from the group consisting of Al, Ca, Mg, Na, K, Ba and NH 4 ; and
- Z 3 is selected from the group consisting of an optical dye, -OH, and any combination thereof, so long as at least one Z 3 group is an optical dye.
- all the Z 3 groups may be optical dye, or the Z 3 groups may be some combination of optical dye, and/or -OH groups, so long as at least one Z 3 group is an optical dye.
- the optical dye may be bonded to a metal atom (such as Al, Ca, Mg, Na, K, or Ba) located in an R group (i.e., -SO 3 M(Z 3 ) b and/or -PO 3 M(Z 3 ) b ), wherein both Z 3 groups are —OH groups, both Z 3 groups are optical dye, or the Z 3 groups are some combination of optical dye, and/or -OH.
- the optical dye may be bonded to a metal atom (such as Al, Ca, Mg, Na, K, or Ba) located in the complex group (i.e., [M(Z 3 ) a ] x [H 2 O] y ), wherein all Z 3 groups are optical dye, all Z 3 groups are -OH groups, or the Z 3 groups are some combination of optical dye, and/or -OH.
- a metal atom such as Al, Ca, Mg, Na, K, or Ba
- the complex group i.e., [M(Z 3 ) a ] x [H 2 O] y
- the Z 3 groups are some combination of optical dye, and/or -OH.
- at least one Z 3 group should be an optical dye.
- all the R groups may be -SO 3 M(Z 3 ) b , all the R groups may be - PO 3 M(Z 3 ) b , or the R groups may be some combination of -SO 3 M(Z 3 ) b , and/or -PO 3 M(Z 3 ) b , and/or hydrogen, so long as at least one R group is -SO 3 M(Z 3 ) b or -PO 3 M(Z 3 ) b .
- the optical dye is bonded to one or more of the hydroxyl oxygen atoms present in the saccharide molecule.
- the optical dye is bonded either directly or indirectly to a hydroxyl oxygen atom that is also bound to a metal atom located in the -R group, or to a hydroxyl oxygen atom that is also bound to a metal atom located in the complexed group.
- the optical dye substituted saccharide resulting from this type of substitution may have general formula (10):
- R is selected from the group consisting of -SO 3 M(OZ 4 ) b , -PO 3 M(OZ 4 ) b , hydrogen, and any combination thereof, so long as at least one -R group is -SO 3 M(Z 4 ) b or - PO 3 M(Z 4 ) b ;
- M is independently selected from the group consisting of Al, Ca, Mg, Na, K, Ba and NH 4 ;
- Z 4 is an optical dye, hydrogen, and any combination thereof, so long as at least one Z 4 group is an optical dye;
- b is the valence of M minus 1 (b is 0 to 2), x is 1 to 15; and y is 0 to 35.
- all the Z 4 groups may be optical dye, or the Z 4 groups may be some combination of optical dye, and/or hydrogen, so long as at least one Z 4 group is an optical dye.
- the optical dye may be bonded to a hydroxyl oxygen atom that is also bound to a metal atom (such as Al, Ca, Mg, Na, K, or Ba) located in the -R group (i.e., -SO 3 M(OZ 4 ) b and/or -PO 3 M(OZ 4 ) b ;), wherein both Z 4 groups are hydrogen, both Z 4 groups are optical dye, or the Z 4 groups are some combination of optical dye, and/or hydrogen.
- a metal atom such as Al, Ca, Mg, Na, K, or Ba
- the optical dye may be bonded to a hydroxyl oxygen atom that is also bound to a metal atom (such as Al, Ca, Mg, Na, K, or Ba) located in the complex group (i.e., [M(OZ 4 ) a ] x [H 2 O] y ), wherein all Z 4 groups are optical dye, all Z 4 groups are hydrogen, or the Z 4 groups are some combination of optical dye, and/or hydrogen.
- a metal atom such as Al, Ca, Mg, Na, K, or Ba
- the Z 4 groups are some combination of optical dye, and/or hydrogen.
- at least one of the Z 4 groups should be optical dye.
- the optical dye can be introduced into the saccharide molecule at a combination of one or more of the sites described above.
- the optical dye can be introduced by replacing an -R group and an -OR group and bonded to a metal atom and a hydroxyl oxygen atom, or any combination thereof.
- one type of optical dye may be attached at multiple positions on the saccharide. Alternately, two or more different types of optical dye may be attached to the same saccharide molecule at any of the above described positions.
- the number of optical dyes is not critical, so long as the optical dye substituted sulfated and/or phosphated saccharide composition comprises sufficient optical dye to enable detection of damaged areas of the gastrointestinal tract.
- optical dyes described herein may be attached to the sulfated and/or phosphated saccharide molecules at one or more of the positions described above using any suitable means known in the art.
- the optical dyes may be directly attached to the sulfated and/or phosphated saccharide molecules at the positions described above, or indirectly attached at these positions using linking means, chelator means, coupling means, and/or cross- linking means, among others.
- linking means it is meant that the optical dye is not attached to the sulfated and/or phosphated saccharide by some type of connector, such as a linker, chelator, or coupler, among others.
- the optical dye may be attached to the saccharide via one of the following or similar linkages, e.g., carbon-carbon bond, carbon-nitrogen bond, carbon-oxygen bond, oxygen-carbon bond, or oxygen-sulfur bond using conventional chemical reaction technology well known to those of ordinary skill in the art.
- linkages e.g., carbon-carbon bond, carbon-nitrogen bond, carbon-oxygen bond, oxygen-carbon bond, or oxygen-sulfur bond using conventional chemical reaction technology well known to those of ordinary skill in the art.
- indirect attachment it is meant that the optical dye is attached to the sulfated and/or phosphated saccharide molecule by means of some type of connector.
- suitable connector means include chelators, linkers, couplers, among others, or various combinations thereof. Because various attachment means are readily known in the art, they will be described only briefly herein.
- One suitable method for directly attaching the optical dye to the sulfated and/or phosphated saccharide includes, for example, reacting the -COOH group (or its equivalent) of the dye with an -OH group of the saccharide molecule leading to the formation of an ester linkage. Another option would be to react the -OH group of an optical dye with the -OH group of the saccharide molecule resulting in the formation of an ether linkage.
- the optical dye is attached to the sulfated and/or phosphated saccharide molecule via a linker by first attaching a functional group to the appropriate location in the sulfated and/or phosphated saccharide molecule and/or to an appropriate location in the optical dye to facilitate reaction between the sulfated and/or phosphated saccharide and optical dye.
- Suitable functional groups include, but are not limited to, isocyanate groups, amino groups, haloacetyl groups, tosylate groups (-OTs), and sulfonyl halides, among others. Suitable functional groups are also described in U.S. Pat. No. 6,521,209.
- Suitable linkers include polymers and coupling agents, among others, hi one embodiment, the linker is a polymer.
- the polymer may be initially attached to the sulfated and/or phosphated saccharide molecule and then, in a second reaction, used to connect the sulfated and/or phosphated saccharide to the optical dye.
- the polymer may be initially attached to the optical dye, and then, in a second reaction, used to connect the optical dye to the sulfated and/or phosphated saccharide molecule.
- the optical dye and sulfated and/or phosphated saccharide may simultaneously be attached to the polymer in one reaction.
- functional groups may be added to the optical dye and/or sulfated and/or phosphated saccharide molecule to facilitate attachment to the linker.
- the optical molecules of the present invention may include any physiologically acceptable particulate materials containing one or more optical molecule.
- Such particles may be solid particles (e.g., uncoated or coated to provide stability in aqueous systems), or fluid (e.g., liquid particles in an emulsion), or may be aggregates (e.g., fluid containing liposomes) containing one or more optical molecule.
- the particulate material has a particle size smaller than or similar to the incident light wavelength.
- the particles are preferably water-insoluble or at least sufficiently poorly soluble so as to retain their desired particle size for a sufficient time following administration to the patient to be optically imaged. Examples of such particulate materials are described in U.S. Pat. No. 6,540,981.
- these particles are nanoparticles suitable for optical imaging.
- Such nanoparticles can be either quantum dots, nanoparticles of Si or Si/Ge, or nanoparticles having a suitable optical dye, e.g. a fluorophore, encapsulated therein.
- the luminescence wavelength of nanoparticles such as quantum dots and Si or Si/Ge nanoparticles is dependent on the size of the nanoparticles.
- the methods for producing such nanoparticles are well known in the art. For example, U.S. Pat. No. 6,585,947, herein incorporated by reference in its entirety, discloses a method for producing uniform (1-3 nanometer in diameter) Si nanoparticles.
- Such nanoparticles can be physically entrapped within or coated by the sulfated and/or phosphated saccharides of the present invention, particularly the sulfated and/or phosphated saccharide metal salt matrix, and used for the optical imaging applications of the present invention.
- the above-described sulfated and/or phosphated saccharide metal salt matrix containing optical molecules could further contain ferromagnetic and/or superparamagnetic particles.
- the ferromagnetic and superparamagnetic particles are known to function as MRI contrast agent. Ferromagnetic materials tend to have a strong magnetism; that is, the dipole moments of the atoms tend to spontaneously align in the same direction. This may occur even in the absence of an externally applied magnetic field.
- Examples of materials that exhibit ferromagnetism include, among others, iron, cobalt, nickel, gadolinium, dysprosium, and their alloys, as well as CrO 2 , MnOFe 2 O 3 , FeOFe 2 O 3 , NiOFe 2 O 3 , CuOFe 2 O 3 , MgOFe 2 O 3 , EuO, Y 3 Fe 5 O 12 , and various iron oxide compounds, such as magnetite (Fe 3 O 4 ) and ferrite (Fe 2 O 3 ).
- Superparamagnetic materials have a magnetic susceptibility between that of ferromagnetic and paramagnetic materials, and typically are small particles (i.e., below about 150 nanometers).
- superparamagnetic materials include various iron containing contrast agents, such as superparamagnetic iron oxides ("SPIOs"), and including ultrasmall SPIOs.
- SPIOs superparamagnetic iron oxides
- suitable SPIOs include appropriate particle sized magnetite particles (e.g., with a particle size below 10 nm), ferrite particles, maghemite ( ⁇ -Fe 2 O 3 ) particles, and magnetoferritin particles.
- ultrasmall SPIOs examples include ferumoxide coated with carboxydextran (Resovist® ferucarbotran, Schering AG), monocrystalline iron oxide nanoparticles coated with Dextran T-IO (Combidex® ferumoxtran, Advanced Magnetics, Inc.), and monocrystalline iron oxide nanopreparations (MION) coated with Dextran T-IO (such as MION-37 having a particle size of 22 + 6 nm and MION-46 having a particle size of 21 ⁇ 3 nm).
- MION monocrystalline iron oxide nanopreparations
- Other examples of ferromagnetic and superparamagnetic particles are known in the art and described in U.S. Pat. No. 5,653,959, herein incorporated by reference in its entirety, and U.S. Pat. No. 5,023,072.
- the superparamagnetic or ferromagnetic particles could be coated with a suitable material that provides increased stability under acidic conditions. Such materials for coating superparamagnetic or ferromagnetic particles
- the particles for use in the present invention are optical dye encapsulated in a microsphere particle such as those having a particle size in the range of about 40 ⁇ m to about 1200 ⁇ m, e.g., trisacryl gelatin microspheres such as those commercially available from BioSphere Medical as Embosphere® microspheres.
- a microsphere particle such as those having a particle size in the range of about 40 ⁇ m to about 1200 ⁇ m, e.g., trisacryl gelatin microspheres such as those commercially available from BioSphere Medical as Embosphere® microspheres.
- These microspheres can be physically entrapped within or coated by the sulfated and/or phosphated saccharides of the present invention, particularly the sulfated and/or phosphated saccharide metal salt matrix, and used for the optical imaging applications of the present invention.
- the optical molecule substituted sulfated and/or phosphated saccharide formulation may be administered to a patient to aid in the detection of damaged areas of the gastrointestinal tract.
- patient means any animal in which it may be necessary to detect damaged areas of the gastrointestinal tract.
- the animal is a mammal, and most commonly is a human.
- the optical dye substituted sulfated and/or phosphated saccharide compositions described herein can be formulated into diagnostic compositions for administration.
- the optical dye substituted sulfated and/or phosphated saccharide compositions are suitable for in vivo, such as oral or rectal, administration.
- the compositions are administered orally.
- the compositions may comprise other pharmaceutically acceptable carriers, diluents, or excipients, including buffers, surfactants, emulsifiers, thixotropic agents, stabilizing agents, and flavoring agents and other ingredients for enhancing the organoleptic qualities of the composition.
- compositions may also comprise antibiotic or antifungal agents (e.g., paraben) and anti-gas agents (e.g., simethicone).
- antibiotic or antifungal agents e.g., paraben
- anti-gas agents e.g., simethicone
- the composition may be formulated into any conventional pharmaceutical administration form, such as tablets, coated tablets, capsules, pills, powders, solutions, suspensions, dispersions, syrups, emulsions, etc.
- the dose of the optical molecule substituted sulfated and/or phosphated saccharide containing composition administered is not particularly limited, so long as the dose enables detection of damaged areas of the gastrointestinal tract.
- the dose will vary depending on the patient, the optical molecule selected, and the detection technique being used, but may readily be optimized by one skilled in the art.
- the composition is administered in an amount of about 0.001 g to about 2 g of optical dye substituted sulfated and/or phosphated saccharide per 5 to 50 mL of suspension, preferably the composition is administered in an amount of about O.OOlg to about 1 g of optical dye substituted sulfated and/or phosphated saccharide per 10 to 20 mL of suspension.
- the composition is administered in an amount of about 0.001 g to about 2 g of sulfated and/or phosphated saccharide metal salt matrix containing optical molecule per 5 to 50 mL of suspension, preferably the composition is administered in an amount of about O.OOlg to about 1 g of sulfated and/or phosphated saccharide metal salt matrix containing optical molecule per 10 to 20 mL of suspension.
- the compositions of the present invention are administered to the patient at a suitable time before the optical detection technique is performed. Such suitable time will be well known to those skilled in the art. In one embodiment, the compositions are administered at least 15 minutes before the optical detection technique is performed. In another embodiment, the compositions are administered at least 1 hour before the optical detection technique is performed.
- optical detection means such as light imaging techniques.
- Light imaging technology takes advantage of either transmitted, scattered, or emitted (fluorescence) photons or a combination of these effects.
- light imaging techniques use an illumination source in the ultraviolet, visible, or infrared region of the electromagnetic spectrum.
- the light which is transmitted through, scattered by, or reflected (or re-emitted in the case of fluorescence) from the body, is detected and an image is directly or indirectly generated.
- Numerous examples of optical detection means are known in the art.
- the detection means is selected from the group consisting of optical tomographic, endoscopic, photoacoustic, and sonofluorescence applications.
- optical tomographic, endoscopic, photoacoustic, and sonofluorescence applications are known in the art and described in, for example, U.S. Pat. No. 6,258,340; U.S. Pat. No. 6,540,981; and WO 00/16810.
- the present invention additionally provides a method for detecting damaged areas of the gastrointestinal tract.
- the method comprises administering to a patient a composition comprising an optical molecule containing, e.g., optical dye substituted, saccharide molecule and detecting damaged areas of the gastrointestinal tract with a detection means.
- the saccharide is selected from the group consisting of sulfated saccharide, phosphated saccharide, and combinations thereof.
- the sulfated saccharide is sucralfate
- the optical dye contains one or more groups selected from — SO 3 H, -PO 4 H 2 , -COOH, or combinations thereof wherein the dye does not contain aliphatic chains or groups substituted with primary amine, secondary amine, aldehyde or ketone groups.
- an MRI contrast agent in an amount sufficient to enable detection by magnetic resonance imaging, i.e. a superparamagnetic or ferromagnetic particle, is physically incorporated into the sulfated and/or phosphated saccharide composition containing the optical molecule.
- magnetic resonance imaging may be used to detect the damaged areas of the gastrointestinal tract, instead of or in addition to optical detection means.
- the detection means employed may vary depending on the optical molecule used.
- optical molecules in combination with sulfated and/or phosphated saccharide to detect ulcerated and inflamed sites of the gastrointestinal tract may provide numerous advantages over previously known methods of detection which utilize conventional dyes.
- the specificity of sucralfate for damaged sites of the gastrointestinal tract allows for specific targeting of ulcers using a lower dose of the optical dye-substituted sulfated and/or phosphated saccharide, as compared to conventional contrast agents which are not ulcer- specific. This in turn increases the ease and accuracy of diagnosis which reduces the risk to the patient.
- sucralfate is only minimally absorbed by the body, most sucralfate molecules that do not form a coating over the inflamed or ulcerated tissue should simply pass through the gastrointestinal tract.
- the relative absorption by the body of dye compounds attached to the sucralfate should be decreased relative to absorption of unattached dye compounds. This would result in a safer composition and reduced background artifacts during detection, which gives improved imaging specificity.
- the low dose volume, safety of ingredients, and low potential absorption through the gastrointestinal tract should also result in minimal patient side effects, thus resulting in improved patient compliance.
- Attachment of an optical dye to sulfated and/or phosphated saccharide molecules, and in particular to sucralfate, according to the present invention is not expected to result in the problem of fluorescence quenching.
- attachment of an optical dye to sulfated and/or phosphated saccharide molecules according to the present invention is not expected to block the optical properties of the dyes.
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EP2289563A1 (en) * | 2009-08-28 | 2011-03-02 | Fujifilm Corporation | Near infrared fluorescent imaging agent |
US11077211B2 (en) | 2013-11-11 | 2021-08-03 | Medibeacon Inc. | Compositions and methods for assessing gut function |
US11285223B2 (en) | 2013-11-11 | 2022-03-29 | Medibeacon Inc. | Compositions and methods for assessing gut function |
US11285224B2 (en) | 2013-11-11 | 2022-03-29 | Medibeacon Inc. | Compositions and methods for assessing gut function |
US12048751B2 (en) | 2013-11-11 | 2024-07-30 | Medibeacon Inc. | Compositions and methods for assessing gut function |
Also Published As
Publication number | Publication date |
---|---|
WO2007002332A3 (en) | 2007-04-26 |
CN101203248A (en) | 2008-06-18 |
JP2008546798A (en) | 2008-12-25 |
EP1901781A2 (en) | 2008-03-26 |
US20100055040A1 (en) | 2010-03-04 |
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