WO2024254612A2 - Agent de contraste ultrasonore activé par ultrasons - Google Patents

Agent de contraste ultrasonore activé par ultrasons Download PDF

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Publication number
WO2024254612A2
WO2024254612A2 PCT/US2024/033302 US2024033302W WO2024254612A2 WO 2024254612 A2 WO2024254612 A2 WO 2024254612A2 US 2024033302 W US2024033302 W US 2024033302W WO 2024254612 A2 WO2024254612 A2 WO 2024254612A2
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WIPO (PCT)
Prior art keywords
contrast
sterilized
polymer
enhanced ultrasound
polyethylenimine
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PCT/US2024/033302
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English (en)
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WO2024254612A3 (fr
Inventor
Travis J. Williams
Jesse Tong-Pin Yen
Van Khanh DO
Andy Yu-How CHANG
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Childrens Hospital Los Angeles
University of Southern California USC
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Childrens Hospital Los Angeles
University of Southern California USC
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Publication of WO2024254612A2 publication Critical patent/WO2024254612A2/fr
Publication of WO2024254612A3 publication Critical patent/WO2024254612A3/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/22—Echographic preparations; Ultrasonic imaging preparations
    • A61K49/222—Echographic preparations; Ultrasonic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
    • A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/481—Diagnostic techniques involving the use of contrast agents, e.g. microbubbles introduced into the bloodstream
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions

Definitions

  • an ultrasound-activated ultrasound contrast agent is provided.
  • Bladder catheterization particularly in pediatric patients, is often poorly tolerated and can be a significant source of discomfort and dissatisfaction among adults. Beyond the immediate discomfort, catheterization is associated with a considerable risk of urinary tract infections (UTls). Studies have shown infection rates range from 2% to 22% during voiding cystourethrograms (VCUGs) and from 2.1% to 21% during urodynamic studies. The invasiveness and complications associated with catheterization led the 2006 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Strategic Plan for Pediatric Urology to prioritize the development of a catheter-free VCUG procedure as a critical national health research goal. However, despite the passage of nearly 20 years since this call to action, an effective catheter-free method has not yet been successfully developed.
  • NIDDK National Institute of Diabetes and Digestive and Kidney Diseases
  • VUR vesicoureteral reflux
  • a nanoparticle is capable of the on-demand release of CO2 with ultrasound energy with visualization of released bubbles with diagnostic ultrasound for the purpose of disease diagnosis and treatment.
  • a method for visualizing bladder-to-kidney urine reflux is provided.
  • a sterilized polymer is covalently loaded with CO2 and then administered to a subject.
  • the CO2 is released with ultrasound once the polymer is in the bladder. This then enables the bubbling of CO2 as an ultrasound contrast agent.
  • the methods set forth herein allow the avoidance of urinary catheterization in diagnostic urologic tests.
  • the intravenous injection of covalently bound CO2 nanoparticles are excreted by the kidneys into the urine. Once in the bladder, these nanoparticles are activated by ultrasound to generate CO2 bubbles. The presence of bubbles in the ureters or kidneys, as visualized by ultrasound, would indicate vesicoureteral reflux.
  • a contrast-enhanced ultrasound agent in another aspect, includes a sterilized liquid carrier and a sterilized polymer dispersed and/or dissolved in the sterilized liquid carrier.
  • the sterilized polymer includes amino groups that are at least partially functionalized with CO2 at a plurality of the amino groups.
  • a contrast-enhanced ultrasound agent in another aspect, includes a sterilized liquid carrier and a sterilized nanoparticle composed of a polyethylenimine dispersed and/or dissolved in the sterilized liquid carrier. Characteristically, the polyethylenimine includes amino groups that are at least partially functionalized with CO2 at a plurality of the amino groups.
  • a method for delivering releasable, caged CO2 in vivo is provided. The method includes a step of administering a contrast-enhanced ultrasound agent to a subject.
  • the contrast-enhanced ultrasound agent includes a polymer that includes amino groups to a subject.
  • the polymer includes amino groups functionalized with CO2 at a plurality of the amino groups. Ultrasonic energy is directed into a subject’s urinary tract to release CO2 from the contrast-enhanced ultrasound agent.
  • FIGURE 1 Schematic of syringe holding a contrast-enhanced ultrasound agent that releases CO2.
  • FIGURE 2 Schematic flowchart illustrating a method for delivering releasable, caged CO2 in vivo.
  • FIGURE 3 Schematic drawing of experimental apparatus. A rubber balloon filled with nanoparticle solution is “activated” by a sonication transducer releasing carbon dioxide bubbles. An imaging transducer allows for visualization of this process.
  • FIGURE 4 Representative ultrasonographic image of CO? formation in nanoparticle- filled balloon after activation.
  • FIGURE 5 Representative ultrasonographic image of water-filled balloon without evidence of CO2 formation after sonication.
  • FIGURE 6 Successful visualization of CO? bubbles after sonication in nanoparticle- filled balloon overlayed with thick pork belly.
  • R groups include hydrogen, alkyl, lower alkyl, C1-6 alkyl, Ce-io aryl, C6-10 heteroaryl, alylaryl (e.g., C1-8 alkyl C6-10 aryl).
  • R’, R” and R' are Ci-10 alkyl or Ce-i8 aryl groups, M is a metal ion, and L" is a negatively charged counter ion; R groups on adjacent carbon atoms can be combined as -OCH2O-; single letters (e.g., "n” or "o") are 1, 2, 3, 4, or 5; in the compounds disclosed herein a CH bond can be substituted with alkyl, lower alkyl, C i-6 alkyl, C 6 -io aryl. C 6 -io heteroaryl, -NO 2 .
  • M + is a metal ion
  • L" is a negatively charged counter ion
  • hydrogen atoms on adjacent carbon atoms can be substituted as -OCH 2 O-
  • a given chemical structure includes a substituent on a chemical moiety (e.g., on an aryl, alkyl, etc.) that substituent is imputed to a more general chemical structure encompassing the given structure; percent, "parts of," and ratio values are by weight;
  • the term “polymer” includes “oligomer,” “copolymer,” “terpolymer,” and the like; molecular weights provided for any polymers refers to weight average molecular weight unless otherwise indicated; the description of a group or class of materials as suitable or preferred for a given purpose in connection with the invention implies that mixtures of any two or more of the members of the group or class are equally suitable or preferred; description of constituents in chemical terms refers to the constituents at the time of addition to any combination specified in the description, and does not necessarily preclude chemical interactions among
  • the term “about” means that the amount or value in question may be the specific value designated or some other value in its neighborhood. Generally, the term “about” denoting a certain value is intended to denote a range within +/- 5% of the value. As one example, the phrase “about 100” denotes a range of 100 +/- 5, i.e. the range from 95 to 105. Generally, when the term “about” is used, it can be expected that similar results or effects according to the invention can be obtained within a range of +/- 5% of the indicated value. [0025] As used herein, the term ‘‘and/or” means that either all or only one of the elements of said group may be present. For example, “A and/or B” shall mean “only A, or only B. or both A and B”. In the case of “only A”, the term also covers the possibility that B is absent, i.e. “only A, but not B”.
  • the term “one or more” means “at least one” and the term “at least one” means “one or more.”
  • the terms “one or more” and “at least one” include “plurality” and “multiple” as a subset. In a refinement, “one or more” includes “two or more.”
  • the term “substantially,” “generally,” or “about” may be used herein to describe disclosed or claimed embodiments.
  • the term “substantially” may modify a value or relative characteristic disclosed or claimed in the present disclosure. In such instances, “substantially” may signify that the value or relative characteristic it modifies is within ⁇ 0%, 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, or 10% of the value or relative characteristic.
  • integer ranges explicitly include all intervening integers.
  • the integer range 1-10 explicitly includes 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.
  • the range 1 to 100 includes 1, 2, 3, 4. . . . 97, 98, 99, 100.
  • intervening numbers that are increments of the difference between the upper limit and the lower limit divided by 10 can be taken as alternative upper or lower limits. For example, if the range is 1.1. to 2.1 the following numbers 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8. 1.9, and 2.0 can be selected as lower or upper limits.
  • the term “less than” includes a lower non-included limit that is 5 percent of the number indicated after “less than.”
  • “less than 20” includes a lower non-included limit of 1 in a refinement. Therefore, this refinement of “less than 20” includes a range between 1 and 20.
  • the term “less than” includes a lower non-included limit that is, in increasing order of preference, 20 percent, 10 percent, 5 percent, or 1 percent of the number indicated after “less than.”
  • concentrations, temperature, and reaction conditions e.g., pressure. pH, flow rates, etc.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 50 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • concentrations, temperature, and reaction conditions e.g., pressure, pH, flow rates, etc.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 30 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 10 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • concentrations, temperature, and reaction conditions e.g., pressure, pH, flow rates, etc.
  • reaction conditions e.g., pressure, pH, flow rates, etc.
  • concentrations, temperature, and reaction conditions can be practiced with plus or minus 10 percent of the values indicated rounded to or truncated to two significant figures of the value provided in the examples.
  • values of the subscripts can be plus or minus 30 percent of the values indicated rounded to or truncated to two significant figures. In still another refinement, values of the subscripts can be plus or minus 20 percent of the values indicated rounded to or truncated to two significant figures.
  • the term '‘electrical communication” means that an electrical signal is either directly or indirectly sent from an originating electronic device to a receiving electrical device.
  • Indirect electrical communication can involve processing of the electrical signal, including but not limited to, filtering of the signal, amplification of the signal, rectification of the signal, modulation of the signal, attenuation of the signal, adding of the signal with another signal, subtracting the signal from another signal, subtracting another signal from the signal, and the like.
  • Electrical communication can be accomplished with wired components, wirelessly connected components, or a combination thereof.
  • the term “substantially,” “generally,” or “about” may be used herein to describe disclosed or claimed embodiments.
  • the term “substantially” may modify a value or relative characteristic disclosed or claimed in the present disclosure. In such instances, “substantially” may signify that the value or relative characteristic it modifies is within ⁇ 0%, 0.1%, 0.5%, 1%, 2%, 3%, 4%. 5%, or 10% of the value or relative characteristic.
  • CEUS means contrast-enhanced ultrasound.
  • CO2 means carbon dioxide
  • CTIP means The West Coast Consortium for Technology & Innovation in Pediatrics.
  • NIDDK National Institute of Diabetes and Digestive and Kidney Diseases.
  • nanometer means nanometer
  • PBS phosphate-buffered saline
  • PEG polyethylene glycol
  • PEI polyethylenimine
  • RF radio frequency
  • UTIs urinary tract infections
  • VCUG means voiding cystourethrogram
  • VUR means vesicoureteral reflux
  • a contrast-enhanced ultrasound agent is provided.
  • Figure 1 proides a schematic of a syringe holding the contrast-enhanced ultrasound agent.
  • the contrast- enhanced ultrasound agent 10 includes a liquid earner 12, and in particular, sterilized liquid polymer, and a polymer 14, and in particular, sterilized polymer 14, dispersed and/or dissolved in the sterilized liquid carrier.
  • the sterilized polymer includes amino groups that are at least partially functionalized with CO2 at a plurality of the amino groups.
  • the sterilized polymer 14 is water-soluble and nontoxic. It should be appreciated that the terms “polymer” and “sterilized polymer” are interchangeable.
  • liquid polymer” and “sterilized liquid polymer” are interchangeable.
  • a nanoparticle in another aspect, includes the sterilized polymer.
  • the nanoparticles are small enough to be filtrated by the kidneys, which requires an average diameter of less than about 10 nm.
  • the average diameter of the nanoparticle is less than about 5.5 nm.
  • the nanoparticle has an average diameter greater than 0.5 nm.
  • the nanoparticles have a maximum dimension of less than about 10 nm or 5.5 nm. In a refinement, the nanoparticles have a maximum dimension greater than about 0.5 nm.
  • the sterilized polymer is a poly(amine) material or a poly(amine) material that is functionalized with PEG groups.
  • the sterilized polymer is a polyethylenimine.
  • the sterilized polymer is a linear polyethylenimine.
  • the sterilized polymer before carboxylation has the following formula n is an integer from about 40 to 1000.
  • the sterilized polymer includes monomer units having following formula where dashed line represent bonds to a polymer backbone.
  • the sterilized polymer is a branched polyethylenimine.
  • the sterilized polymer before carboxylation can include a monomer unit having the following formula incorporated into the polymer backbone: where dashed line represent bonds to a polymei' backbone.
  • the sterilized polymer is a dendritic polyethylenimine.
  • the sterilized polymer has a weight average molecular weight from about 86 D to 40,000 D. In a refinement, the sterilized polymer has a weight average molecular weight from about 10,000 D to 30,000 D. In some refinements, the sterilized polymer has a weight average molecular weight greater than or equal to 86D, 100 D, 500 D, 1000 D, 5000 D, or 10,000 D. In some further refinements, the sterilized polymer has a weight average molecular weight less than or equal to 50,000 D, 45,000 D, 40,000 D, 35,000 D, 30,000 D, 25,000 D, 20,000 D, or 15000 D.
  • contrast-enhanced ultrasound agent 10 includes a sterilized liquid carrier 12 and a sterilized nanoparticle 14 composed of a polyethylenimine dispersed and/or dissolved in the sterilized liquid carrier.
  • the polyethylenimine includes amino groups functionalized with CO2 at a plurality of the amino groups.
  • the nanoparticles are small enough to be filtrated by the kidneys, which requires an average diameter of less than about 10 nm. In a refinement, the average diameter of the nanoparticle is less than about 5.5 nm.
  • the nanoparticle has an average diameter greater than 0.5 nm.
  • the nanoparticles have a maximum dimension of less than about 10 nm or 5.5 nm. In a refinement, the nanoparticles have a maximum dimension greater than about 0.5 nm.
  • the polyethylenimine is functionalized with PEG groups.
  • the polyethylenimine is a linear polyethylenimine.
  • the polyethylenimine before carboxylation has the following formula n is an integer from about 40 to 1000.
  • the polyethylenimine includes monomer units having following formula thereof, where dashed line represent bonds to a polymer backbone.
  • the polyethylenimine is a branched polyethylenimine.
  • the polyethylenimine before carboxylation can include a monomer unit having the following formula incorporated into the polymer backbone:
  • thepolyethylenimine is a dendritic polyethylenimine.
  • the polyethylenimine has a weight average molecular weight from about 86 D to 40,000 D.
  • the polyethylenimine has a weight average molecular weight from about 10,000 D to 30,000 D.
  • the sterilized polymer has a weight average molecular weight greater than or equal to 86 D, 100 D, 500 D. 1000 D, 5000 D, or 10,000 D.
  • the sterilized polymer has a weight average molecular weight less than or equal to 50,000 D. 45,000 D, 40,000 D, 35,000 D, 30,000 D, 25,000 D, 20,000 D, or 15000 D.
  • a method for delivering releasable, caged CO2 in vivo is provided.
  • a schematic flow chart illustrating the method is provided.
  • a contrast-enhanced ultrasound agent 10 is administered to subject 18.
  • the contrast-enhanced ultrasound agent includes a polymer including amino groups functionalized with CO2 at a plurality of the amino groups.
  • the ultrasonic energy from source 20 is directed into a part of a subject’s body to release CO2 from the contrast-enhanced ultrasound agent. Details of the contrast-enhanced ultrasound agent are set forth above.
  • the part of a subject’s body is a subject's urinary tract.
  • the method further includes collecting diagnostic ultrasound images from the subject.
  • diagnostic ultrasound images are collected from the subject with ultrasound imaging equipment 22 which is in electrical communication with the computing system 24.
  • Ultrasound images can be displayed on a monitor 26 in computing system 24. These ultrasonic images can be used to determine if the subject has vesicoureteral reflux (VUR) from the ultrasound images.
  • VUR vesicoureteral reflux
  • CO2 effervescence can be used to diagnose or surveil VUR.
  • caged CO2 and ultrasound activation can be used as an alternative to a voiding cystourethrogram (VCUG), or any other methodology that involves bladder catheterization.
  • VCUG voiding cystourethrogram
  • computing system 24 can have algorithms encoded therein for performing the calculations from the imaging data.
  • polymeric carbamic acid materials obtained by carboxylating the amino-containing material can serve as contrast agents for contrast- enhanced ultrasound (CEUS) imaging wherein amine-bound CO2 can be uncaged from the material in vitro by focused ultrasound.
  • CEUS contrast- enhanced ultrasound
  • ultrasonic energy is low-power.
  • Low-power ultrasound in medical imaging involves using ultrasound waves at lower intensities, typically below 720 mW/cm 2 Ispta. 190 W/cnr I spP a, and a mechanical index of 1.9, to produce diagnostic images safely. Operating at frequencies between 2 to 18 MHz, it balances depth and resolution, making it ideal for various applications like obstetrics for fetal monitoring, cardiology for heart and blood vessel imaging, abdominal imaging for organs such as the liver and kidneys, musculoskeletal imaging for assessing muscles and tendons and guiding procedures like biopsies.
  • the method further includes determining if the subject has vesicoureteral reflux (VUR) from the ultrasound images.
  • VUR vesicoureteral reflux
  • the polymer is a poly(amine) material or a poly(amine) material that is functionalized with PEG groups.
  • the polymer is a polyethylenimine as set forth above.
  • the sterilized polymer has a weight average molecular weight from about 86 D to 40,000 D.
  • the sterilized polymer has a weight average molecular weight from about 10,000 D to 30,000 D.
  • the sterilized polymer has a weight average molecular weight greater than or equal to 86 D, 100 D, 500 D. 1000 D, 5000 D, or 10,000 D.
  • the sterilized polymer has a weight average molecular weight less than or equal to 50,000 D, 45,000 D, 40,000 D, 35,000 D, 30.000 D, 25,000 D, 20,000 D, or 15000 D.
  • the method further includes using (i.e., applying) CO2 effervescence to diagnose or surveil VUR.
  • caged CO2 and ultrasound activation is applied as an alternative to a voiding cystourethrogram (VCUG), or any other methodology that involves bladder catheterization.
  • VCUG voiding cystourethrogram
  • the method further includes determining bladder pressure from the volume of a CO2 bubble in a subject's bladder or kidney.
  • a controlled volume of CO2 is placed in a subject's bladder or kidney to generate a gas bubble via release of caged CO2.
  • VUR vesicoureteral reflux
  • Figures 4 and 5 show the nanoparticle and water solutions upon stimulation with ultrasound, respectively in the balloon-only model. This work demonstrates the potential to produce and visualize microbubbles when applied to CCh-loaded nanoparticles. Additionally, visualization was successful with a 37 mm thick layer of pork belly interposed between the ultrasound and balloon ( Figure 6).
  • Example 2 Selective release of CCh-loaded nanoparticles from a pig bladder
  • a young adult female swine was chosen due to its similar bladder size to humans and to ensure urinary catheter access.
  • the pig was anesthetized and placed in the supine position for the duration of the procedure.
  • a catheter was inserted through the urethra into the bladder, which was subsequently drained of any existing urine.
  • CCh-loaded PEI solutions which performed the best ex vivo, were fabricated, with molecular weights of either 1.8 kDa, 10 kDa, or 25 kDa, and NaaPO j buffer levels at either 0 or 7.5%.
  • the bladder was filled via the catheter with one of the CCh-loaded PEI solutions until full (at or above 300 mL).
  • the stimulating transducer (1.1 MHz, spherically focused) was placed on the midline suprapubic region and coupled to the skin with ultrasound gel. For all trials, a duty cycle of 10% (1 ms on, 9 ms off) and a pulse count of 500 (for a total sonication time of 5 seconds) were used. Power levels varied between 10W and 3OW.
  • the transducer was held with light pressure over the bladder. After sonication ceased, the imaging probe was quickly placed in the same position to capture the resulting bubbling. Between solutions, the bladder was emptied of the previous volume.

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Abstract

Un agent de contraste ultrasonore activé par ultrasons comprend un support liquide stérilisé; et un polymère stérilisé dispersé et/ou dissous dans le support liquide stérilisé. De manière avantageuse, le polymère stérilisé comprend des groupes amino qui sont au moins partiellement fonctionnalisés avec du CO2 au niveau d'une pluralité des groupes amino.
PCT/US2024/033302 2023-06-09 2024-06-10 Agent de contraste ultrasonore activé par ultrasons Pending WO2024254612A2 (fr)

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US202363471994P 2023-06-09 2023-06-09
US63/471,994 2023-06-09

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3313947A1 (de) * 1983-04-15 1984-10-18 Schering AG, 1000 Berlin und 4709 Bergkamen Mikropartikel und gasblaeschen enthaltende ultraschall-kontrastmittel

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