Abstract: Novel targeted compositions which may be used for diagnostic and therapeutic use. The compositions may comprise lipid, protein or polymer gas-filled vesicles which further comprise novel compounds of the general formula L-P-T, wherein L comprises a hydrophobic compound, P comprises a hydrophilic polymer, and T comprises a targeting ligand which targets tissues, cells or receptors, including myocardial cells, endothelial cells, epithelial cells, tumor cells and the glycoprotein GPIIbIIIa receptor. The compositions can be used in conjunction with diagnostic imaging, such as ultrasound, as well as therapeutic applications, such as therapeutic ultrasound.

Abstract: A method for producing surfactant-stabilized microcapsules or nanocapsules including the steps of (a) preparing a suspension comprising a non-ionic sorbitan detergent and a salt in phosphate buffered saline; (b) adding to the suspension a nonionic polyoxyethylenesorbitan detergent to produce a solution; (c) heating while stirring the solution of step (b) to 55±5° C. and maintaining the temperature of the solution at 55±5° C. for several minutes; (d) allowing the solution to cool to room temperature; (e) autoclaving the solution; (f) creating surfactant-stabilized microbubbles and nanobubbles in the solution; and (g) collecting surfactant-stabilized nanocapsules and microcapsules formed from the microbubbles and nanobubbles.

Abstract: Medical apparatus and processes controllably generate medically useful micro or nano bubbles of medically desirable and controllably selectable size, size distribution, homogeneity and concentration (and/or other key bubble parameters) for patient infusion, and/or which may incorporate therapeutic or other agents for patient infusion and/or may be combined with therapeutic or other agents prior to infusion into patients. The bubble generation apparatus and processes controllably permit the adjustment and selection of key bubble parameters through bubble generation actuation and orientation techniques and through selection of bubble fluid compositions in order to facilitate medical research and/or to optimize treatment for imaging, therapy, sonoporation, inertial and non-inertial cavitation, and acoustic activation, among other medical uses. Disposable cartridges containing such bubbles are provided and may include means for patient infusion.

Abstract: A method and kit for therapeutically treating bone and tissue injuries using ultrasound. The method includes the steps of introducing an ultrasound contrast agent into the patient, preferably, the patient's blood stream, and impinging ultrasonic waves in proximity to an injury. The ultrasound contrast agent facilitate in lowering the cavitation threshold, i.e., the energy required for the cavitation, to a level attainable by the ultrasonic waves to induce acoustic intracellular microstreaming to accelerate the healing process. The method further includes the steps of maintaining the resonance bubble frequency of the microbubbles of the ultrasound contrast agent from 0.5 MHz to 10 MHz; maintaining the acoustic transmit frequency of the ultrasound waves from 10 kHz to 10 MHz; and maintaining the acoustic spatial average-temporal average (SATA) intensity of the ultrasonic waves from 5 to 500 mW/cm2.

Abstract: Disclosed herein is a class of linkable tetrasaccharide compounds that includes the amino phenyl glycoside of sialyl Lewis X (SLeX) and related analogs. These compounds have conjugatable nucleophilic groups, making them useful in preparing multimeric SLeX compositions. In particular, the disclosed SLeX compounds can be used to prepare selectin binding ligand conjugates by linking them to a reporter moiety, such as a contrast agent, a radiodiagnostic agent, or a cytotoxic or chemotherapeutic agent. The SLeX compounds and conjugates of the invention exhibit binding to selectin that is similar to native Sialyl Lex, and are, therefore, useful for diagnosing and treating selectin-mediated disorders and related conditions.

Abstract: A composition is provided accompanying nanoparticles having diameters in the range of about 100 to 800 nanometers with hollow cores and outer shells with mechanical properties such that they rupture on exposure to predetermined ultrasound energy. The composition is useful for identifying sentinel lymph nodes.

Abstract: Peptide vectors having high KDR binding affinity and processes for making such vectors are provided. The peptide vectors may be conjugated to phospholipids and included in ultrasound contrast agent compositions. Such ultrasound contrast agents are particularly useful in therapeutic and diagnostic methods, such as in imaging KDR-containing tissue and in the evaluation and treatment of angiogenic processes associated with neoplastic conditions. The present invention also provides processes for the large scale production of highly pure dimeric and monomeric peptide phospholipid conjugates as well as precursor materials used to form the conjugates. The present invention further provides processes for the large scale production of highly pure peptide phospholipid conjugates which contain very low levels of TFA.

Abstract: New ultrasound contrast agents that comprise microbubbles encapsulating a gas within a shell made from a blend of bipolar compounds having mixed carbon chain length. The compounds have hydrophobic groups selected from the group consisting of straight-chained alkyls, alkylethers, alkylthiolethers, alkyldisulfides, polyfluoroalkyls, and polyfluoroalkylethers having a carbon chain length greater than or equal to 16 and less than or equal to 32. The polar groups are connected to the hydrophobic groups by means of a linker. The polar head groups are selected from the group consisting of CO2-M+, SO3?M+, SO4?M+, PO3?M+, PO4?M+2, N(R)4+, a pyridinium or substituted pyridinium group, and a zwitterionic group; R is selected from the group consisting of —H, —CH3, alkyl, cycloalkyl, substituted cycloalkyls containing one or more heteroatoms, and benzyl and can be the same or different; and Z? is a nonionic and M is a cation.

Abstract: A method for ultrasonic harmonic imaging is disclosed, which uses microbubbles particularly selected for their properties of reradiating ultrasound energy at frequencies other than the exciting frequency.

Abstract: Peptide vectors having high KDR binding affinity and processes for making such vectors are provided. The peptide vectors may be conjugated to phospholipids and included in ultrasound contrast agent compositions. Such ultrasound contrast agents are particularly useful in therapeutic and diagnostic methods, such as in imaging KDR-containing tissue and in the evaluation and treatment of angiogenic processes associated with neoplastic conditions. The present invention also provides processes for the large scale production of highly pure dimeric and monomeric peptide phospholipid conjugates as well as precursor materials used to form the conjugates. The present invention further provides processes for the large scale production of highly pure peptide phospholipid conjugates which contain very low levels of TFA.

Abstract: A method of delivering a therapeutic drug to a brain of a patient, involving intrathecally administering a microbubble composite containing a therapeutic agent, allowing the composite to rise into the cranium, and applying ultrasound to the cranium to explode the microbubbles.

Abstract: Methods, compositions and apparatus for localized delivery of compounds are provided. In certain embodiments, radiation force is used to direct carriers to a target site, and additional radiation is used to fragment the localized carriers, releasing associate compounds. Ultrasound radiation is preferred as the source for radiation force and for fragmentation. Also encompassed are embodiments in which targeting and fragmentations are combined with imaging of the treatment site. Alternate embodiments are disclosed in which compounds are locally delivered without use of carriers.

Abstract: Low density microspheres, methods for preparing same, and use of same as contrast agents are described. The microspheres have a void which contains a gas or the vapor of a volatile liquid selected from the group consisting of aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons.

Abstract: Methods and compositions for the site-selective delivery of a gene to a site within the body of an animal where virus not encapsulated within the microbubbles is inactivated, for example by treatment with a virus-inactivating agent.

Abstract: Novel ultrasound methods comprising administering to a patient a targeted vesicle composition which comprises vesicles comprising a lipid, protein or polymer, encapsulating a gas, in combination with a targeting ligand, and scanning the patient using ultrasound. The scanning may comprise exposing the patient to a first type of ultrasound energy and then interrogating the patient using a second type of ultrasound energy. The targeting ligand preferably targets tissues, cells or receptors, including myocardial cells, endothelial cells, epithelial cells, tumor cells and the glycoprotein GPIIbIIIa receptor. The methods may be used to detect a thrombus, enhancement of an old or echogenic thrombus, low concentrations of vesicles and vesicles targeted to tissues, cells or receptors.

Abstract: This invention provides a gas bubble-generating agent that can be used as a contrast medium or a blocking agent in vivo. Such gas bubble-generating agent is produced by a method for producing a gas bubble-generating agent comprising the following steps of: (a) preparing a mixed solution of an amphiphilic substance, an amphiphilic substance comprising a water-soluble polymer chemically bound thereto, a hardly water-soluble substance having a boiling point of lower than 60° C. at atmospheric pressure, and a physiologically acceptable isotonic solution; (b) pressurizing the mixed solution; and (c) centrifuging the mixed solution after the step of pressurization, wherein a molar concentration of the amphiphilic substance in the mixed solution prepared in step (a) is 10 times or more higher than that of the amphiphilic substance comprising a water-soluble polymer chemically bound thereto.

Abstract: A treatment is described for delivering oxygen to tissue, especially hypoxic tissue. A medium saturated with gas is delivered to the tissue. Dissolved gas is transferred from the medium to the tissue. Ultrasound is transmitted to the tissue to enhance the transfer of gas to the tissue.

Abstract: Highly hydrophilic indole and benzoindole derivatives that absorb and fluoresce in the visible region of light are disclosed. These compounds are useful for physiological and organ function monitoring. Particularly, the molecules of the invention are useful for optical diagnosis of renal and cardiac diseases and for estimation of blood volume in vivo.

Abstract: Methods and devices for enhanced ultrasound detection based upon changing temperature and ultrasound reflectivity of a temperature-dependent contrast agent bound to an ultrasound target are disclosed. The methods and devices can be used for enhanced imaging alone or in conjunction with drug delivery, with therapeutic approaches such as hyperthermia or cryotherapy or with other imaging modalities.

Abstract: A gas emulsion forming composition comprising a dry, hollow, particulate, approximately microspherical material permeated with a gas or gas mixture, which upon dissolution in aqueous liquid forms a gas emulsion comprising a plurality of bubbles surrounded by a layer of at least a first and a second surfactant, wherein the first surfactant consists essentially of a phospholipid or mixture of phospholipids having at least one acyl chain which comprises at least 10 carbon atoms, and comprising at least about 5% w/w of total surfactant, and wherein the second surfactant may or may not be a phospholipid and is more water soluble than the first surfactant; kits for preparing such microbubbles; and methods for using such microbubbles as contrast agents.

Abstract: The present invention relates to targetable constructs which may be bound by a bi-specific antibody or antibody fragment having at least one arm that specifically binds construct. The targetable construct comprises a carrier portion which comprises or bears at least one epitope recognizable by at least one arm of said bi-specific antibody or antibody fragment. The targetable construct further comprises one or more therapeutic or diagnostic agents or enzymes. The invention provides constructs and methods for producing the targetable constructs and bi-specific antibodies or antibody fragments, as well as methods for using them.

Abstract: The invention relates to a new and improved pharmaceutical composition and method for delivery of therapeutic agents. The methods and composition of the invention can be used with several therapeutic agents and can achieve site specific delivery of a therapeutic or diagnostic substance. This can allow for lower doses and for improved efficacy with drugs which traditionally reach targeted sites and can result in improved utility for agents such as oligonucleotides and polynucleotides which are plagued with problems with biodistribution.

Abstract: The present invention describes, inter alia, oxygen delivery agents or blood substitutes comprising a fluorinated gas and a stabilizing material, uses for the oxygen delivery agents or blood substitutes, and apparatus for making and delivering the oxygen delivery agents or blood substitutes.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain surfactants and, optionally, hydrophilic stabilizers. The surfactants can be in the form of liposomes. The suspensions are obtained by exposing the surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003. Contrast agents with particular mixtures of gases are also disclosed that have advantageous properties.

Abstract: Methods of and apparatus for preparing temperature activated gaseous precursor-filled liposomes are described. Gaseous precursor-filled liposomes prepared by these methods are particularly usefull for example, in ultrasonic imaging applications and in therapeutic drug delivery systems. Gas, gaseous precursors and perfluorocarbons are presented as novel potentiators for ultrasonic hyper-thermia. The gas, gaseous precursors and perfluorocarbons which may be administered into the vasculature, interstitially or into any body cavity are designed to accumulate in cancerous and diseased tissues. When therapeutic ultrasonic energy is applied to the diseased region heating is increased because of the greater effectiveness of sound energy absorption caused by these agents.

Abstract: A surgical irrigating fluid composition, especially for endoscopic surgery, is provided comprising a rinsing fluid and nitrous oxide added as a marker to the rinsing fluid in an amount which is detectable in the expired breath from a mammal, especially man, that is subjected to the surgery.

Abstract: A method for generating colonography images for colorectal screening of a patient. The patient is administered an amount of radiopaque stool marker which will enable stool present in the patient's colon to be distinguished from soft tissue. The patient's colon is imaged after the stool marker has been administered to generate colonography images. Preparation of the colon is simulated by processing the colonography images to remove marked stool before the images are observed during a diagnosis session.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase.

Abstract: A method for removing a gas from a site comprising placing cells having gas vesicles under conditions that induce the cells to float to a surface of an aqueous medium, harvesting the cells from the surface of the medium, lysing the cells, separating the gas vesicles from the lysed cells, crosslinking the gas vesicles with a crosslinking agent, loading a gas with a lowered partial pressure for the compound to be removed into the gas vesicles, and placing the gas vesicles such that the gas compound is removed from the site. Harvesting gas-vesicle-containing cells is achieved by placing the cells under conditions that induce the cells to rise to the surface of an aqueous medium—such as darkness, exponential growth stage, flocculation, or dissolved gas flotation—then collecting the cells from the surface of the medium. Gas vesicles are isolated by lysing the cells and separating the gas vesicles from the lysate. Once the gas vesicles are isolated, they can be modified, such as by crosslinking with glutaraldehyde.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760-x) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; kits for preparing microbubbles; and methods for using such microbubbles as ultrasound contrast agents.

Abstract: The invention concerns composite nanospheres having a diameter ranging between about 50 and 1000 nm plus or minus 5%, preferably between about 100 and 500 nm plus or minus 5% and advantageously between 100 and 200 nm plus or minus 5%, and comprising an essentially liquid core consisting of an organic phase and inorganic nanoparticles, distributed inside the organic phase, and a skin consisting of at least a hydrophilic polymer derived from the polymerisation of at least one water soluble monomer, in particular N-alkylacrylamide or a N-N-dialkylacrylamide; conjugates derived from said nanospheres; their preparation methods and their uses.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase. One can impart outstanding resistance against collapse under pressure to these gas-filled microbubbles used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760?x) mm Hg at 37 C., where x is the vapor pressure of the second gas at 37 C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37 C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; kits for preparing microbubbles; and methods for using such microbubbles as ultrasound contrast agents.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ration of from about 1:100 to abut 1000:1, and wherein the first gas has a vapor pressure of at least about (760?X) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.; also disclosed are methods for preparing microbubble compositions, including compositions that rapidly shrink from a first average diameter to a second average diameter less than about 75% of the first average diameter and are stabilized at the second average diameter; methods and kits for preparing microbubbles; and methods for using such microbubbles as contrast agents.

Abstract: Microspheres are prepared by a process comprising (i) spray-drying a solution or dispersion of a wall-forming material in order to obtain intermediate microspheres and (ii) reducing the water-solubility of at least the outside of the intermediate microspheres. Suitable wall-forming materials include proteins such as albumin and gelatin. The microspheres have walls of 40-500 nm thick and are useful in ultrasonic imaging. The control of size, size distribution and degree of insolubilisation and cross-linking of the wall-forming material allows novel microsphere preparations to be produced. In particular, the microspheres may be 15-20 ?m, targeted to selected areas of the body or of prolonged life in the circulation.

Abstract: A method is provided to prepare gas-filled, porous microparticles having a polymer matrix interior which are useful as ultrasound echogenic contrast agents. An oil-in-water suspension is formed, both phases are frozen, then the aqueous and nonaqueous frozen phases are removed by sublimation. The resulting porous microparticles can receive a gas and be used as an ultrasound contrast agent.

Abstract: Gas or air filled microbubble suspensions in aqueous phases usable as imaging contrast agents in ultrasonic echography. They contain laminarized surfactants and, optionally, hydrophilic stabilizers. The laminarized surfactants can be in the form of liposomes. The suspensions are obtained by exposing the laminarized surfactants to air or a gas before or after admixing with an aqueous phase.

Abstract: Improved methods for providing an image of an internal region of a patient, especially the cardiovascular region. Embodiments of the invention involve the administration to the patient of a contrast agent which comprises a vesicle composition comprising lipid or polymer vesicles and a gas or gaseous precursor, in combination with a coronary vasodilator. The patient is scanned using diagnostic imaging, such as ultrasound, to obtain a visible image of the region. The methods are particularly useful for diagnosing the presence of diseased tissue in the cardiovascular region of a patient, as well as for measuring blood flow in the cardiovascular region of a patient.

Abstract: One can impart outstanding resistance against collapse under pressure to gas-filled microvesicle used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.

Abstract: Disclosed herein are agents for enhancing the contrast in an ultrasound image. These agents are extremely small bubbles, or “microbubbles,” comprised of specially selected gases. The microbubbles described herein exhibit long life spans in solution and may be produced at a size small enough to traverse the lungs, thus enabling improved ultrasound imaging of the cardiovascular system and other vital organs. Also disclosed herein is a method for selecting gases from which contrast agents may be produced. The method is based on calculations using inherent physical properties of gases and describes a means to associate the properties of a gas with the time for dissolution of microbubbles comprised of the gas.

Abstract: The invention concerns composite nanospheres having a diameter ranging between about 50 and 1000 nm plus or minus 5%, preferably between about 100 and 500 nm plus or minus 5% and advantageously between 100 and 200 nm plus or minus 5%, and comprising an essentially liquid core consisting of an organic phase and inorganic nanoparticles, distributed inside the organic phase, and a skin consisting of at least a hydrophilic polymer derived from the polymerisation of at least one water soluble monomer, in particular N-alkylacrylamide or a N—N-dialkylacrylamide; conjugates derived from said nanospheres; their preparation methods and their uses.

Abstract: An apparatus, system or method enables microbubbles to be created on demand for use as the contrast agent within a contrast medium administrable to a patient for purposes of a medical procedure. The system comprises a reservoir, a pressurizing device, a microbubble generator, and a controller. The reservoir stores a liquid. The pressurizing device conveys the liquid, along with the medium formed therewith, through the system. The microbubble generator is used to create the microbubbles within the liquid to form the medium. The microbubble generator has an inlet for receiving the liquid and an outlet for communication of the medium to the patient. The controller controls the operation of the system so that the microbubbles created by the microbubble generator are generated according to the demands of the medical procedure and are administrable within the medium to the patient.

Abstract: Use of a gas or gas precursor for the manufacture of a monitoring agent for a diganostic method for monitoring cardiac output in a mammal, including man, wherein said monitoring agent is a diagnostically acceptable gas in the gaseous state adapted for intravenous use, said gas being of such a nature, and being used in such an amount, that it is detectable via the expired breath from the mammal in question. An especially preferable gas is nitrous oxide. Monitoring agent for such a diagnostic method as well as such a diagnostic method.

Abstract: A method of identifying a patient at increased risk for myocardial infarction utilizes detection of a site or sites of pathologic vascular function in the coronary circulation of the patient. In the method, microbubbles are formed, each consisting of an encapsulated biocompatible gas characterized by rapid dissolution in blood, and the microbubbles are labeled with a prescribed antibody. These microbubbles are then injected into the patient's circulation to allow them to preferentially attach to a site of antigens specific to the pathologic vascular function in the coronary circulation. Ultrasonic energy is applied to the patient's coronary circulation at a level sufficient to burst the microbubbles that are preferentially attached to the targeted site and allow the encapsulated gas to escape from the burst microbubbles for absorption by the blood. Location of the targeted site is identified by detecting a signal representing reflectance of ultrasonic energy from the site.

Abstract: A microbubble preparation formed of a plurality of microbubbles comprising a first gas and a second gas surrounded by a membrane such as a surfactant, wherein the first gas and the second gas are present in a molar ratio of from about 1:100 to about 1000:1, and wherein the first gas has a vapor pressure of at least about (760-x) mm Hg at 37° C., where x is the vapor pressure of the second gas at 37° C., and wherein the vapor pressure of each of the first and second gases is greater than about 75 mm Hg at 37° C.

Abstract: Low density microspheres, methods for preparing same, and use of same as contrast agents are described. The microspheres have a void having a volume that comprises at least about 75% of the total volume of the microspheres, and which contains a gas or the vapor of a volatile liquid selected from the group consisting of aliphatic hydrocarbons, chlorofluorocarbons, tetraalkyl silanes and perfluorocarbons.

Abstract: A combined preparation comprising: i) an ultrasound contrast agent capable of accumulation in tissue microvasculature; and ii) a pharamacologically effective amount of a vasodilator drug may be used in perfusion imaging, especially of the myocardium. The contrast agent accumulates in tissue in concentrations related to the regional rate of tissue perfusion, and the vasodilator drug enhances distinction between normally perfused and underperfused tissue.

Abstract: Use of a gas or gas precursor for the manufacture of a monitoring agent for a diagnostic method for monitoring fallopian tube abnormalities in a female mammal, including man, wherein said monitoring agent is diagnostically acceptable gas in the gaseous state or dissolved in a diagnostically acceptable liquid as a true solution, said gas being of such a nature, and being used in such an amount, that is detectable via the expired breath from the mammal in question. An especially preferable gas in nitrous oxide. Said use is preferably for the detection of infertility of the mammal.

Abstract: The present invention is directed to charged lipids, compositions comprising charged lipids, and the use of these compositions in drug delivery, targeted drug delivery, therapeutic imaging and diagnostic imaging, as well as their use as contrast agents.

Abstract: One can impart outstanding resistance against collapse under pressure to gas-filled microvesicle used as contrast agents in ultrasonic echography by using as fillers gases whose solubility in water, expressed in liter of gas by liter of water under standard conditions, divided by the square root of the molecular weight does not exceed 0.003.