US20060121123A9 - Optical contrast agents for optically modifying incident radiation - Google Patents

Optical contrast agents for optically modifying incident radiation Download PDF

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US20060121123A9
US20060121123A9 US10/463,835 US46383503A US2006121123A9 US 20060121123 A9 US20060121123 A9 US 20060121123A9 US 46383503 A US46383503 A US 46383503A US 2006121123 A9 US2006121123 A9 US 2006121123A9
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microparticles
sample
image
forming
imaging
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US7198777B2 (en
US20040258762A1 (en
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Stephen Boppart
Daniel Marks
Kenneth Suslick
Farah Toublan
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University of Illinois
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6925—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a microcapsule, nanocapsule, microbubble or nanobubble
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • Contrast agents which produce a strong emission or reflection signal, have been utilized in virtually every imaging modality including ultrasound [2], computed tomography [57], magnetic resonance imaging [58], and optical microscopy [59].
  • OCT optical coherence tomography
  • Cross-sectional OCT imaging is performed by measuring the backscattered intensity of light from structures in tissue. This imaging technique is attractive for medical imaging because it permits the imaging of tissue microstructure in situ, yielding micron-scale imaging resolution without the need for excision and histological processing. Because OCT performs imaging using light, it has a one- to two-order-of-magnitude higher spatial resolution than ultrasound and does not require contact with tissue.
  • OCT was originally developed and demonstrated in ophthalmology for high-resolution tomographic imaging of the retina and anterior eye [22-24]. Because the eye is transparent and is easily optically accessible, it is well-suited for diagnostic OCT imaging. OCT is promising for the diagnosis of retinal disease because it can provide images of retinal pathology with 10 ⁇ m resolution, almost one order-of-magnitude higher than previously possible using ultrasound. Clinical studies have been performed to assess the application of OCT for a number of macular diseases [23,24]. OCT is especially promising for the diagnosis and monitoring of glaucoma and macular edema associated with diabetic retinopathy because it permits the quantitative measurement of changes in the retinal or retinal nerve fiber layer thickness. Because morphological changes often occur before the onset of physical symptoms, OCT can provide a powerful approach for the early detection of these diseases.
  • OCT optical coherence tomography
  • Imaging studies have also been performed to investigate applications in gastroenterology, urology, and neurosurgery [30-32].
  • High resolution OCT using short coherence length, short-pulse light sources has also been demonstrated and axial resolutions of less than 5 ⁇ m have been achieved [33,34].
  • High-speed OCT at image acquisition rates of 4 to 8 frames per second for 500 to 250 square pixel images has been achieved [35].
  • OCT has been extended to perform Doppler imaging of blood flow and birefringence imaging to investigate laser intervention [36-38].
  • Different imaging delivery systems including transverse imaging catheters and endoscopes, and forward imaging devices have been developed to enable internal body OCT imaging [39,40].
  • OCT has been combined with catheter-endoscope-based delivery to perform in vivo imaging in animal models and human patients [41-44].
  • OCT has been demonstrated as an emerging investigational tool for cell and developmental biology.
  • OCT has imaged the development of numerous animal models including Rana pipiens and Xenopus laevis (Leopard and African frog), and Brachydanio rerio (zebrafish) [45-46].
  • High-speed OCT imaging has permitted the morphological and functional imaging of the developing Xenopus cardiovascular system, including changes in heart function following pharmacological interventions [47].
  • High-resolution imaging has permitted the real-time tracking of cell dynamics in living specimens including mesenchymal cell mitosis and neural crest cell migration [48].
  • OCT is advantageous in microscopy applications because repeated non-invasive imaging of the morphological and functional changes in genetically modified animals can be performed overtime without having to histologically process multiple specimens.
  • the high-resolution, cellular-imaging capabilities suggest that OCT can be used to diagnose and monitor early neoplastic changes in humans.
  • OCT optical computed tomography
  • Albunex® is an FDA-approved, air-filled albumin composed of microparticles produced ultrasonically, that is used intravenously as an echo-contrast agent for echocardiography, and as a contrast agent for ultrasound imaging [2-4]. These microparticles may be formed with encapsulated liquid, to form a unique colloidal delivery vehicle.
  • protein used for the microparticle shell, the material encapsulated within the microparticle, a multitude of biomedical applications have been developed [3,5-9].
  • Some of the applications of these protein microparticles include biocompatible blood substitutes, magnetic resonance imaging and echocardiographic contrast agents, and novel drug delivery systems. These are described in the following U.S. Pat. Nos.
  • These protein microparticles may be created from ultrasonic irradiation of aqueous protein solutions.
  • the mechanism responsible for microparticle formation is, in fact, a combination of two acoustic phenomena: emulsification and cavitation.
  • Ultrasonic emulsification creates the microscopic dispersion of the protein solution necessary to form the proteinaceous microparticles.
  • emulsification is insufficient to produce long-lived microparticles. For example, emulsions produced by vortex mixing produce no long-lived microparticles.
  • Ultrasonic irradiation of liquids can also produce cavitation, the formation, growth, and implosive collapse of bubbles.
  • the collapse of such bubbles creates transient hot-spots with enormous peak temperatures [14].
  • Sonolysis of water is known to produce H+, OH ⁇ , H 2 , H 2 O 2 , and in the presence of oxygen, HO 2 [13].
  • Superoxide creates inter-protein disulfide bonds that cross-link the proteins and hold the microparticles together. This dispersion of gas or nonaqueous liquid into the protein solution, coupled with chemical cross-linking of the protein at the microparticle interface results in the formation of long-lived microparticles filled with air or nonaqueous liquid.
  • the present invention is a method of forming an image of a sample, comprising forming an image of a mixture, by exposing the mixture to electromagnetic radiation.
  • the mixture comprises the sample and microparticles.
  • the present invention is a method of enhancing the contrast of an image of a sample, comprising forming an image of a mixture, by exposing the mixture to electromagnetic radiation.
  • the mixture comprises the sample and microparticles.
  • the present invention is a method of forming an image by optical coherence tomography, including exposing a patient to electromagnetic radiation, collecting reflected electromagnetic radiation, and forming an image from the collected electromagnetic radiation, the improvement comprising administering a contrast agent to the patient to enhance contrast of the image.
  • FIG. 1 is a scanning electron microscope image of microparticles
  • FIG. 2 shows a plot of the distribution of microparticle sizes
  • FIG. 3 is a graph of the “biological window” in tissue
  • FIG. 4 is a schematic of magnetically- or electrically switchable contrast agents
  • FIG. 5 is a schematic of low-coherence interferometry
  • FIG. 6 is a schematic of an OCT instrument
  • FIGS. 7 ( a ) and ( b ) are images of air-filled microparticles in a tissue model
  • FIG. 7 ( c ) shows plots indicating the degree of optical backscatter versus depth for the boxed areas in FIGS. 7 ( a ) and ( b );
  • FIG. 8 is an illustration of the step for forming microparticles
  • FIGS. 9 ( a ) and ( b ) are diagrams of the standard cell and inverted cell, respectively, for forming microparticles.
  • FIG. 10 depicts a method of coating colloidal suspensions onto microparticles.
  • microparticles may be used to enhance the contrast in analyses and imaging techniques that use electromagnetic radiation, particularly those techniques which use radiation in the frequency range of infra-red to ultraviolet, such as OCT, light microscopy, holography, confocal microscopy, multi-photon microscopy, and endoscopy.
  • enhancing the contrast means that an image produced with the enhancement shows a greater difference in adsorbed, scattered or reflected electromagnetic radiation between parts of the image, than an otherwise identical image produced without the enhancement.
  • image means data produced by receipt of electromagnetic radiation, which may or may not be formed into a picture viewable by the human eye. This includes images produced directly onto a medium such as film or video.
  • frequency range of infra-red to ultraviolet means electromagnetic radiation having a frequency of 10 12 to 10 17 Hz, which excludes radio waves, microwaves, X-rays and gamma rays.
  • light means visible light.
  • Microparticles have a solid component, such as an outer shell, and may have an inner core which is gas, liquid or solid (which may be the same or different from the outer shell).
  • the microparticles Preferably, the microparticles have an outer shell containing biodegradable polymers. More preferably, the microparticles have an outer shell containing cross-linked protein.
  • solid includes cross-linked proteins; cross-linked polymers; and materials which exhibit a melting point (T m ) or a glass transition temperature (T g ) in differential scanning calorimetry (DSC) which is above 30° C., more preferably above 50° C., most preferably above 100°C.
  • T m melting point
  • T g glass transition temperature
  • the microparticles have an average diameter of at least 100 nm, more preferably at least 0.5 microns, even more preferably 0.5-15 microns, most preferably 0.5-5 microns.
  • the microparticles have an average diameter of at most 50 microns, more preferably 100 nm to 50 microns.
  • the term “diameter” and “average diameter”, in the context of microparticles, means number average diameter.
  • Varying the microparticle diameter enables size-selectivity for use in the living microcirculation or for optimizing the wavelength-specific scattering properties of the contrast agents.
  • Mie scattering predicts the behavior of the scattered light and can be used to maximize scattering for particular wavelengths.
  • any protein may be used in the microparticles.
  • the term “protein” includes proteins, peptides and polypeptides, both natural and synthetic.
  • the first two steps are a result of the mixing effect caused by ultrasound.
  • the third step is a result of the sonolysis of water. When exposed to high intensity ultrasound (20 kHz), water molecules are split into highly reactive intermediates. Superoxide, which is produced during the sonolysis of water, cross-links the protein molecules.
  • the cross-linking of the microparticles is done via the oxidation of the cysteine residues to form inter-protein disulfide bonds.
  • the general process is depicted in FIG. 8 .
  • microparticles Using this particular set-up, a variety of microparticles have been produced.
  • the material to be encapsulated should be dissolved into a two-phase system comprising an aqueous phase and an oil phase during the emulsification.
  • solids and gasses can also be encapsulated inside the microparticle.
  • air has been encapsulated in protein microparticles.
  • AlbunexTM is commercially available as an echo contrast agent.
  • cysteine residues are reacted, forming disulfide bonds that cross-link the protein. If the protein does not contain cysteine residues, the protein may be modified with 2-iminothiolane (Traut's reagent) using the chemical scheme shown below.
  • any protein can be used for microparticle synthesis.
  • the polymers for use with the present invention are materials which decompose when placed inside an organism. This can be observed as a decline in the molecular weight of the polymer over time.
  • Polymer molecular weights can be determined by a variety of methods including size exclusion chromatography (SEC), and are generally expressed as weight averages or number averages.
  • SEC size exclusion chromatography
  • a polymer is biodegradable if, when in phosphate buffered saline (PBS) of pH 7.4 and a temperature of 37° C., its weight-average molecular weight is reduced by at least 25% over a period of 6 months as measured by SEC.
  • PBS phosphate buffered saline
  • biodegradable polymers include proteins, polyesters, such as poly( ⁇ -caprolactone), poly(glycolic acid), poly(L-lactic acid), poly(D-lactic acid), poly(hydroxybutyrate) and copolymers of caprolactone, glycolic acid, lactic acid, and hydroxybutyrate; polyanhydrides, such as poly(adipic anhydride); poly(paradioxanone); poly( ⁇ -malic acid); polyethylene glycol; polyamines; polyurethanes; polyesteramides; polyorthoesters; polyacetals; polyketals; polycarbonates; polyorthocarbonates; polyphosphazenes; poly(malic acid); poly(amino acids); polyvinylpyrrolidone; polyhydroxycellulose; chitin; chitosan; and copolymers and mixtures thereof.
  • polyanhydrides such as poly(adipic anhydride); poly(paradioxanone); poly( ⁇ -malic acid); polyethylene glycol;
  • biodegradable polymer may be used to fabricate the shell of microparticles.
  • biodegradable polymers that contain sulfhydryl functionality may be used to fabricate microparticles, as sonolysis will yield interpolymer disulfide bonds between adjacent polymers.
  • Biodegradable polymers that contain reactive groups other than sulfhydryl groups, such as amine groups can be modified initially with Traut's reagent as described previously to introduce the requisite sulfhydryl functionality for fabricating the cross-linked polymer shell of microparticles using sonolysis.
  • biodegradable polymers that contain multiple functionalities, such as amino, carboxylate, ester, hydroxyl, and sulfhydryl functionalities, would enable fabrication of microparticles having cross-linked polymer shells that may be subject to further surface modification.
  • biodegradable polymers that make up the polymer shell of microparticles need not be homopolymers nor uniform mixtures of a given polymer.
  • Biodegradable homopolymers, heteropolymers, or mixtures thereof may be used in microparticle fabrication protocols, provided the polymers possess sulfhydryl functionality necessary for formation of microparticle having a cross-linked biodegradable polymer shell.
  • Such polymers are commercially available or may be prepared using methods routinely available to one of ordinary skill in the art.
  • One or more materials may be encapsulated in each microparticle. Changes in the inner core allows for versatility of the microparticles in biomedical applications. Table 1 lists some of the types of microparticles that have been synthesized. In addition to the inner core materials in the list, melanin granules, colloidal gold, iron oxide, and fluorophores, all of which have the potential to absorb, scatter, spectrally-modify, or modulate the incident radiation, may be used.
  • liquid crystalline materials include liquid crystalline materials, biocompatible liquid crystals in the cholesterol family such as cholesterol oleyl carbonate, fatty alcohol esters of tartaric acid and cholesteryl oligo(L-lactic acids), chiral agents such as helocenes, tartaric acid and esters thereof, other optically active organic compounds, and birefringent materials, which may be used in conjunction with planar or circularly polarized light.
  • Dye and pigments may also be included, such as porphyrins, metalloporphyrins, nile red, rhodamine, and phthalocyanines.
  • the microparticle are optically dense; the term “optically dense” means that the microparticles absorbs at least twice as much visible light than an equivalent thickness of water-filled microparticles formed from bovine serum albumin.
  • the microparticles are X-ray dense; the term “X-ray dense” means that the microparticles absorb at least twice as much C ⁇ K ⁇ X-ray radiation, than an equivalent thickness of water-filled microparticles formed from bovine serum albumin.
  • Hydrophilic materials and charged material can be introduced in the microparticles using a modification of the cell employed (inverted cell as opposed to the standard cell). Diagrams of the standard cell (left), as well as one of the inverted cell (right) are shown in FIG. 9 .
  • Two or more different materials may be encapsulated in each microparticle to provide high or low contrast under different conditions, such as in an applied alternating field.
  • one or more of the encapsulated material is either charged (for electrically-modulated agents) or magnetic (for magnetically-modulated agents). These agents may be responsible for either low or high contrast.
  • the second type of material to be encapsulated is intended to provide the opposite contrast of the first such as titanium oxide, or may be a bulk material such as oil, or both.
  • charged agents include Reichardt's dye (RD; a solvatochromic agent) and 1-ethyl-4-methoxycarbonyl) pyridinium iodide (PYI), the structures of which are shown below.
  • magnétique agents examples include iron particles, iron oxide, ferrox cube A, alnico 8, cunife, cunico, iron particles coated titanium oxide (formed by sputtering the iron particles with titanium oxide), and cobalt particles coated with gold (formed by plating of gold onto cobalt particles).
  • microparticles have been examined by optical microscopy, scanning and transmission electron microscopy, and particle counting.
  • the microparticles have a uniform size distribution with diameters of roughly 2 ⁇ m, permitting unimpeded motion throughout the circulatory system.
  • the protein shells may be quite thin (roughly 50 angstroms across) and gas permeable, the particles are physically robust and will survive filtration and centrifugation. Their synthesis produces very large concentrations (>10 10 microparticles/mL after purification).
  • Sonochemical methods that use high-intensity ultrasound and simple protein solutions may be used to make both air-filled microparticles and liquid and particle-filled microcapsules [5].
  • a 1-15% weight per volume solution of protein in water may be mixed with the liquid or the particles to be encapsulated.
  • High intensity 20 kHz ultrasound may be applied at the interface of the materials for 1-10 minutes at an acoustic power of 30-150 watts/cm 2 .
  • Temperature should be controlled by a water bath.
  • Microparticles may be washed multiple times by centrifuge filtration, for example at 3 g for 20 minutes. The microparticle-containing layer may then be separated and remaining layers discarded.
  • Contrast agents that can have their contrast modulated by external electric or magnetic fields are fabricated in a similar manner, except, two or more different materials are encapsulated in each microparticle.
  • Microparticle diameter can be controlled by varying the acoustic power of the ultrasound wave. This sonochemical technique produces micron-sized particles with a cross-linked protein shell and a core which may be selected freely.
  • the surface of the microparticles can be altered to vary the in vivo pharmacokinetics and biodistribution.
  • attached molecules include, but are not limited to, polyethylene glycol chains (PEG) (to extend their lifetime in the blood pool), membrane receptor ligands (e.g., folate, hemes, steroids, neurotransmitters), bioactive peptides, and even antibody chains.
  • PEG polyethylene glycol chains
  • membrane receptor ligands e.g., folate, hemes, steroids, neurotransmitters
  • bioactive peptides e.g., folate, hemes, steroids, neurotransmitters
  • lipase can be attached to the surface of the microparticles to preferentially target the small intestines.
  • PEG polyethylene glycol
  • the folate in this instance is activated using a dicyclohexyl carbodiimide (DCC) coupling reaction.
  • DCC dicyclohexyl carbodiimide
  • the activated folate is then coupled to a PEG moiety. This process is depicted below.
  • the resulting modified PEG is attached to the surface of the microparticles in the same manner as depicted above via a cyanuric chloride coupling reaction.
  • the conjugation of folate to the microparticle surface allows targeting to folate-binding tumor cells.
  • Ovarian, breast, and human nasopharyngeal tumors all possess a high concentration of folate receptors on their surface [52,53].
  • liposomes modified by folate-PEG conjugates target folate receptor bearing KB tumor cells and exhibit an inhibitory effect on their growth [54].
  • these contrast agents are expected to target induced squamous cell carcinoma with the folate-modified microparticles.
  • many oral and upper gastrointestinal tract tumors have a high affinity for various hemes (which greatly assists in the use of hematoporphyrins as photodynamic therapy agents) [55,56].
  • Microparticles with surface hemes attached may also be used to target induced squamous cell carcinoma.
  • the modification of the protein microparticles with antibodies allows targeting of T-cell receptors. This modification was carried out using monoclonal antibodies that are specific for T-cell receptors. These monoclonal antibodies were covalently linked to the surface of the microparticles via a dimethylaminoprol-carbodiimide hydrochloride (EDC) coupling reaction. In this coupling reaction the glutamates (residues which contain carboxylates groups) and the lysines (residues which contain primary amine groups) of both the antibodies and the protein microparticles are cross-linked. The general scheme of this process is shown below. This may be used to form a surface coat of any protein which contains glutamate and lysine residues.
  • EDC dimethylaminoprol-carbodiimide hydrochloride
  • Modifications using aqueous colloidal suspension relies on the surface charge of the microparticles for particulate adhesion.
  • This method has been employed in the thin film industry to place charged particles onto a template.
  • a microparticle having a negative charge for example one formed from BSA and kept at a pH of 7.4, is formed and positively charged material may be adhered onto the surface following a layer-by-layer approach, by simply mixing it with the colloidal material. This method is depicted in FIG. 10 .
  • microparticles may be put on the surface by following the usual microparticle synthesis route but by using a non-colloid suspension of the desired material in the oil phase. Because the oil does not appropriately solvate the suspended particles, upon microparticle formation these particles preferentially attach to the exterior of the protein shell to avoid contact with the oil phase. Examples of these microparticles are the melanin and carbon surface coat containing microparticles.
  • the protein shell of serum albumin microparticles with a n-C 9 F 20 core can be modified.
  • the measured circulation half-life of non-modified microparticles was approximately 5 minutes, while surface modification with PEG extends this to more than 70 minutes.
  • Sonochemically-generated contrast agents containing any combination of shell and encapsulated material may be used to increase local contrast within biological and non-biological specimens and samples.
  • Contrast agents can be delivered to the area of interest by a number of techniques including syringe injection interstitially, intravenouly, intermuscularly, subdermally, interparatenielly, and interthecally. Other techniques include oral, rectal and topical administration.
  • the surface modifications to the agents enable them to localize to target tissues or cells by means include receptor-mediated adhesion, antigen-antibody localization, or phagocytosis (engulfing) or endocytosis (uptake) by target cells.
  • the microparticles may be prepared as pharmaceutical compositions.
  • Such compositions typically comprise microparticles and a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., compatible with pharmaceutical administration [61].
  • Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. Except when a conventional media or agent is incompatible with an active compound, use of these compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition is formulated to be compatible with the intended route of administration, including intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.
  • compositions suitable for injection include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • suitable carriers include physiological saline, bacteriostatic water, CREMOPHOR EL (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS).
  • the composition must be sterile and should be fluid so as to be administered using a syringe.
  • Such compositions should be stable during manufacture and storage and must be preserved against contamination from microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (such as glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures.
  • Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the required particle size in the case of dispersion and by using surfactants.
  • Various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, and thimerosal, can control microorganism contamination.
  • Isotonic agents such as sugars, polyalcohols such as manitol, sorbitol, and sodium chloride can be included in the composition.
  • Sterile injectable solutions or dispersions can be prepared by incorporating microparticles in an appropriate solvent with one or a combination of ingredients, followed by sterilization.
  • Sterile powders for the preparation of sterile injectable solutions methods of preparation include vacuum drying and freeze-drying that yield a powder and any desired ingredient from a sterile solutions.
  • Oral compositions generally include an inert diluent or an edible carrier.
  • the microparticles can be incorporated with excipients and used in the form of tablets, troches, or capsules.
  • Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included.
  • Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, PRIMOGEL, or corn starch; a lubricant such as magnesium stearate or STEROTES; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, PRIMOGEL, or corn starch
  • a lubricant such as magnesium stearate or STEROTES
  • a glidant such as colloidal silicon dioxide
  • the compounds are delivered as an aerosol spray from a nebulizer or a pressurized container that contains a suitable propellant, e.g., a gas such as carbon dioxide.
  • a suitable propellant e.g., a gas such as carbon dioxide.
  • Systemic administration can also be mucosal or dermal.
  • penetrants that can permeate the target barrier(s) are selected.
  • Mucosal penetrants include, detergents, bile salts, and fusidic acid derivatives.
  • Nasal sprays or suppositories can be used for mucosal administration.
  • the microparticles are formulated into ointments, salves, gels, or creams.
  • the microparticles can also be prepared in the form of suppositories (e.g., with bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • Unit dosage form refers to physically discrete units suited as single doses for a subject, containing a effective quantity of microparticles in association with a pharmaceutical carrier.
  • compositions can be included in a kit, container, pack, or dispenser together with instructions for administration.
  • the different components of the composition may be packaged in separate containers and admixed immediately before use. Such packaging of the components separately may permit better long-term storage.
  • the reagents included in the kits can be supplied in containers of any sort such that the life of the different components are preserved and are not adsorbed or altered by the materials of the container.
  • sealed glass ampules may contain lyophilized luciferase or buffer that have been packaged under a neutral non-reacting gas, such as nitrogen.
  • Ampules may consist of any suitable material, such as glass, organic polymers, such as polycarbonate, polystyrene, etc., ceramic, metal or any other material typically employed to hold reagents.
  • suitable containers include bottles that may be fabricated from similar substances as ampules, and envelopes, that may consist of foil-lined interiors, such as aluminum or an alloy.
  • Containers include test tubes, vials, flasks, bottles, syringes, etc.
  • Containers may have a sterile access port, such as a bottle having a stopper that can be pierced by a hypodermic injection needle.
  • Other containers may have two compartments that are separated by a readily removable membrane that upon removal permits the components to mix.
  • Removable membranes may be glass, plastic, rubber, etc.
  • Kits may also be supplied with instructional materials. Instructions may be printed on paper or other substrate, and/or may be supplied as an electronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, Zip disc, videotape, audio tape, etc. Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an internet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mail.
  • contrast agents Once contrast agents have reached their target tissue or cell, they may remain localized and provide contrast either passively or actively. Passive contrast agents may absorb, scatter, or spectrally-modify the incident radiation. Active contrast agents have their contrast modulated by alternating, externally-applied electric or magnetic fields.
  • Electromagnetic radiation is directed toward the specimen, sample or part of a patient containing the contrast agent. Following interaction with the contrast agent, the affected radiation is detected, typically in either the transmitted (forward) or reflected (backward) directions relative to the direction of the incident radiation. This detected radiation carries information about the specimen, sample or patient, as well as the presence of the contrast agent. This information can be measured and displayed numerically, graphically, or in the form of an image. For active contrast agents that have their contrast modulated by an external field, an alternating electric or magnetic field is applied, inducing an alternating contrast within the agents ( FIG. 4 ).
  • An apparatus for implementing switchable contrast agents would include pairs, series, or arrays of electrodes that would have an electrical potential (dc or ac) and establish an electric field within the specimen to cause the charged particles to be oriented, aligned, or displaced.
  • Magnetic fields may be established using solenoids or coil configurations through which electrical current is passed. Static and alternating magnetic fields and gradients may be used.
  • MRI Magnetic Resonance Imaging
  • the contrast will modulate at the same frequency as the applied field. Detection with a lock-in amplifier (locked in at the same frequency as the applied field) is used to enhance the sensitivity of the contrast agents.
  • the detection of a signal at the lock-in frequency may be amplified, compared to other signals, thereby enhancing the sensitivity of the detection scheme.
  • moving particles caused by the alternating fields will cause a Doppler-shift in the incident light, and using OCT these frequency shifts would provide a signal that can be detected with high sensitivity, since the background tissue will not be moving.
  • the lifetime of the contrast agents in living specimens is likely to range from minutes to days, depending on the stability of the agent, the ability of the agent to localize and attach to specific tissue or cells, and the ability of the body to breakdown or clear the agent.
  • Studies of similar agents used in ultrasound and MRI indicate that the agents are cleared rapidly within hours and excretion occurs via both the renal (kidneys) and hepatic (liver) systems. Because of the expected rapid clearance of the agents, side-effects are expected to be minimal.
  • the contrast agents described here may be used in optical detection and imaging technologies for biological, non-biological, medical, and display applications.
  • OCT is an emerging high-resolution imaging technology that currently lacks contrast agents to enhance its diagnostic capabilities.
  • OCT performs optical ranging and is analogous to ultrasound, except reflections of near-infrared light is detected rather than sound. Because the speed of light is much faster than sound, optical low-coherence interferometry ( FIG. 5 ) must be used to determine the precise location of the optical backscatter.
  • the OCT technology is fiber-optic-based and relies on the rapid technology development of lasers and fiber optics driven by the telecommunications industry. A schematic of the OCT instrument is shown in FIG. 6 .
  • the OCT imaging beam can be delivered to internal body locations with the use of fiber-optic probes and catheters.
  • the use of optical contrast agents localized to regions of early cancer will facilitate detection of cancer at early stages, when it is most responsive to treatment.
  • FIG. 7 illustrates the use of air-filled microparticles, in a tissue model.
  • Layers of agarose gel mixed with milk to emulate the optical properties of human skin were used to demonstrate how microparticles enhance contrast deep below the surface.
  • a layer of contrast agents can be seen in FIG. 7 b.
  • FIG. 7 c shows axial plots of data that illustrate the enhancement of contrast up to 650 microns below the surface of the tissue model.
  • the contrast agents investigated in this study are similar to those used in ultrasound echocardiography [4]. These agents are hollow microparticles 0.5 to 5 microns in diameter with a 50 ⁇ thick protein shell.
  • FIG. 1 shows a scanning electron micrograph of the microparticles. The microparticles utilized were air-filled and produced by sonicating a 5% weight per volume solution of bovine serum albumin (BSA) in water. The high-intensity ultrasound necessary for the reaction was generated by a titanium horn with tip diameter of 0.5 inches, driven at 20 kHz. The BSA solution was sonicated for 3 minutes at an acoustic power of 76 W/cm 2 [3].
  • BSA bovine serum albumin
  • the diameter of the microparticles is dependent on the acoustic power and the frequency of ultrasound used. Diameters ranging from 0.5 microns to 15 microns may be produced with ultrasound.
  • the sample of microparticles was washed 5 times with nanopure water and filtered to remove unwanted particles.
  • FIG. 2 shows a plot of the distribution of microparticle sizes from a 10 ⁇ L sample of contrast agents in water. Approximately 1.3 ⁇ 10 5 microparticles/ ⁇ L are present within this sample. The distribution plot data was generated from a COULTER® Multisizer II analysis of the sample.
  • microparticle sizes are generally under 5 microns with an average and standard deviation of 2.2 ⁇ 0.5 ⁇ m. This size distribution should enable them to pass readily through the microcirculation.
  • These microparticles can also be filled with other scattering substances such as melanin, gold, or iron particles suspended in oil [5].
  • the air-filled particles (refractive index n ⁇ 1) are expected to scatter strongly in tissue (n ⁇ 1.38) because of the difference in refractive indices.
  • Scattering tissue models were developed to determine if the contrast agents could be detected in an environment similar to biological tissues. These models consisted of agarose gelatin in which skim milk was added as a scatterer to achieve a reduced scattering coefficient of 15-25 cm ⁇ 1 at 800 nm wavelength, which is comparable to that measured in human epidermal tissue [18]. The reduced scattering coefficients for each model were measured by oblique-incidence fiber-optic reflectometry [62]. Tissue models were prepared by heating a solution of agarose and water near boiling and adding approximately 25% milk by volume to achieve the desired scattering properties. The agarose-milk solution was cooled to form a scattering layer.
  • microparticles 1.3 ⁇ 10 5 microparticles/ ⁇ L
  • gelatin a 50 ⁇ L drop of microparticles (1.3 ⁇ 10 5 microparticles/ ⁇ L)) and gelatin was deposited and cooled.
  • Tissue model samples were imaged with a fiber-optic based OCT system.
  • the broad-bandwidth optical source consisted of a Nd:YVO 4 diode-pumped titanium:sapphire laser which produced 500 mW average power and approximately 90 fs pulses with an 80 MHz repetition rate at 800 nm center wavelength. About 350 mW of this power was coupled into a single mode fiber and was split into two paths by a broadband 50:50 fiber coupler (Gould Fiber Optics, Inc.). When passed through this coupler, the spectral bandwidth of the pulse broadened from 25 to 50 nm FWHM. The axial and transverse resolutions of the system were 6 ⁇ m and 14 ⁇ m, respectively.
  • the reference arm of the OCT interferometer contained a galvanometer-driven retroreflector delay line that was scanned a distance of 5 mm at a rate of 30 Hz to provide axial reflectance data.
  • the sample arm consisted of a fiber-optic collimator to produce a 2 mm diameter beam from the fiber. The beam was focused into the tissue by a 12.5 mm diameter, 30 mm focal length achromatic lens. The beam was scanned over the tissue with a pair of orthogonal galvanometer-controlled mirrors. Approximately 6 mW of power was incident on the tissue. The reflected light was recollected by the lens and collimator and recombined in the fiber coupler with the delayed reference signal.
  • the interference signal was measured by a silicon photodiode, bandpass-filtered by an analog filter, and rectified by a logarithmic envelope detection circuit. The resulting scattering magnitude was digitized to 12-bit accuracy. Adjacent axial scans were assembled to produce two-dimensional OCT images that were displayed on the computer using custom data acquisition and display software.
  • FIG. 7 ( b ) is due to contrast agents and not the sample preparation method.
  • FIG. 7 ( c ) is a series of plots of the average scattering intensity as a function of depth (averaged over 75 axial scans) for the five boxed regions in FIGS. 7 ( a ) and 7 ( b ).
  • the optical backscatter intensity is normalized by the magnitude of the scattering near the surface to account for variations in intensity due to the scanning angle of the OCT beam.
  • the control region is from the sample without contrast agents to show that the backscatter ratio remains under one.
  • the other four regions are from the sample containing contrast agents at increasing depths under the surface.
  • Samples 1, 2, and 3 have peak backscatter ratios near 2.0, which indicate that the contrast is 2:1 over the background.
  • Sample 4 is slightly decreased, showing that the signal is decreasing at that depth (approximately 650 ⁇ m). This suggests that this particular sample and concentration of contrast agents may not provide a useful signal at depths significantly greater than 700-800 ⁇ m. Because the scattering properties of the microparticles can be manipulated by changing the size distribution and by encapsulating scattering particles, higher contrast should be possible.
  • Albunex a new ultrasound contrast agent consisting of air-filled albumin microparticles suspended in a solution of human albumin. Biotechnol. Appl. Biochem. 19:307-320, 1994.
  • Boppart S A Bouma B E, Pitris C, Tearney G J, Southern J F, Brezinski M E, Fujimoto J G. Intraoperative assessment of microsurgery with three-dimensional optical coherence tomography. Radiology. 208:81-86, 1998.
  • Boppart S A Boppart S A, Bouma B E, Pitris C, Teamey G J, Fujimoto J G. Forward-imaging instruments for optical coherence tomography. Opt. Lett. 22:1618-1620, 1997.
  • Boppart S A Brezinski M E, Bouma B E, Tearney G J, Fujimoto J G. Investigation of developing embryonic morphology using optical coherence tomography. Dev. Biol. 177:54-63, 1996.
  • Boppart S A Brezinski M E, Tearney G J, Bouma B E, Fujimoto J G. Imaging developing neural morphology using optical coherence tomography. J. Neurosci. Meth. 2112:65-72, 1996.
  • Boppart S A Tearney G J, Bouma B E, Southern J F, Brezinski M E, Fujimoto J G. Noninvasive assessment of the developing Xenopus cardiovascular system using optical coherence tomography. Proc. Natl. Acad. Sci. USA 94:4256- 4261, 1997.
  • Boppart S A Surgical Diagnostics, Guidance, and Intervention using Optical Coherence Tomography. Ph.D. Thesis. Harvard-MIT Division of Health Sciences and Technology, Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Mass., 1998.
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