Compounds for Targeting Endothelial Cells, Compositions Containing the Same and Methods for Their Use

Abstract

The present invention provides compounds for targeting endothelial cells, tumor cells or other cells that express the NP-1 receptor, compositions containing the same and methods for their use. Additionally, the present invention includes diagnostic, therapeutic and radiotherapeutic compositions useful for visualization, therapy or radiotherapy.

Description

CROSS REFERENCE INFORMATION[0001]The present application is a continuation-in-part of U.S. application Ser. No. 09 / 871,974 filed Jun. 4, 2001, which is a continuation-in-part of U.S. application Ser. No. 09 / 585,364, filed Jun. 2, 2000, now abandoned, the entire contents of all of which are incorporated herein by reference.FIELD OF THE INVENTION[0002]The present invention relates to compounds useful for targeting endothelial cells or cells that express markers in common with endothelial cells, including certain tumor cells, compositions containing the same, uses thereof and methods for screening them. More particularly the present invention provides novel compounds, and compositions containing the same which may be selectively targeted to endothelial cells, or cells expressing markers in common with endothelial cells accessible to the compositions after parenteral or topical administration, of humans and animals, in vivo and in vitro, the compounds and compositions of the invention m...

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Benefits of technology

[0173]The polymers B3 useful for the preparation of the microballoons of the present invention can be selected from the biodegradable physiologically compatible polymers, such as any of those described in any of the following patents: EP 458745, U.S. Pat. No. 5,711,933, U.S. Pat. No. 5,840,275, EP 554213, U.S. Pat. No. 5,413,774 and U.S. Pat. No. 5,578,292, the entire contents of each of which are incorporated herein by reference. In particular, the polymer which constitutes the envelope or bounding membrane can be selected from biodegradable physiologically compatible polymers, such as polysaccharides of low water solubility, polylactides and polyglycolides and their copolymers, copolymers of lactides and lactones such as ε-caprolactone, γ-valerolactone and polypeptides. The great versatility in the selection of synthetic polymers is another advantage of the present invention since, as with sensitive patients, one may wish to avoid using microballoons made of natural proteins (albumin, gelatin) as in U.S. Pat. No. 4,276,885 or EP-A-324.938. Other suitable polymers include poly(ortho)esters (see for instance U.S. Pat. No. 4,093,709; U.S. Pat. No. 4,131,648; U.S. Pat. No. 4,138,344; U.S. Pat. No. 4,180,646); polylactic and polyglycolic acid and their copolymers, for instance DEXON (see J. Heller, Biomaterials 1 (1980), 51; poly(DL-lactide-co-γ-valerolactone), poly(DL-lactide-co-γ-valerolactone), poly(DL lactide-co-γ-butyrolactone), polyalkylcyanoacrylates; polyamides, polyhydroxybutyrate; polydioxanone; poly-β-aminoketones (Polymer 23 (1982), 1693); polyphosphazenes (Science 193 (1976), 1214); and polyanhydrides. References on biodegradable polymers can be found in R. Langer et al., Macromol. Chem. Phys. C23 (1983), 61-126. Polyamino-acids such as polyglutamic and polyaspartic acids can also be used as well as their derivatives, i.e., partial esters with lower alcohols or glycols. One useful example of such polymers is poly(t.butyl-glutamate). Copolymers with other amino acids such as methionine, leucine, valine, proline, glycine, alamine, etc. are also possible. Recently, novel derivatives of polyglutamic and polyaspartic acid with controlled biodegradability have been reported (see WO 87 / 03891; U.S. Pat. No. 4,888,398 and EP-130.935, incorporated here by reference). The lipids B3a useful in the present including are discussed infra.

[0174]The microballoons which may be particularly useful in certain applications of the present invention are pressure sustaining microballoons bounded by a soft and elastic membrane which can temporarily deform under variations of pressure and are endowed with enhanced echogenicity and are biodegradable.

[0175]The amount of the compounds of general formula (I) that may be incorporated in the microballoon of the present invention may vary depending, for example, on the particular polymer B3 or lipid B3a involved. In certain preferred embodiments, the microballoons composition comprising the targeting moiety may comprise as low as 0.5% mol. of a compound of general formula (I) up to 50% of the total polymer B3 or the lipid B3a. The more preferred range is between 5% and 15% of the total.

[0176]The microballoons of the present invention are preferably prepared by emulsifying with an emulsifier a hydrophobic phase in an aqueous phase (usually containing viscosity increasing agents as emulsion stabilizers) thus obtaining an oil-in-water type emulsion of droplets of the hydrophobic phase and thereafter adding thereto a membrane forming polymer dissolved in a volatile organic solvent not miscible with the aqueous phase.

[0177]Known techniques can be adapted to the preparation of air or gas filled microballoons suited for ultrasonic imaging, according to the present invention, provided that appropriate conditions are found to control sphere size in the desired ranges, balloon-wall permeability or imperviousness and replacement of the encapsulated liquid phase by air or a selected gas. Control of overall sphere size is important to adapt the microballoons for their intended use, i.e., parenteral administration (about 0.5-10 μm average size). Control of balloon-wall permeability is important to ensure that injectable aqueous carrier phase does not infiltrate or infiltrates at a slow enough rate so as not to impair the echographic measurements but is still sufficient to ensure relatively fast after-test biodegradability, i.e. ready metabolization of the suspension by the organism. Also the microporous structure of the microballoons envelope (pores of a few nm to a few hundreds of nm or more for microballoons envelopes of thickness ranging from 50-500 nm) influences their resiliency, i.e. the microspheres can readily accept pressure variations without breaking The preferred range of pore sizes is about 50-2000 nm.

[0178]A preferred method for forming the microballoons with a biodegradable envelope constituted by polymers B3 in mixture with the compounds (la) of the present invention, is as follows:

Problems solved by technology

However studies show that tuftsin labeled with a radionuclide metal undesirably accumulates in non-target tissues.

The use of echocardiography for the diagnosis of cardiovascular diseases has generally been limited to indirect methods that involve the detection and quantitation of abnormalities in the wall motion of the heart.

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