EP0963209A2 - Verbesserungen in oder an diagnostischen/ therapeutischen mitteln - Google Patents
Verbesserungen in oder an diagnostischen/ therapeutischen mittelnInfo
- Publication number
- EP0963209A2 EP0963209A2 EP97910518A EP97910518A EP0963209A2 EP 0963209 A2 EP0963209 A2 EP 0963209A2 EP 97910518 A EP97910518 A EP 97910518A EP 97910518 A EP97910518 A EP 97910518A EP 0963209 A2 EP0963209 A2 EP 0963209A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- agent
- vector
- microbubbles
- gas
- reporter
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Definitions
- tissue-specific ultrasonic image enhancement may be achieved using acoustically reflective oligolamellar liposomes conjugated to tissue-specific ligands such as antibodies, peptides, lectins etc.
- the liposomes are deliberately chosen to be devoid of gas and so will not have the advantageous echogenic properties of gas-based ultrasound contrast agents .
- Further references to this technology e.g. in targeting to fibrin, thrombi and atherosclerotic areas are found in publications by Alkanonyuksel , H. et al . in J “ . Pharm . Sci . (1996) 85(5), 486-490; J “ . Am. Coll . Cardiol . (1996) 27(2) Suppl A,
- the present invention is based on the finding that gas-containing and gas-generating diagnostic and/or therapeutic agents coupled to non-bioactive vectors are particularly useful targeting agents by virtue of their enhanced safety relative to conventional targeting agents, which may elicit undesirable and unwanted biological effects in the subject.
- the reporter may be made by any convenient process, for example by making gas-containing or gas- generating formulations.
- Representative examples include the preparation of a suspension of gas microbubbles by contacting a surfactant with gas and mixing them in the presence of an aqueous carrier, as described in WO
- a suitable process for attachment of the desired vector to the reporter comprises a surface modification of the preformed reporter with a suitable linker employing reactive groups on the surface of both the reporter and vector. It may be particularly advantageous physically to mix the reporter material with the vector- containing substance at any step of the process. Such a process will result in incorporation or an attachment of the vector to the reporter. An optional process step may remove the excess of vector not bound to the reporter by washing the gas-containing particles following separation, by for example, floatation.
- a preferred aspect is the use of lipopeptide structures incorporating functional groups such as thiol, maleimide biotin etc. which can be premixed if desired with other reporter molecules before formation of gas-containing agents .
- the attachment of vector molecules may be carried out using the linker reagents listed below.
- Carbonyl groups such as aldehyde functions may be reacted with weak protein bases at a pH such that nucleophilic protein side-chain functions are protonated.
- Weak bases include 1 , 2-aminothiols such as those found in N-terminal cysteine residues, which selectively form stable 5-membered thiazolidine rings with aldehyde groups, e.g. as described by Ratner, S. et al . in J. Am. Chem . Soc . (1937) 59, 200.
- Other weak bases such as phenyl hydrazones may be used, e.g. as described by Heitzman, H. et al . in Proc . Na tl . Acad . Sci . USA (1974) 71, 3537.
- carboxylic acid modifying reagents include isoxazolium derivatives such as Woodwards reagent K; chloroformates such as p- nitrophenylchloroformate; carbonyldiimidazoles such as 1 , 1 ' -carbonyldiimidazole ; and N- carbalkoxydihydroquinolines such as N- (ethoxycarbonyl) - 2-ethoxy-l, 2-dihydroquinoline .
- isoxazolium derivatives such as Woodwards reagent K
- chloroformates such as p- nitrophenylchloroformate
- carbonyldiimidazoles such as 1 , 1 ' -carbonyldiimidazole
- N- carbalkoxydihydroquinolines such as N- (ethoxycarbonyl) - 2-ethoxy-l, 2-dihydroquinoline .
- the reporter unit will usually remain attached to the vectors.
- the vector (often, a monoclonal antibody) is administered alone; subsequently, the reporter is administered, coupled to a moiety which is capable of specifically binding the vector molecule (when the vector is an antibody, the reporter may be coupled to an immunoglobulin-binding molecule, such as protein A or an anti-immunoglobulin antibody) .
- an immunoglobulin-binding molecule such as protein A or an anti-immunoglobulin antibody
- the therapeutic may be covalently linked to the membrane or matrix surface using a suitable linking agent, e.g. as described herein.
- a suitable linking agent e.g. as described herein.
- one may initially prepare a phospholipid or lipopeptide or derivative thereof to which the drug is bonded through a biodegradable bond or linker, and then incorporate this derivative into the material used to prepare the reporter, as described above.
- the product may initially be prepared without the therapeutic, which may then be coupled to or coated on the microbubbles or microparticles prior to use.
- a therapeutic could be added to a suspension of microbubbles or microparticles in aqueous media and shaken in order to attach or adhere the therapeutic thereto.
- a preferred application of the present invention relates to angiogenesis, which is the formation of new blood vessels by branching from existing vessels.
- the primary stimulus for this process may be inadequate supply of nutrients and oxygen (hypoxia) to cells in a tissue.
- the cells may respond by secreting angiogenetic factors, of which there are many; one example is vascular endothelial growth factor. These factors initiate the secretion of proteolytic enzymes which break down the proteins of the basement membrane, as well as inhibitors which limit the action of these potentially harmful enzymes.
- the combined effect of loss of attachment and signals from the receptors for angiogenetic factors is to cause the endothelial cells to move, multiply, and rearrange themselves, and finally to synthetise a basement membrane around the new vessels .
- Contrast agents according to the present invention are therefore useful in all imaging modalities since contrast elements such as X-ray contrast agents, light imaging probes, spin labels or radioactive units may readily be incorporated in or attached to the reporter units .
- Spacer elements may typically consist of aliphatic chains which effectively separate the reactive moieties of the linker by distances of between 5 and 30 A. They may also comprise macromolecular structures such as poly (ethylene glycols). Such polymeric structures, hereinafter referred to as PEGs, are simple, neutral polyethers which have been given much attention in biotechnical and biomedical applications (see e.g. Milton Harris, J.
- spacer elements may contain cleavable groups such as vicinal glycol, azo, sulfone, ester, thioester or disulphide groups .
- polymers of esters of 2- cyanoacrylic acid - these are biodegradable and have been used in the form of nanoparticles for selective drug delivery (see Forestier, F., Gerrier, P., Chaumard, C, Quero, A.M., Couvreur, P. and Labarre, C. in J " . Antimicrob . Chemoter. (1992) 30, 173-179) ; iv) polyvinyl alcohols, which are water-soluble and generally regarded as biocompatible (see e.g. Langer, R. in J. Control . Release (1991) 16, 53-60); v) copolymers of vinyl methyl ether with maleic anhydride, which have been stated to be bioerodible (see Finne, U.
- Dacron R which are non-degradable but highly biocompatible; ix) block copolymers comprising biodegradable segments of aliphatic hydroxyacid polymers (see e.g. Younes, H., Nataf, P.R., Cohn, D., Appelbaum, Y.J., Pizov, G. and Uretzky, G. in Bioma ter. Artif . Cells Artif . Organs (1988) 16, 705-719) , for instance in conjunction with polyurethanes (see Kobayashi , H., Hyon, S.H. and Ikada, Y. in "Water-curable and biodegradable prepolymers" - J". Biomed . Mater. Res .
- Antibodies which can be used as vectors for a very wide range of targets, and which have advantageous properties such as very high specificity, high affinity (if desired) , the possiblity of modifying affinity according to need etc. Whether or not antibodies will be bioactive will depend on the specific vector/target combination. Both conventional and genetically engineered antibodies may be employed, the latter permitting engineering of antibodies to particular needs, e.g. as regards affinity and specificity. The use of human antibodies may be preferred to avoid possible immune reactions against the vector molecule.
- a further useful class of antibodies comprises so-called bi- and multi-specific antibodies, i.e. antibodies having specificity for two Or more different antigens in one antibody molecule.
- the vectors stated are bioactive it is understood that either: (1) non-bioactive analogs are used; (2) the vectors are used in doses too low to generate a biological response; or (3) the vectors are used in combinations in such a way that the resulting diagnostic and/or therapeutic composition gives no biological response.
- Protein and peptide vectors - cell adhesion molecules etc Protein and peptide vectors - cell adhesion molecules etc .
- Vectors comprising non-peptide agonists/antagonists or non-bioactive binders of receptors for cytokines/growth factors/peptide hormones/cell adhesion molecules
- Biotin may be attached to microbubbles in many different ways, e.g. in a similar way to that described by Corley, P. and Loughrey, H.C. in (1994) Biochim . Biophys . Acta 1195, 149-156.
- the resulting bubbles are analysed by flow cytometry, e.g. by employing fluorescent streptavidin to detect attachment of biotin to the bubbles.
- radioactive or enzyme-labelled streptavidin/avidin is used to analyse biotin attachment .
- Example 5 Gas-filled microbubbles encapsulated with phosphatidylserine and biotinylated oligonucleotide non- covalently bound to streptavidin-Succ-PEG-DSPE
- the peptide FNFRLKAGOKIRFGAAAWEPPRARI comprising phosphatidylserine-binding and heparin-binding sections, is synthesised.
- the peptide is added to preformed phosphatidylserine-encapsulated perfluorobutane microbubbles and thoroughly mixed.
- Example 5(a) To a mixture (5 mg) of phosphatidylserine (90-99.9 mol%) and Succ-PEG 3400 -DSPE (10 - 0.1 mol%, prepared as in Example 5(a)) is added 5% propyleneglycol -glycerol in water (1 ml) . The dispersion is heated to not more than 80 °C for 5 minutes and is then cooled to ambient temperature. The dispersion (0.8 ml) is transferred to a vial (1 ml) and the head space is flushed with perfluorobutane . The vial is shaken in a cap-mixer for 45 seconds, whereafter the sample is put on a roller table. After centrifugation the infranatant is exchanged with water and the washing is repeated. Alternatively the microbubbles may be prepared as described in Preparation 1(f).
- Example 8 Gas-containing microparticles comprising polymer from ethylidene bis (16-hydroxyhexadecanoate) and adipoyl chloride and biotin-amidocaproate-Ala covalently attached to the polymer a) Synthesis of Z-Ala-polymer (3 -0- (carbobenzyloxy-L- alanyl) -polymer)
- the polymer is prepared from ethylidene bis (16- hydroxyhexadecanoate) and adipoyl chloride as described in WO-A- 9607434 , and a polymer fraction with molecular weight 10000 is purified using gel permeation chromatography (GPC) .
- GPC gel permeation chromatography
- 10 g of the material (corresponding to 1 mmol OH groups), Z-alanine (5 mmol) and dimethylaminopyridine (4 mmol) are dissolved in dry dimethylformamide/tetrahydrofuran and dicyclohexylcarbodiimide is then added.
- the reaction mixture is stirred at ambient temperature overnight.
- Dicyclohexylurea is filtered off and the solvent is removed using rotary evaporation.
- the product is purified by chromatography, fractions containing the ti tle compound are combined and the solvent is removed using rotary evaporation.
- the structure of the product is
- Z-Ala-polymer (0.1 mmol) is stirred in toluene/tetrahydrofuran and glacial acetic acid (15% of the total volume) and hydrogenated in the presence of 5 % palladium on charcoal for 2 hours. The reaction mixture is filtered and concentrated in vacuo .
- the agent from Example 7, comprising phosphatidylserine- encapsulated microbubbles having inactivated human thrombin-Succ-PEG 3400 -DSPE incorporated into the encapsulating membrane is lyophilised from 0.01 M phosphate buffer, pH 7.4.
- the product is redispersed in sterile water and injected intravenously into a patient with suspected venous thrombosis in a leg vein.
- the leg is examined by standard ultrasound techniques.
- the thrombus is located by increased contrast as compared with surrounding tissue.
- a cell adhesion study using human endothelial cells grown in culture dishes (Type CRL 1730) was performed with the above-described microbubbles, the uncoated microbubbles being used as a control. Microscopy of the endothelial cells after incubation showed a much increased number of poly-L-lysine-coated microbubbles adhering to endothelial cells in comparison to the uncoated microbubbles .
- the lipopeptide was synthesised on a ABI 433A automatic peptide synthesiser starting with Fmoc-Ile-Wang resin (Novabiochem) on a 0.1 mmol scale using 1 mmol amino acid cartridges. All amino acids and palmitic acid were preactivated using HBTU before coupling.
- DSPS vanti, 4.5 mg
- lipopeptide from a 0.5 mg
- DSPS 0.8 mL
- a solution of 1.4% propylene glycol/2.4% glycerol was added to each vial.
- the mixture was warmed to 80°C for 5 minutes (vials shaken during warming) .
- the samples were cooled to room temperature and the head space flushed with perfluorobutane gas.
- the vials were shaken in a cap mixer for 45 s and the microbubbles rolled overnight.
- Bubbles were washed several times with deionised water and analysed by Coulter counter (Size: 1-3 micron (87 %), 3-5 micron (11.5%)) and acoustic attenuation (frequency max att . : 3.5 MHz) .
- the microbubbles were stable at 120 mm Hg .
- MALDI mass spectral analysis was used to confirm incorporation into DSPS microbubbles as follows; ca . 0.05-0.1 mL of microbubble suspension was transferred to a clean vial and 0.05-0.1 mL methanol added. The suspension was sonicated for 30 s and the solution analysed by MALDI MS. Positive mode gave M+H at 2200, expected for lipopeptide, 2198.
- the human endothelial cell line ECV 304 derived from a normal umbilical cord (ATCC CRL-1998) was cultured in 260 mL Nunc culture flasks (chutney 153732) in RPMI 1640 medium (Bio Whittaker) to which L-Glutamine 200 mM,
- Penicillin/ Streptomycin (10.000 U/mL and 10.000 mcg/mL) and 10% Fetal Bovine Serum (Hyclone Lot no. AFE 5183) were added.
- the cells were subcultured with a split ratio of 1:5 to 1:7 when reaching confluence.
- FITC labelled CD71 anti-transferrin receptor Ab 100 ⁇ g/ mL, Becton Dickinson
- 0.7 mL in PBS was modified with Traut's reagent (0.9 mg, Pierce) at room temperature for 1 h.
- Excess reagent was separated from modified protein on a NAP-5 column (Pharmacia) .
- Fig. 1 of the accompanying drawing represents the flow cytometric comparison of negative control microbubbles of DSPS (left curve) with bubbles conjugated with CD71 FITC- labelled anti-transferrin antibody (filled curve, right), showing that 92% of the population fluoresce. Incorporation into the microbubbles of lipopeptide was confirmed by MALDI mass spectrometry as described in example 12 b) .
- This example is directed to the preparation of microbubbles containing multiple protein vectors for targeted ultrasound/therapy.
- DSPS vanti, 5.0 mg
- thiol containing lipid structure from example 15 a 1.0 mg
- the mixture was warmed to 80°C for 5 minutes (vials shaken during warming) and filtered while still hot through a 40 micron filter.
- the samples were cooled to room temperature and the head space flushed with perfluorobutane gas.
- the vials were shaken in a cap mixer for 45 s and the microbubbles placed on roller table overnight. Bubbles were washed several times with deionised water and analysed for thiol group incorporation using Ellmans
- Example 17 Gas-containing microbubbles of DSPS comprising a lipopeptide for endothelial cell targeting and a captopril containing molecule. This example is directed to the preparation of ultrasound agents for combined targeting and therapeutic applications .
- Example 34 Flotation of endothelial cells by micro bubbles with vectors that specifically bind to the endothelial cells
- Poly-L-lysine HBr (Sigma, 20.6 mg) was dissolved in 2 mL water then an aliquot (0.4 mL) made up to 2 mL water. To 1.2 mL of the diluted poly-L-lysine solution was added 0.12 mL of the DSPS-lipopeptide bubble suspension. Following incubation excess polylysine was removed by extensive washing with water.
Applications Claiming Priority (20)
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GB9622366 | 1996-10-28 | ||
GB9622364 | 1996-10-28 | ||
GBGB9622367.2A GB9622367D0 (en) | 1996-10-28 | 1996-10-28 | Improvements in or relating to diagnostic/therapeutic agents |
GBGB9622364.9A GB9622364D0 (en) | 1996-10-28 | 1996-10-28 | Improvements in or relating to diagnostic/therapeutic agents |
GB9622367 | 1996-10-28 | ||
GBGB9622366.4A GB9622366D0 (en) | 1996-10-28 | 1996-10-28 | Improvements in or relating to diagnostic/therapeutic agents |
GB9700698 | 1997-01-15 | ||
GBGB9700699.3A GB9700699D0 (en) | 1997-01-15 | 1997-01-15 | Improvements in or relating to diagnostic/therapeutic agents |
GBGB9700698.5A GB9700698D0 (en) | 1997-01-15 | 1997-01-15 | Improvements in or relating to diagnostic/therapeutics agents |
GB9700699 | 1997-01-15 | ||
GBGB9708265.5A GB9708265D0 (en) | 1997-04-24 | 1997-04-24 | Contrast agents |
GB9708265 | 1997-04-24 | ||
US4926497P | 1997-06-06 | 1997-06-06 | |
US4926597P | 1997-06-06 | 1997-06-06 | |
US4926797P | 1997-06-06 | 1997-06-06 | |
GB9711842 | 1997-06-06 | ||
GB9711844 | 1997-06-06 | ||
GBGB9711844.2A GB9711844D0 (en) | 1997-06-06 | 1997-06-06 | Improvements in or relating to diagnostic/therapeutic agents |
GBGB9711842.6A GB9711842D0 (en) | 1997-06-06 | 1997-06-06 | Improvements in or relating to diagnostic/therapeutic agents |
PCT/GB1997/002958 WO1998018498A2 (en) | 1996-10-28 | 1997-10-28 | Improvements in or relating to diagnostic/therapeutic agents |
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US6245747B1 (en) | 1996-03-12 | 2001-06-12 | The Board Of Regents Of The University Of Nebraska | Targeted site specific antisense oligodeoxynucleotide delivery method |
WO1998010798A1 (en) * | 1996-09-11 | 1998-03-19 | Imarx Pharmaceutical Corp. | Improved methods for diagnostic imaging using a contrast agent and a vasodilator |
US5846517A (en) * | 1996-09-11 | 1998-12-08 | Imarx Pharmaceutical Corp. | Methods for diagnostic imaging using a renal contrast agent and a vasodilator |
EP1024837A1 (de) * | 1997-10-21 | 2000-08-09 | Nycomed Imaging As | Ultraschall-abbildung mittels zielgerichten kontrastmittel und vasodilatierende wirkstoff |
US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
GB9808599D0 (en) * | 1998-04-22 | 1998-06-24 | Nycomed Imaging As | Improvements in or realting to contrast agents |
US6548048B1 (en) | 1998-04-28 | 2003-04-15 | Amersham Health As | Lipopeptide stabilized microbubbles as diagnostic/therapeutic agents |
GB9809084D0 (en) * | 1998-04-28 | 1998-06-24 | Nycomed Imaging As | Improvements in or relating to diagnostic/therapeutic agents |
AU743695B2 (en) * | 1998-07-13 | 2002-01-31 | Board Of Regents Of The University Of Nebraska, The | Targeted site specific drug delivery compositions and method of use |
EP1210125A2 (de) * | 1999-09-08 | 2002-06-05 | INSTITUT FÜR DIAGNOSTIKFORSCHUNG GmbH AN DER FREIEN UNIVERSITÄT BERLIN | L-selectin-kontrastmittel |
WO2001091805A2 (en) | 2000-06-02 | 2001-12-06 | Bracco Research Usa | Compounds for targeting endothelial cells |
US8263739B2 (en) | 2000-06-02 | 2012-09-11 | Bracco Suisse Sa | Compounds for targeting endothelial cells, compositions containing the same and methods for their use |
US6984373B2 (en) | 2000-12-23 | 2006-01-10 | Dyax Corp. | Fibrin binding moieties useful as imaging agents |
US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
US8623822B2 (en) | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
EP1587944A4 (de) | 2002-03-01 | 2007-03-21 | Dyax Corp | Kdr und vegf/kdr-bindende peptide und ihre diagnostische und therapeutische veranwendung bei der diagnose und therapie |
US7794693B2 (en) | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
AU2003213730A1 (en) | 2002-03-01 | 2003-09-16 | Bracco International B.V. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
US7226577B2 (en) | 2003-01-13 | 2007-06-05 | Bracco Imaging, S. P. A. | Gastrin releasing peptide compounds |
DK2949658T3 (en) | 2003-03-03 | 2018-10-01 | Dyax Corp | Peptides that specifically bind HGF receptor (cMet) and uses thereof |
US7785566B2 (en) | 2003-11-06 | 2010-08-31 | Ge Healthcare, Inc. | Pharmaceutical compounds |
ES2428964T3 (es) | 2005-12-09 | 2013-11-12 | Bracco Suisse Sa | Conjugados de vectores específicos de una diana-fosfolípidos |
EP2147684A1 (de) | 2008-07-22 | 2010-01-27 | Bracco Imaging S.p.A | Selektiv gegen Metallproteasen wirkende Diagnosemittel |
WO2015038968A1 (en) | 2013-09-13 | 2015-03-19 | The General Hospital Corporation | Activatable fibrin-binding probes |
CN107206111B (zh) | 2014-12-31 | 2021-04-27 | 蓝瑟斯医学影像公司 | 脂质封装的气体微球组合物及相关方法 |
EP3452108A4 (de) | 2016-05-04 | 2019-12-25 | Lantheus Medical Imaging, Inc. | Verfahren und vorrichtungen zur herstellung von ultraschallkontrastmitteln |
US9789210B1 (en) | 2016-07-06 | 2017-10-17 | Lantheus Medical Imaging, Inc. | Methods for making ultrasound contrast agents |
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US5733572A (en) * | 1989-12-22 | 1998-03-31 | Imarx Pharmaceutical Corp. | Gas and gaseous precursor filled microspheres as topical and subcutaneous delivery vehicles |
US5580575A (en) * | 1989-12-22 | 1996-12-03 | Imarx Pharmaceutical Corp. | Therapeutic drug delivery systems |
DE4232755A1 (de) * | 1992-09-26 | 1994-03-31 | Schering Ag | Mikropartikelpräparationen aus biologisch abbaubaren Mischpolymeren |
US5565215A (en) * | 1993-07-23 | 1996-10-15 | Massachusettes Institute Of Technology | Biodegradable injectable particles for imaging |
EP0712421A1 (de) * | 1993-07-23 | 1996-05-22 | Massachusetts Institute Of Technology | Nanopartikel und mikropartikel aus nichtlinearen hydrophilen-hydrophoben multiblockcopolymeren |
US5534241A (en) * | 1993-07-23 | 1996-07-09 | Torchilin; Vladimir P. | Amphipathic polychelating compounds and methods of use |
PT717617E (pt) * | 1993-09-09 | 2001-04-30 | Schering Ag | Microparticulas com gas e pprincipios activos |
EP0727225A3 (de) * | 1995-02-14 | 1997-01-15 | Sonus Pharma Inc | Zusammensetzungen und Verfahren zur Herstellung von gerichteter Ultraschallabbildung |
WO1996040277A2 (en) * | 1995-06-07 | 1996-12-19 | Brown University Research Foundation | Spray dried polymeric microparticles containing imaging agents |
US5780010A (en) * | 1995-06-08 | 1998-07-14 | Barnes-Jewish Hospital | Method of MRI using avidin-biotin conjugated emulsions as a site specific binding system |
US5849727A (en) * | 1996-06-28 | 1998-12-15 | Board Of Regents Of The University Of Nebraska | Compositions and methods for altering the biodistribution of biological agents |
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