~(131)I-Evans blue: evaluation of necrosis targeting property and preliminary assessment of the mechanism in animal models
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摘要
Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents(NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of ~(131)I-evans blue( ~(131)I-EB) and its mechanism. The biodistribution of ~(131)I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of ~(131)I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after ~(131)I-EB incubation. The DNA binding study demonstrated that evans blue(EB) has strong binding affinity with calf-thymus DNA(CT-DNA)(K_(sv)= 5.08×10~5 L/(mol/L)). Furthermore,the accumulation of ~(131)I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB.In conclusion, ~(131)I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.
Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents(NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of ~(131)I-evans blue( ~(131)I-EB) and its mechanism. The biodistribution of ~(131)I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of ~(131)I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after ~(131)I-EB incubation. The DNA binding study demonstrated that evans blue(EB) has strong binding affinity with calf-thymus DNA(CT-DNA)(K_(sv)= 5.08×10~5 L/(mol/L)). Furthermore,the accumulation of ~(131)I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB.In conclusion, ~(131)I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.
Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents(NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of ~(131)I-evans blue( ~(131)I-EB) and its mechanism. The biodistribution of ~(131)I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of ~(131)I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after ~(131)I-EB incubation. The DNA binding study demonstrated that evans blue(EB) has strong binding affinity with calf-thymus DNA(CT-DNA)(K_(sv)= 5.08×10~5 L/(mol/L)). Furthermore,the accumulation of ~(131)I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB.In conclusion, ~(131)I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.
引文
1.Smith BA,Smith BD.Biomarkers and molecular probes for cell death imaging and targeted therapeutics.Bioconjugate Chem 2012;23:1989-2006.
2.De Saint-Hubert M,Prinsen K,Mortelmans L,Verbruggen A,Mottaghy FM.Molecular imaging of cell death.Methods 2009;48:178-87.
3.Edinger AL,Thompson CB.Death by design:apoptosis,necrosis and autophagy.Curr Opin Cell Biol 2004;16:663-9.
4.Eguchi A,Wree A,Feldstein AE.Biomarkers of liver cell death.JHepatol 2014;60:1063-74.
5.Dean E,Greystoke A,Ranson M,Dive C.Biomarkers of cell death applicable to early clinical trials.Exp Cell Res 2012;318:1252-9.
6.Ni YC,Huyghe D,Verbeke K,De Witte PA,Nuyts J,Mortelmans Let al.First preclinical evaluation of mono-[123I]iodohypericin as a necrosis-avid tracer agent.Eur J Nucl Med Mol Imag 2006;33:595-601.
7.Marvsael T,Putte MV,Fonge H,Cona MM,Li JJ,Bormans G,et al Radiolabeled iodohypericin as tumor necrosis avid tracer:diagnostic and therapeutic potential.Int J Cancer 2012;131:129-37.
8.Ni YC,Bormans G,Chen F,Verbruggen A,Marchal G.Necrosis avid contrast agents:functional similarity versus structural diversity Investig Radiol 2005;40:526-35.
9.Fonge H,Chitneni SK,Jin LX,Vunckx K,Prinsen K,Nuyts J,et al Necrosis avidity of99mTc(CO)3-labeled pamoic acid derivatives synthesis and preliminary biological evaluation in animal models of necrosis.Bioconjugate Chem 2007;18:1924-34.
10.Wang H,Sun X,Chen F,De Keyzer F,Yu J,Landuyt W,et al Treatment of rodent liver tumor with combretastatin A4 phosphate noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology.Investig Radiol 2009;44:44-53.
11.Delmonte A,Sessa C.AVE8062:a new combretastatin derivative vascular disrupting agent.Exp Opin Investig Drug 2009;18:1541-8.
12.Li JJ,Sun ZP,Zhang J,Shao HB,Cona MM,Wang HJ,et al.A dualtargeting anticancer approach:soil and seed principle.Radiology2011;260:799-807.
13.Shao HB,Ni YC,Dai X,Zhang J,Chen F,Fan GG,et al.Diffusionweighted MR imaging allows monitoring the effect of combretastatin A4 phosphate on rabbit implanted VX2 tumor model:12-day dynamic results.Eur J Radiol 2011;81:578-83.
14.Jeong AK,Sang IC,Dong HK,Park SB,Lee SS,Choi SN,et al.Evaluation by contrast-enhanced MR imaging of the lateral border zone in reperfused myocardial infarction in a cat model.Korean JRadiol 2000;2:21-7.
15.Lund GK,Higgins CB,Wendland MF,Watzinger N,Weinmann HJ,Saeed M.Assessment of nicorandil therapy in ischemic myocardial injury by using contrast-enhanced and functional MR imaging.Radiology 2001;221:676-82.
16.Ni YC,Cresens E,Adriaens P,Miao Y,Verbeke K,Dymarkowski S,et al.Necrosis-avid contrast agents:introducing nonporphyrin species.Acad Radiol 2002;9:98-101.
17.Van DPM,Roskams T,Bormans G,Verbruggen A,De Witte PA.The impact of aggregation on the biodistribution of hypericin.Int J Oncol2006;28:655-60.
18.Cooksey C.Quirks of dye nomenclature.1.Evans blue.Biotech Histochem 2014;89:111-3.
19.Oskar SW,Igor K.Selective vulnerability of the blood-brain barrier in chemically induced lesions.J Neuropathol Exp Neurol 1996;25:542-59.
20.Young TE,Gallie DR,Demason DA.Ethylene-mediated programmed cell death during maize endosperm development of wild-type and shrunken2 genotypes.Plant Physiol 1997;115:737-51.
21.Atkinson MM,Keppler LD,Orlandi EW,Baker JC,Mischiefs CF.Involvement of plasma membrane calcium influx in bacterial induction of the Kt/Htand hypersensitive responses in tobacco.Plant Physiol1990;92:215-21.
22.Baker CJ,Mock NM.An improved method for monitoring cell death in cell suspension and leaf disc assays using evans blue.Plant Cell Tissue Org Cult 1994;39:7-12.
23.Leist M,Nicotera P.28-Cell death:apoptosis versus necrosis.In:KMA Welch,Caplan LR,Reis DJ,Bo KS,Weir B,editors.Primer on Cerebrovascular Disease.2rd ed.Philadelphia:Academic Press;1997.p.101-4.
24.Farquhar WB,Hunt BE,Taylor JA,Darling SE,Freeman R.Blood volume and its relation to peak O2consumption and physical activity in patients with chronic fatigue.Am J Physiol Heart Circ Physiol2002;282:66-71.
25.Scoon GS,Hopkins WG,Mayhew S,Cotter JD.Effect of post-exercise sauna bathing on the endurance performance of competitive male runners.J Sci Med Sport 2007;10:259-62.
26.Dasari M,Lee S,Sy J,Kim D,Lee S,Brown M,et al.Hoechst-IR:an imaging agent that detects necrotic tissue in vivo by binding extracellular DNA.Org Lett 2010;12:3300-3.
27.Ragazzon PA,Iley J,Missailidis S.Structure-activity studies of the binding of the flavonoid scaffold to DNA.Anticancer Res2009;29:2285-93.
28.Cona MM,Koole M,Feng YB,Liu Y,Verbruggen A,Oyen R,et al.Biodistribution and radiation dosimetry of radioiodinated hypericin as a cancer therapeutic.Int J Oncol 2014;44:819-29.
29.Flotats A,CarrióI.Non-invasive in vivo imaging of myocardial apoptosis and necrosis.Eur J Nucl Med Mol Imaging2003;30:615-30.
30.Reichmann ME,Rice SA,Thomas CA,Doty P.A further examination of the molecular weight and size of desoxypentose nucleic acid.J Am Chem Soc 1954;76:3047-53.
31.Lepecq JB,Paoletti C.A fluorescent complex between ethidium bromide and nucleic acids physical-chemical characterization.J Mol Biol 1967;27:87-106.
32.Kressel M,Groscurth P.Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA.Cell Tissue Res 1994;278:549-56.
33.Bischoff G,Hoffmann S.DNA-binding of drugs used in medicina therapies.Curr Med Chem 2002;9:312-48.
34.Strekowski L,Wilson B.Noncovalent interactions with DNA:an overview.Mutat Res 2007;623:3-13.
35.Yang HX,Song W,Jing MY,Liu R.Study on the interaction mechanism of 2-aminoanthraquinone with calf thymus DNA.JBiochem Mol Toxicol 2013;27:272-8.
36.Valle JD,Camins A,Pallàs M,Vilaplana J,Pelegríc C.A new method for determining blood-brain barrier integrity based on intracardiac perfusion of an evans blue-hoechst cocktail.J Neurosci Methods2008;174:42-9.
37.Apalkov V,Berashevich J,Chakraborty T.Unique magnetic signatures of mismatched base pairs in DNA.J Chem Phys 2010;132:085102.
38.Huang M,Shen AJ,Ding J,Geng MY.Molecularly targeted cancer therapy:some lessons from the past decade.Trends Pharmacol Sc2014;35:41-50.
39.Li JJ,Chen F,Cona MM,Feng YB,Himmelreich U,Oyen R,et al.Areview on various targeted anticancer therapies.Target Onco2012;7:69-85.
40.Wang JH,Jiang CH,Jiang X,Li Y,Zhang J,Sun ZP,et al.The research on biodistribution of~131I-iodosennoside a in normal mice and to evaluate myocardial activity.J Isot 2013;26:98-103.
41.Gibson JG,Evans WA.Clinical studies of the blood volume.I.Clinical application of a method employing the azo dye"evans blue"and the spectrophotometer.J Clin Investig 1937;16:301-16.
42.Linderkamp O,Mader T,Butenandt O,Riegel KP.Plasma volume estimation in severely ill infants and children using a simplified evans blue method.Eur J Pediatr 1977;125:135-41.
43.Kulkarni S,Bogart A,Buxbaum J,Matsuoka L.Surgical transgastric debridement of walled off pancreatic necrosis:an option for patients with necrotizing pancreatitis.Surg Endosc 2015;29:575-82.
44.Bohuslavizki KH,Klutmann S,Brenner W,Mester J,Henze E,Clausen M.Salivary gland protection by amifostine in high-dose radioiodine treatment:results of a double-blind placebo-controlled study.J Clin Oncol 1998;16:3542-9.
45.Frid P,Anisimov SV,Popovic N.Congo red and protein aggregation in neurodegenerative diseases.Brain Res Rev 2007;53:135-60.
46.Liu XJ,Jiang CH,Yue L,Liu W,Yao N,Gao M,et al.Evaluation of hypericin:effect of aggregation on targeting biodistribution.J Pharm Sci 2015;104:215-22.
2.De Saint-Hubert M,Prinsen K,Mortelmans L,Verbruggen A,Mottaghy FM.Molecular imaging of cell death.Methods 2009;48:178-87.
3.Edinger AL,Thompson CB.Death by design:apoptosis,necrosis and autophagy.Curr Opin Cell Biol 2004;16:663-9.
4.Eguchi A,Wree A,Feldstein AE.Biomarkers of liver cell death.JHepatol 2014;60:1063-74.
5.Dean E,Greystoke A,Ranson M,Dive C.Biomarkers of cell death applicable to early clinical trials.Exp Cell Res 2012;318:1252-9.
6.Ni YC,Huyghe D,Verbeke K,De Witte PA,Nuyts J,Mortelmans Let al.First preclinical evaluation of mono-[123I]iodohypericin as a necrosis-avid tracer agent.Eur J Nucl Med Mol Imag 2006;33:595-601.
7.Marvsael T,Putte MV,Fonge H,Cona MM,Li JJ,Bormans G,et al Radiolabeled iodohypericin as tumor necrosis avid tracer:diagnostic and therapeutic potential.Int J Cancer 2012;131:129-37.
8.Ni YC,Bormans G,Chen F,Verbruggen A,Marchal G.Necrosis avid contrast agents:functional similarity versus structural diversity Investig Radiol 2005;40:526-35.
9.Fonge H,Chitneni SK,Jin LX,Vunckx K,Prinsen K,Nuyts J,et al Necrosis avidity of99mTc(CO)3-labeled pamoic acid derivatives synthesis and preliminary biological evaluation in animal models of necrosis.Bioconjugate Chem 2007;18:1924-34.
10.Wang H,Sun X,Chen F,De Keyzer F,Yu J,Landuyt W,et al Treatment of rodent liver tumor with combretastatin A4 phosphate noninvasive therapeutic evaluation using multiparametric magnetic resonance imaging in correlation with microangiography and histology.Investig Radiol 2009;44:44-53.
11.Delmonte A,Sessa C.AVE8062:a new combretastatin derivative vascular disrupting agent.Exp Opin Investig Drug 2009;18:1541-8.
12.Li JJ,Sun ZP,Zhang J,Shao HB,Cona MM,Wang HJ,et al.A dualtargeting anticancer approach:soil and seed principle.Radiology2011;260:799-807.
13.Shao HB,Ni YC,Dai X,Zhang J,Chen F,Fan GG,et al.Diffusionweighted MR imaging allows monitoring the effect of combretastatin A4 phosphate on rabbit implanted VX2 tumor model:12-day dynamic results.Eur J Radiol 2011;81:578-83.
14.Jeong AK,Sang IC,Dong HK,Park SB,Lee SS,Choi SN,et al.Evaluation by contrast-enhanced MR imaging of the lateral border zone in reperfused myocardial infarction in a cat model.Korean JRadiol 2000;2:21-7.
15.Lund GK,Higgins CB,Wendland MF,Watzinger N,Weinmann HJ,Saeed M.Assessment of nicorandil therapy in ischemic myocardial injury by using contrast-enhanced and functional MR imaging.Radiology 2001;221:676-82.
16.Ni YC,Cresens E,Adriaens P,Miao Y,Verbeke K,Dymarkowski S,et al.Necrosis-avid contrast agents:introducing nonporphyrin species.Acad Radiol 2002;9:98-101.
17.Van DPM,Roskams T,Bormans G,Verbruggen A,De Witte PA.The impact of aggregation on the biodistribution of hypericin.Int J Oncol2006;28:655-60.
18.Cooksey C.Quirks of dye nomenclature.1.Evans blue.Biotech Histochem 2014;89:111-3.
19.Oskar SW,Igor K.Selective vulnerability of the blood-brain barrier in chemically induced lesions.J Neuropathol Exp Neurol 1996;25:542-59.
20.Young TE,Gallie DR,Demason DA.Ethylene-mediated programmed cell death during maize endosperm development of wild-type and shrunken2 genotypes.Plant Physiol 1997;115:737-51.
21.Atkinson MM,Keppler LD,Orlandi EW,Baker JC,Mischiefs CF.Involvement of plasma membrane calcium influx in bacterial induction of the Kt/Htand hypersensitive responses in tobacco.Plant Physiol1990;92:215-21.
22.Baker CJ,Mock NM.An improved method for monitoring cell death in cell suspension and leaf disc assays using evans blue.Plant Cell Tissue Org Cult 1994;39:7-12.
23.Leist M,Nicotera P.28-Cell death:apoptosis versus necrosis.In:KMA Welch,Caplan LR,Reis DJ,Bo KS,Weir B,editors.Primer on Cerebrovascular Disease.2rd ed.Philadelphia:Academic Press;1997.p.101-4.
24.Farquhar WB,Hunt BE,Taylor JA,Darling SE,Freeman R.Blood volume and its relation to peak O2consumption and physical activity in patients with chronic fatigue.Am J Physiol Heart Circ Physiol2002;282:66-71.
25.Scoon GS,Hopkins WG,Mayhew S,Cotter JD.Effect of post-exercise sauna bathing on the endurance performance of competitive male runners.J Sci Med Sport 2007;10:259-62.
26.Dasari M,Lee S,Sy J,Kim D,Lee S,Brown M,et al.Hoechst-IR:an imaging agent that detects necrotic tissue in vivo by binding extracellular DNA.Org Lett 2010;12:3300-3.
27.Ragazzon PA,Iley J,Missailidis S.Structure-activity studies of the binding of the flavonoid scaffold to DNA.Anticancer Res2009;29:2285-93.
28.Cona MM,Koole M,Feng YB,Liu Y,Verbruggen A,Oyen R,et al.Biodistribution and radiation dosimetry of radioiodinated hypericin as a cancer therapeutic.Int J Oncol 2014;44:819-29.
29.Flotats A,CarrióI.Non-invasive in vivo imaging of myocardial apoptosis and necrosis.Eur J Nucl Med Mol Imaging2003;30:615-30.
30.Reichmann ME,Rice SA,Thomas CA,Doty P.A further examination of the molecular weight and size of desoxypentose nucleic acid.J Am Chem Soc 1954;76:3047-53.
31.Lepecq JB,Paoletti C.A fluorescent complex between ethidium bromide and nucleic acids physical-chemical characterization.J Mol Biol 1967;27:87-106.
32.Kressel M,Groscurth P.Distinction of apoptotic and necrotic cell death by in situ labelling of fragmented DNA.Cell Tissue Res 1994;278:549-56.
33.Bischoff G,Hoffmann S.DNA-binding of drugs used in medicina therapies.Curr Med Chem 2002;9:312-48.
34.Strekowski L,Wilson B.Noncovalent interactions with DNA:an overview.Mutat Res 2007;623:3-13.
35.Yang HX,Song W,Jing MY,Liu R.Study on the interaction mechanism of 2-aminoanthraquinone with calf thymus DNA.JBiochem Mol Toxicol 2013;27:272-8.
36.Valle JD,Camins A,Pallàs M,Vilaplana J,Pelegríc C.A new method for determining blood-brain barrier integrity based on intracardiac perfusion of an evans blue-hoechst cocktail.J Neurosci Methods2008;174:42-9.
37.Apalkov V,Berashevich J,Chakraborty T.Unique magnetic signatures of mismatched base pairs in DNA.J Chem Phys 2010;132:085102.
38.Huang M,Shen AJ,Ding J,Geng MY.Molecularly targeted cancer therapy:some lessons from the past decade.Trends Pharmacol Sc2014;35:41-50.
39.Li JJ,Chen F,Cona MM,Feng YB,Himmelreich U,Oyen R,et al.Areview on various targeted anticancer therapies.Target Onco2012;7:69-85.
40.Wang JH,Jiang CH,Jiang X,Li Y,Zhang J,Sun ZP,et al.The research on biodistribution of~131I-iodosennoside a in normal mice and to evaluate myocardial activity.J Isot 2013;26:98-103.
41.Gibson JG,Evans WA.Clinical studies of the blood volume.I.Clinical application of a method employing the azo dye"evans blue"and the spectrophotometer.J Clin Investig 1937;16:301-16.
42.Linderkamp O,Mader T,Butenandt O,Riegel KP.Plasma volume estimation in severely ill infants and children using a simplified evans blue method.Eur J Pediatr 1977;125:135-41.
43.Kulkarni S,Bogart A,Buxbaum J,Matsuoka L.Surgical transgastric debridement of walled off pancreatic necrosis:an option for patients with necrotizing pancreatitis.Surg Endosc 2015;29:575-82.
44.Bohuslavizki KH,Klutmann S,Brenner W,Mester J,Henze E,Clausen M.Salivary gland protection by amifostine in high-dose radioiodine treatment:results of a double-blind placebo-controlled study.J Clin Oncol 1998;16:3542-9.
45.Frid P,Anisimov SV,Popovic N.Congo red and protein aggregation in neurodegenerative diseases.Brain Res Rev 2007;53:135-60.
46.Liu XJ,Jiang CH,Yue L,Liu W,Yao N,Gao M,et al.Evaluation of hypericin:effect of aggregation on targeting biodistribution.J Pharm Sci 2015;104:215-22.