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1.
Preclinical studies of monoclonal antibodies for intravesical radioimmunotherapy of human bladder cancer 总被引:2,自引:0,他引:2
Russell Pamela J. Davis Karyn Kingsley Elizabeth Humphreys Julie Hanley Janelle O'Grady Helen Pearce Nicholas 《Cell biochemistry and biophysics》1994,24(1-3):155-161
Eighty percent of bladder cancers present as superficial disease. Many are multifocal, and apparently successful treatment
is frequently followed by recurrence. The use of monoclonal antibodies (MAbs) to target radiotherapy to these tumors offers
great potential, especially since they can be administered directly into the bladder (intravesically) bypassing many of the
side effects encountered to date with systemic MAb-based therapy. Implantation of human bladder cancer cell lines in the bladder
wall of nude rats results in tumor formation, providing an excellent model to test this. Tumor size can be monitored by X-ray
analysis after administration of urograffin. Comparative studies of two murine MAbs, BLCA-8, IgG3, and C1-137, IgG1, against
malignant human bladder cancer cells have been performed. Radio-immunoconjugates produced with125Iodine (125I) have been used for biodistribution studies following administration directly into rat bladder. Radioiodinated intact MAbs
or Fabs administered intravesically into nontumor bearing rats did not leak into the systemic circulation and were stable
in urine for up to 100 h. Biodistribution studies carried out following intravesical administration of radio-immunoconjugates
to tumor-bearing nude rats indicate better tumor uptake of C1-137 than BLCA-8. Further studies to test two-step intravesical
administration of biotinylated MAb followed by radioiodinated streptavidin are in progress. Our studies indicate that the
C1-137 MAb may have considerable potential for intravesical radioimmunotherapy of patients with superficial bladder tumors. 相似文献
2.
Zhengyuan Zhou Satish K Chitneni Nick Devoogdt Michael R. Zalutsky Ganesan Vaidyanathan 《Bioorganic & medicinal chemistry》2018,26(8):1939-1949
In a previous study, we evaluated a HER2-specific single domain antibody fragment (sdAb) 2Rs15d labeled with 18F via conjugation of a residualizing prosthetic agent that was synthesized by copper-catalyzed azide-alkyne cycloaddition (CuAAC). In order to potentially increase overall efficiency and decrease the time required for labeling, we now investigate the use of a strain-promoted azide-alkyne cycloaddition (SPAAC) between the 2Rs15d sdAb, which had been pre-derivatized with an azide-containing residualizing moiety, and an 18F-labeled aza-dibenzocyclooctyne derivative. The HER2-targeted sdAb 2Rs15d and a nonspecific sdAb R3B23 were pre-conjugated with a moiety containing both azide- and guanidine functionalities. The thus derivatized sdAbs were radiolabeled with 18F using an 18F-labeled aza-dibenzocyclooctyne derivative ([18F]F-ADIBO) via SPAAC, generating the desired conjugate ([18F]RL-II-sdAb). For comparison, unmodified 2Rs15d was labeled with N-succinimidyl 4-guanidinomethyl-3-[125I]iodobenzoate ([125I]SGMIB), the prototypical residualizing agent for radioiodination. Radiochemical purity (RCP), immunoreactive fraction (IRF), HER2-binding affinity and cellular uptake of [18F]RL-II-2Rs15d were assessed in vitro. Paired label biodistribution of [18F]RL-II-2Rs15d and [125I]SGMIB-2Rs15d, and microPET/CT imaging of [18F]RL-II-2Rs15d and the [18F]RL-II-R3B23 control sdAb were performed in nude mice bearing HER2-expressing SKOV-3 xenografts. A radiochemical yield of 23.9?±?6.9% (n?=?8) was achieved for the SPAAC reaction between [18F]F-ADIBO and azide-modified 2Rs15d and the RCP of the labeled sdAb was >95%. The affinity (Kd) and IRF for the binding of [18F]RL-II-2Rs15d to HER2 were 5.6?±?1.3?nM and 73.1?±?22.5% (n?=?3), respectively. The specific uptake of [18F]RL-II-2Rs15d by HER2-expressing BT474M1 breast carcinoma cells in vitro was 14–17% of the input dose at 1, 2, and 4?h, slightly higher than seen for co-incubated [125I]SGMIB-2Rs15d. The uptake of [18F]RL-II-2Rs15d in SKOV-3 xenografts at 1?h and 2?h p.i. were 5.54?±?0.77% ID/g and 6.42?±?1.70% ID/g, respectively, slightly higher than those for co-administered [125I]SGMIB-2Rs15d (4.80?±?0.78% ID/g and 4.78?±?1.39% ID/g). MicroPET/CT imaging with [18F]RL-II-2Rs15d at 1–3?h p.i. clearly delineated SKOV-3 tumors while no significant accumulation of activity in tumor was seen for [18F]RL-II-R3B23. With the exception of kidneys, normal tissue levels for [18F]RL-II-2Rs15d were low and cleared rapidly. To our knowledge, this is the first time SPAAC method has been used to label an sdAb with 18F, especially with residualizing functionality. 相似文献
3.
T Yokota T Yamaguchi K Kitamura E Otsuji K Sawai T Takahashi 《The journal of histochemistry and cytochemistry》1990,38(4):585-588
We examined the tissue localization of biotin-labeled murine monoclonal antibody (MAb) S202 directed against the human scirrhous gastric carcinoma cell line MK-01 in normal and tumor-bearing mice after intravenous (IV) administration. The biotin-labeled MAb proved to be stable in vivo under normal conditions, antibody titer being 1:256 at 4 hr after IV injection. At 24 hr after injection, the tumor was stained by the avidin-biotin-peroxidase complex (ABC) method. Biotin-labeled MAb was found to be suitable for detection of the xenografted tumor of nude mice. This study provides new information concerning the dynamics of the distribution of biotin-labeled MAb in vivo. 相似文献
4.
Izumi Uno Takashi Kozaka Daisuke Miwa Yoji Kitamura Mohammad Anwar-ul Azim Kazuma Ogawa Junichi Taki Seigo Kinuya Kazuhiro Shiba 《PloS one》2016,11(1)
Purpose
To develop a superior VAChT imaging probe for SPECT, radiolabeled (-)-OIDV and (+)-OIDV were isolated and investigated for differences in their binding affinity and selectivity to VAChT, as well as their in vivo activities.Procedures
Radioiodinated o-iodo-trans-decalinvesamicol ([125I]OIDV) has a high binding affinity for vesicular acetylcholine transporter (VAChT) both in vitro and in vivo. Racemic [125I]OIDV was separated into its two optical isomers (-)-[125I]OIDV and (+)-[125I]OIDV by HPLC. To investigate VAChT binding affinity (Ki) of two OIDV isomers, in vitro binding assays were performed. In vivo biodistribution study of each [125I]OIDV isomer in blood, brain regions and major organs of rats was performed at 2,30 and 60 min post-injection. In vivo blocking study were performed to reveal the binding selectivity of two [125I]OIDV isomers to VAChT in vivo. Ex vivo autoradiography were performed to reveal the regional brain distribution of two [125I]OIDV isomers and (-)-[123I]OIDV for SPECT at 60 min postinjection.Results
VAChT binding affinity (Ki) of (-)-[125I]OIDV and (+)-[125I]OIDV was 22.1 nM and 79.0 nM, respectively. At 2 min post-injection, accumulation of (-)-[125I]OIDV was the same as that of (+)-[125I]OIDV. However, (+)-[125I]OIDV clearance from the brain was faster than (-)-[125I]OIDV. At 30 min post-injection, accumulation of (-)-[125I]OIDV (0.62 ± 0.10%ID/g) was higher than (+)-[125I]OIDV (0.46 ± 0.07%ID/g) in the cortex. Inhibition of OIDV binding showed that (-)-[125I]OIDV was selectively accumulated in regions known to express VAChT in the rat brain, and ex vivo autoradiography further confirmed these results showing similar accumulation of (-)-[125I]OIDV in these regions. Furthermore, (-)-[123I]OIDV for SPECT showed the same regional brain distribution as (-)-[125I]OIDV.Conclusion
These results suggest that radioiodinated (-)-OIDV may be a potentially useful tool for studying presynaptic cholinergic neurons in the brain. 相似文献5.
Michail I. Dushkin Alfija F. Safina Evgenij I. Vereschagin Yakov Sh. Schwartz 《Cell biochemistry and function》1996,14(3):209-217
In atherosclerotic lesions, macrophages are transformed into foam cells accumulating modified low density lipoproteins (LDL) via the scavenger receptor pathway. We have investigated the effects of carboxymethylated beta-1,3-glucan (CMG) on acetylated LDL (AcLDL) metabolism in murine peritoneal macrophages in vitro and upon the clearance of AcLDL by rat liver in vivo. In cultured murine peritoneal macrophages, CMG reduced substantially the AcLDL-induced synthesis of cholesteryl esters, decreased the binding and degradation of [125I]-AcLDL in a dose-dependent manner with complete inhibition at 20–30 nM , but had no effect on the binding and degradation of native [125I]–LDL. In contrast, other polysaccharides studied, namely zymosan, lipopolysaccharide, non-modified glucan and mannan Rhodexman, had a slight effect at concentrations significantly exceeding the concentrations of CMG. [125I]-AcLDL injected intravenously into rats was cleared from the blood with a half-life of 3.7 min. About 56 per cent of the label of injected [125I]-AcLDL was recovered in the liver 15 min after administration. Co-injection of the labelled AcLDL with CMG (25 mg kg?1 b.w.) decreased the rate of AcLDL clearance so that the half-life increased to 6.0 min. Injections of CMG (25 mg kg?1 b.w.) 48 and 24 h before the determination increased the rate of [125I]-AcLDL clearance (with a half-life of about 2.3 min) and increased the uptake of AcLDL by the liver. We suggest that CMG competed with AcLDL for scavenger receptors in vitro and in vivo and repeated CMG injections before the measurements of AcLDL resulted in the induction of scavenger receptor function. 相似文献
6.
Hisashi Miyazaki Toshihiko Fujii Hideki Amejima Naoko Mikuriya Keiko Nambu Akira Kagemoto Masashi Nakao Yoshinori Oh-e Katashi Matsumoto Yukiharu Matsui Katsuji Nakano Yasunobu Sohmura Noriyuki Sunahara Shigeru Kurooka Masahisa Hashimoto 《Biotherapy》1989,1(1-2):7-18
Disposition of [125I]rHu-TNF was elucidated in BALB/c mice bearing Meth A fibrosarcoma 7 days after transplantation. Afteri.v. administration, [125I]rHu-TNF measured by radioactivity and immunoreactivity biphasically decreased in plasma. Tumor level of [125I]rHu-TNF was the maximum at 1 h, then decreased and finally remained essentially constant. After i.t. administration, plasma level reached the maximum at 1 h. Tumor level decreased quickly and then became essentially constant. [125I]rHu-TNF was suggested to be degraded to small fragments in the tumor. Significant distribution of [125I]rHu-TNF was found in the kidney, lung, liver and tumor. Most tissue levels decreased with time in parallel with plasma levels. [125I]rHu-TNF radioactivity was found in proximal convoluted tubules of kidney and in those areas of tumor consisting of degenerating cells with pyknotic nuclei. Urine contained most of administered radioactivity, which being neither immunoreactive nor protein-bound. 相似文献
7.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1990,17(2):239-245
A series of three 125I-labeled 17α-iodovinylestradiol derivatives previously demonstrated to have a selectivity for estrogen receptor tissues in immature female rats were selected for further evaluation in adult female rats. In normal adult female rats, the iodovinyl analogs of moxestrol (IVβME2) and moxestrol-3-O methyl ether (IVβME2-3-OMe) demonstrated high uterine uptake (0.296–0.437 and 0.135–0.199%ID-kg/g) and selectivity (10–18:1) over the 6 h time period. Subsequent evaluation in two tumor models indicated that [125I]VβME2 also possessed the highest tumor uptake and selectivity in the adult female rats bearing the estrogen responsive 9,10-dimethyl-1,2-benzanthracene(DMBA)-induced mammary tumors and that this was receptor mediated. An estrogen independent tumor, the transplanted Walker 256 mammary adenocarcinoma, showed no selectivity of radioligand uptake compared with nontarget tissues. The results suggest the applicability of this agent to the in vivo detection and characterization of estrogen responsive tumors in man. 相似文献
8.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1991,18(2):191-195
Newly synthesized 17-[18F]fluoro-3-methylheptadecanoic acid ([18F]BMHDA), 16-[18F]fluoropalmitic acid ([18F]PA) and 15-(p-[125I]iodophenyl)-3-R,S-methylpentadecanoic acid ([125I]BMIPP), fatty acid tracers, were examined for the possibility of tumor imaging using 10 tumor models in rats and mice. The highest tumor/muscle ratios with [18F]BMHDA were 2.3 using rat tumor AH109A and 1.9 using mouse tumor B16F1 (tumor accumulation 0.41 ± 0.05, 4.29 ± 0.77% ID/g, respectively). Tumor/muscle ratios with [125I]BMIPP and [18F]PA were lower than those with [18F]BMHDA. Labeled fatty acids seem to have a lower potential for tumor detection. 相似文献
9.
Thomas W. R?sler Andreas Matusch Damiano Librizzi Oscar Arias-Carrión Nils Freundlieb Helmut Hoeffken Wolfgang H. Oertel Candan Depboylu Günter U. H?glinger 《PloS one》2014,9(7)
With the aim to develop beneficial tracers for cerebral tumors, we tested two novel 5-iodo-2′-deoxyuridine (IUdR) derivatives, diesterified at the deoxyribose residue. The substances were designed to enhance the uptake into brain tumor tissue and to prolong the availability in the organism. We synthesized carrier added 5-[125I]iodo-3′,5′-di-O-acetyl-2′-deoxyuridine (Ac2[125I]IUdR), 5-[125I]iodo-3′,5′-di-O-pivaloyl-2′-deoxyuridine (Piv2[125I]IUdR) and their respective precursor molecules for the first time. HPLC was used for purification and to determine the specific activities. The iodonucleoside tracer were tested for their stability against human thymidine phosphorylase. DNA integration of each tracer was determined in 2 glioma cell lines (Gl261, CRL2397) and in PC12 cells in vitro. In mice, we measured the relative biodistribution and the tracer uptake in grafted brain tumors. Ac2[125I]IUdR, Piv2[125I]IUdR and [125I]IUdR (control) were prepared with labeling yields of 31–47% and radiochemical purities of >99% (HPLC). Both diesterified iodonucleoside tracers showed a nearly 100% resistance against degradation by thymidine phosphorylase. Ac2[125I]IUdR and Piv2[125I]IUdR were specifically integrated into the DNA of all tested tumor cell lines but to a less extend than the control [125I]IUdR. In mice, 24 h after i.p. injection, brain radioactivity uptakes were in the following order Piv2[125I]IUdR>Ac2[125I]IUdR>[125I]IUdR. For Ac2[125I]IUdR we detected lower amounts of radioactivities in the thyroid and stomach, suggesting a higher stability toward deiodination. In mice bearing unilateral graft-induced brain tumors, the uptake ratios of tumor-bearing to healthy hemisphere were 51, 68 and 6 for [125I]IUdR, Ac2[125I]IUdR and Piv2[125I]IUdR, respectively. Esterifications of both deoxyribosyl hydroxyl groups of the tumor tracer IUdR lead to advantageous properties regarding uptake into brain tumor tissue and metabolic stability. 相似文献
10.
《Journal of receptor and signal transduction research》2013,33(5):803-817
AbstractWe have investigated the binding characteristics of rat [125I] adrenomedullin (AM) and human [125I] calcitonin gene-related peptide (CGRP) to membranes prepared from a number of porcine tissues including atrium, ventricle, lung, spleen, liver, renal cortex and medulla. These membranes displayed specific, high affinity binding for [125I] rat AM and [125I] human CGRP. Porcine lung displayed the highest density of binding sites for radiolabeled AM and CGRP followed by porcine renal cortex. Competition experiments performed with [125I] rat AM indicated that the rank order of potencies of various peptides for inhibiting [125I] rat AM binding to various tissues were rat AM ≥ human AM ≥ human AM(22–52) > hαCGRP ≥ hαCGRP(8–37) <<<< sCT except spleen, atrium, renal cortex and renal medulla where rAM and hAM were 20–300 fold more potent than hAM(22–52). When the same experiments were performed using [125I] hαCGRP as the radioligand, the rank order potencies for various peptides were rAM = hAM > hαCGRP > hαCGRP(8–37) in most of the tissues except in spleen and liver. where hαCGRP was the most potent ligand. In lung, hαCGRP was almost as potent as rAM and hAM in displacing [125I] hαCGRP binding. These data suggest the existence of distinct CGRP and AM specific binding sites in contrast to previous reports that showed that both peptides interact differently in rat tissues. 相似文献
11.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1991,18(8):891-899
Tumour-to-normal tissue ratios of i.p. injected 125I-labelled monoclonal antibodies (MAbs), reacting with CEA were determined in nude rats xenografted with human colonic cancer cells (LS 174 T). Two MAbs, I-38S1 and II-16, reactive with the GOLD 1-epitope on CEA were tested. MAb I-38S1 was also tested after additional purification using anion exchange chromatography (thereafter named AEC 38). In the external activity measurements, MAb AEC 38 showed significantly better tumour-to-liver ratios than did MAb II-16 on all 4 days after injection. MAb I-38S1 gave intermediate ratios but was significantly better than II-16 only on day 3. The mean tumour-to-blood ratios were 3.0, 2.6 and 1.5 and the mean tumour-to-liver ratios were 6.6, 4.8 and 3.5 for MAbs AEC 38, I-38S1 and II-16 respectively. Gamma camera registrations in 3 animals on 4 days showed good imaging properties for all three MAbs and the patterns of tissue uptake were consistent with those seen in the external measurements. Furthermore, histopathological and immunohistochemical determinations were performed, showing that MAb II-16 gave about the same spatial binding as the previously analysed MAb I-38S1. The results indicate that additional purification of MAbs using anion exchange chromatography may potentiate tumour uptake in this model. 相似文献
12.
《Journal of steroid biochemistry》1980,12(3):333-337
Proliferation of Shionogi carcinoma 115 cells under various endocrine conditions was determined 11 days after transplantation of the tumor in 100 male DS mice by measuring the incorporation of 5-[125I]-iodo-2'-deoxyuridine ([125I]-IdUrd) into the whole tumor. The [125I]-IdUrd uptake almost disappeared after castration. In castrated-hypophysectomized mice, the [125I]-IdUrd uptake in mice given testosterone was much higher than that in mice given oestradiol-17β, progesterone, cortisol or prolactin, which was almost undetectable. The [125I]-IdUrd uptake into the whole tumor stimulated by testosterone was not increased significantly by the addition of prolactin or other pituitary hormones. These results show that growth of Shionogi carcinoma 115 in vivo is stimulated by androgens but not by oestrogens, progestins, glucocorticoids or prolactin. 相似文献
13.
《MABS-AUSTIN》2013,5(5):571-575
A neutralizing antibody to the receptor for the advanced glycation end products (anti-RAGE Ab) was developed as a potential treatment of acute and chronic inflammatory conditions. Previous pharmacology studies demonstrated efficacy of the anti-RAGE antibody in the mouse model of sepsis. We examined pharmacokinetics and lung distribution of [125I]anti-RAGE Ab in RAGE-/- and wild-type (129S5) mice following single IV administration. Serum pharmacokinetics of [125I]anti-RAGE Ab was similar in RAGE-/- and 129S5 mice, with the total body clearance of 0.3 mL/hr/kg and the elimination half-life of 11-12 days, suggesting the target expression had limited impact on overall elimination of [125I]anti-RAGE Ab from mice. [125I]Anti-RAGE Ab accumulated in the lung of 129S5 mice, with ~4% of total dose retained in the lung at days 6-27 and the lung AUC0-∞ of ~300% of that in serum. The SDS-PAGE analysis suggested that most of retained lung radioactivity was attributed to intact antibody. No accumulation of radioactivity was observed in the lung of RAGE-/- mice, indicating that lung uptake of [125I]anti-RAGE Ab was target-dependent in wild-type mice. These data suggest that the anti-RAGE Ab was able to localize to the site of RAGE expression, the lung, and support the findings in the previous pharmacology studies. 相似文献
14.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1988,15(2):203-208
In vivo biodistribution of S- and R-isomers of [125I]IBZM in rats showed a significant initial brain uptake (3.20 and 2.67% dose/organ at 2 min, respectively). The wash-out from the brain was slower for the S-isomer. The striatum to cerebellum ratio for [125I]S-IBZM decreased with an increasing dose of cold carrier or spiperone, suggesting that the brain uptake is stereospecific and saturable, and may be related to the binding of D-2 dopamine receptors. In a dual isotope digital autoradiography study [125I]IBZM and [3H]NMSP(N-methylspiperone) show comparable regional cerebral distribution in rats. 相似文献
15.
Meng-Chao Cui Zi-Jing Li Rui-Kun Tang Bo-Li Liu 《Bioorganic & medicinal chemistry》2010,18(7):2777-2784
In this study, six novel benzothiazole derivatives based on the bithiophene structure were developed as potential β-amyloid probes. In vitro binding studies using Aβ aggregates showed that all of them demonstrated high binding affinities with Ki values ranged from 0.11 to 4.64 nM. In vitro fluorescent staining results showed that these compounds can intensely stained Aβ plaques within brain sections of APP/PS1 transgenic mice, animal model for AD. Two radioiodinated compounds [125I]-2-(5′-iodo-2,2′-bithiophen-5-yl)-6-methoxybenzo[d]thiazole [125I]10 and [125I]-2-(2,2′-bithiophen-5-yl)-6-iodobenzo[d]thiazole [125I]13 were successfully prepared through an iododestannylation reaction. Furthermore, in vitro autoradiography of the AD model mice brain sections showed that both [125I]10 and [125I]13 labeled the Aβ plaques specifically with low background. In vivo biodistribution studies in normal mice indicated that [125I]13 exhibited high brain uptake (3.42% ID/g at 2 min) and rapid clearance from the brain (0.53% ID/g at 60 min), while [125I]10 showed lower brain uptake (0.87% ID/g at 2 min). In conclusion, these preliminary results of this study suggest that the novel radioiodinated benzothiazole derivative [125I]13 may be a candidate as an in vivo imaging agent for detecting β-amyloid plaques in the brain of AD patients. 相似文献
16.
Transgenic Mice Secreting Coronavirus Neutralizing Antibodies into the Milk 总被引:6,自引:1,他引:5
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Isabel Sola Joaquín Castilla Beln Pintado Jos M. Snchez-Morgado C. Bruce A. Whitelaw A. John Clark Luis Enjuanes 《Journal of virology》1998,72(5):3762-3772
Ten lines of transgenic mice secreting transmissible gastroenteritis coronavirus (TGEV) neutralizing recombinant monoclonal antibodies (rMAbs) into the milk were generated. The rMAb light- and heavy-chain genes were assembled by fusing the genes encoding the variable modules of the murine MAb 6A.C3, which binds an interspecies conserved coronavirus epitope essential for virus infectivity, and a constant module from a porcine myeloma with the immunoglobulin A (IgA) isotype. The chimeric antibody led to dimer formation in the presence of J chain. The neutralization specific activity of the recombinant antibody produced in transiently or stably transformed cells was 50-fold higher than that of a monomeric rMAb with the IgG1 isotype and an identical binding site. This rMAb had titers of up to 104 by radioimmunoassay (RIA) and neutralized virus infectivity up to 104-fold. Of 23 transgenic mice, 17 integrated both light and heavy chains, and at least 10 of them transmitted both genes to the progeny, leading to 100% of animals secreting functional TGEV neutralizing antibody during lactation. Selected mice produced milk with TGEV-specific antibody titers higher than 106 as determined by RIA, neutralized virus infectivity by 106-fold, and produced up to 6 mg of antibody per ml. Antibody expression levels were transgene copy number independent and integration site dependent. Comicroinjection of the genomic β-lactoglobulin gene with rMAb light- and heavy-chain genes led to the generation of transgenic mice carrying the three transgenes. The highest antibody titers were produced by transgenic mice that had integrated the antibody and β-lactoglobulin genes, although the number of transgenic animals generated does not allow a definitive conclusion on the enhancing effect of β-lactoglobulin cointegration. This approach may lead to the generation of transgenic animals providing lactogenic immunity to their progeny against enteric pathogens. 相似文献
17.
《International journal of radiation applications and instrumentation. Part B, Nuclear medicine and biology》1992,19(1):87-99
In this report, we have employed macroautoradiography to compare the tumor targeting of 125I-labeled anti-carcinoembryonic antigen (CEA) MAb (NP-4) to 125I-labeled anti-colon-specific antigen-p (CSAp) MAb (Mu-9) and their labeled F(ab′)2 and Fab′ fragments, in nude mice each bearing large dorsal human colonic tumor xenografts, and small nodular tumors in the liver and lungs. Using intact MAbs (NP-4 and Mu-9), clearance of background radioactivity was delayed to 3–7 days post-treatment. Treatment with F(ab′)2 and Fab′ fragments of both NP-4 and Mu-9 MAbs, however, promoted clearance of background 125I-radioactivity which was well advanced by 6–24 h and complete by 24–48 h after injection. Localization of 125I-radioactivity in large and micrometastatic tumor perimeters was the most characteristic uptake pattern observed for both intact and fragmented MAbs. Qualitative analysis of macroautoradiographic images and quantitative densitometry indicated that the higher tumor-to-blood ratios achieved with labeled F(ab′)2 and Fab′ fragments at early time points, compared to labeled whole immunoglobulin, appeared to be more a function of rapid plasma clearance, tumor mass, location of xenografts and specific tumor growth patterns than increased tumor penetrance by lower molecular weight univalent and bivalent immune fragments. 相似文献
18.
Natsumi Ishikawa Takeshi Fuchigami Tatsuya Mizoguchi Sakura Yoshida Mamoru Haratake Morio Nakayama 《Bioorganic & medicinal chemistry》2018,26(12):3111-3116
Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (Kd?=?68.3?nM) to recombinant human survivin, as determined by quartz crystal microbalance (QCM). In vitro studies demonstrated that the [125I]IPI-1 binding in survivin-positive MDA-MB-231 cells was significantly higher than that in survivin-negative MCF-10A cells. In addition, uptake of [125I]IPI-1 by MDA-MB-231 cells decreased in a dose-dependent manner in the presence of the high-affinity survivin ligand S12; this is indicative of specific binding of [125I]IPI-1 to cellular survivin protein in vitro. Biodistribution studies in MDA-MB-231 tumor-bearing mice demonstrated the moderate uptake of [125I]IPI-1 in the tumor tissue (1.37%?ID/g) at 30?min that decreased to 0.32%?ID/g at 180?min. Co-injection of S12 (2.5?mg/kg) slightly reduced tumor uptake and the tumor/muscle ratio of [125I]IPI-1. Although further structural modifications are necessary to improve pharmacokinetic properties, our results indicate that PI derivatives may be useful as tumor-imaging probes targeting survivin. 相似文献
19.
Nurmaya Effendi Kenji Mishiro Takeshi Takarada Daisuke Yamada Ryuichi Nishii Kazuhiro Shiba Seigo Kinuya Akira Odani Kazuma Ogawa 《Bioorganic & medicinal chemistry》2019,27(2):383-393
Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1?h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands. 相似文献
20.
Kinetic studies of the binding and dissociation of [125I]-human growth hormone to rabbit liver and mammary gland membrane receptors have showed that the binding of [125I]-human growth hormone was largely irreversible to liver membrane receptors and completely to the solubilised mammary gland
receptor. As Scatchard analysis assumes complete reversibility of the hormone-receptor interaction the validity of estimates
of affinity and capacity of receptors derived by this analysis may be questionable.
Theoretical considerations show that in unimolecular irreversible interactions of hormone and receptor, a nonlinear (concave)
or a linear Scatchard plot can be obtained. In linear Scatchard plots the capacity of the receptor obtained by extrapolation
represents an overestimation of true capacity. This overestimation correlates with the value of the intercept in the Scatchard
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