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Y Arano

Publications and source records attributed to Y Arano.

At least 37 records · Page 2Linked to original sources
PubMed1999

The relationship of glycosylation and isoelectric point with tumor accumulation of avidin.

UNLABELLED: Radiolabeled avidin markedly accumulated in intraperitoneal tumors and was cleared rapidly from circulation when given intraperitoneally. This study investigated the mechanisms of the tumor localization of avidin. METHODS: Avidin was deglycosylated through endoglycosydase-H digestion and/or neutralized by acetylation of its lysine amino acids with acetic acid N-hydroxysuccinimide ester. Avidin and modified avidins were analyzed using sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS/PAGE) and isoelectric focusing. A tumor model was established by intraperitoneal injection of human colon cancer cells, LS180, in nude mice. Avidin and modified avidins were labeled with 111In using diethyleneamine pentaacetic acid-biotin and were administered intraperitoneally into the tumor-bearing mice. The biodistribution of radioactivity was examined 2 and 24 h postinjection. RESULTS: Deglycosylated avidins revealed a major band of smaller molecules on SDS/PAGE. The isoelectric point of neutralized avidins was reduced to less than 5, whereas that of unneutralized avidins was more than 9.5. Biodistribution study demonstrated that liver uptake was decreased by deglycosylation and kidney accumulation was decreased by neutralization, respectively. The blood clearance was remarkably slowed by combined modification of deglycosylation and neutralization. The tumor uptake of radioactivity was reduced by either deglycosylation or neutralization and was further decreased with combined modification. CONCLUSION: Both high glycosylation and positive charge of avidin contributed to its accumulation in tumor. This study may facilitate development of a new vehicle for the delivery of therapeutic agents to intraperitoneal tumors.

Animals↗
PubMed1998

Avidin targeting of intraperitoneal tumor xenografts.

BACKGROUND: Lectins (proteins that bind specific sugar molecules on glycoproteins and glycolipids) are expressed at various levels on the surface of tumor cells. Conjugation of cytotoxic agents to glycoproteins recognized by lectins could be useful in the treatment of tumors. Avidin (a highly glycosylated, positively charged protein found in egg white) contains terminal N-acetylglucosamine and mannose residues that bind to some lectins. In this study, we tested the ability of avidin, labeled through conjugation to radioactive biotin (a B vitamin), to target intraperitoneal tumors. METHODS: Biotin was radioactively labeled with 111In. Four tumor models (one ovarian, one lung, and two colon) were established in nude mice by intraperitoneal injection of cultured cancer cells. The following two approaches were used in the intraperitoneal administration of avidin: 1) radioactive biotin-avidin conjugates were injected and 2) avidin was injected 1-24 hours before the injection of radioactive biotin (avidin pretargeting; avidin-biotin conjugates formed in vivo). The distribution of injected radioactivity in the tissues of treated animals was assessed. RESULTS: Radiolabeled avidin localized highly and rapidly in the tumors. More than 50% of the administered dose of avidin-biotin conjugate accumulated per gram of tumor tissue 2 hours after injection; high tumor uptake of radioactivity was observed up to 24 hours after conjugate injection. In contrast, accumulation of radioactivity in normal tissues was low, yielding high tumor to nontumor ratios. With avidin pretargeting, accumulation of radioactivity in the liver, kidney, and spleen was reduced to a greater extent than that in the tumor, and tumor to nontumor ratios were increased. CONCLUSIONS: Avidin may be a promising vehicle for the delivery of radioisotopes, drugs, toxins, or therapeutic genes to intraperitoneal tumors.

Animals↗
PubMed1998

Imaging of intraperitoneal tumors with technetium-99m GSA.

99mTc labeled galactosyl serum albumin (GSA) has been used clinically as a receptor-binding agent for the assessment of liver function. The aim of this study was to investigate the usefulness of 99mTc-GSA in intraperitoneal (i.p.) tumor imaging. A tumor model was established by i.p. inoculating nude mice with human ovarian cancer cell SHIN-3, or colon cancer cell LS 180. Radiolabels were i.p. injected into the tumor-bearing mice and the biodistribution of radioactivity was examined. After administration, 99mTc-GSA rapidly accumulated in the tumor. The tumor uptake was 5.82-8.46 %ID/g from 30 min to 6 h after the injection. Radioactivity in the blood was very low, less than 0.3 %ID/g, resulting in high tumor-to-blood ratio. Tumors could be clearly seen by scintigraphic imaging. Accumulation of i.p.-injected 99mTc labeled human serum albumin (HSA) in i.p. tumors was similar to that of 99mTc-GSA, but radioactivity of 99mTc-HSA in the circulation was high, resulting in a significantly lower tumor-to-blood ratio. In conclusion, 99mTc-GSA, when i.p. injected, accumulated in i.p. tumors and cleared from circulation rapidly, which would make it useful for the imaging of i.p. tumors.

Animals↗
PubMed1998

Pharmacokinetic models to evaluate radiolabeling reagents for protein radiopharmaceuticals.

Pharmacokinetic models were constructed to further estimate the hepatic radioactivity levels derived from bifunctional chelating agents used for radiolabeling of proteins. Both galactosyl-neoglycoalbumin (NGA) and mannosyl-neoglycoalbumin (NMA) were labeled with (111)In using two benzyl-EDTA derivatives. Time-activity profiles for the liver with gallbladder, intestine, and blood after administration of (111)In-labeled NGAs in mice were simultaneously fitted to a multi-compartment model, and the first-order rate constants representing the disappearance from parenchymal cells were obtained. Similarly, a model composed of the blood and liver compartment was constructed, and the disappearance rate constants from nonparenchymal cells were calculated from the biodistribution studies following administrations of (111)In-labeled NMAs. Fitting curves showed good agreements with the experimental data. Each rate constant clearly distinguished the elimination rate of the respective radiometabolite from the liver cells. Thus, quantitative estimations of radiolabeling reagents were performed only by animal biodistribution studies, and the present pharmacokinetic analyses would be useful for screening of newly designed reagents for protein radiopharmaceuticals.

Albumins↗
PubMed1998

Synthesis and evaluation of hydroxamamide-based tetradentate ligands as a new class of thiol-free chelating molecules for 99mTc radiopharmaceuticals.

Both N,N'-ethylene bis(benzohydroxamamide) [(C2(BHam)2)] and N,N'-propylene bis(benzohydroxamamide) [(C3(BHam)2)] were designed as new thiol-free chelating molecules for 99mTc radiopharmaceuticals. Synthetic procedures using oxadiazoline intermediates were developed for C2(BHam)2 and C3(BHam)2. Both C2(BHam)2 and C3(BHam)2 formed 99mTc complexes with high yields over a wide pH range (pH 3-12) at room temperature. Complexation yields of over 95% were achieved at ligand concentrations as low as 2.5 x 10(-6) M. Reversed-phase HPLC analyses indicated that both C2(BHam)2 and C3(BHam)2 formed 99mTc complexes as single species with stabilities much higher than those of 99mTc-BHam. Selective complex formation of 99mTc with the two ligands was observed in the presence of human IgG. No decomposition with low protein binding were demonstrated when the two 99mTc complexes were incubated in murine plasma. Although further structural studies are required, these findings implied that the Ham-based tetradentate ligands would serve as new chelating molecules for 99mTc radiopharmaceuticals.

Animals↗
PubMed1998

A radioiodinated biocytin derivative for in-vivo applications.

Radioiodinated biocytin derivatives are potentially useful for multi-step tumour targeting using the avidin-biotin system. We synthesized a radioiodinated biocytin derivative and evaluated its properties in vivo. We labelled biocytin with 125I by coupling biocytin to radioiodinated N-succinimidyl 3-(tri-n-butyl-stannyl) benzoate, and assessed its binding to avidin and its biodistribution in normal and tumour-bearing mice. When the synthesized biocytin was incubated with immobilized avidin, more than 94% of the radioactivity was bound. However, after 2 h incubation in serum, only 40% of the radioactivity was bound to the avidin. The iodinated biocytin derivative was characteristically taken up by the liver and the kidneys when injected intravenously into mice. In mice bearing an intraperitoneal tumour xeno-graft, 125I-biocytin and 111In-biotin were co-injected intraperitoneally 4 h after the intraperitoneal administration of avidin, which accumulated in the intraperitoneal tumours. At 2 and 24 h, the tumour uptake of 125I-biocytin was 8.2 and 3.8% ID/g respectively, whereas that of 111In-biotin was 20.0 and 18.7% ID/g respectively. When radioiodinated, biocytin retains its binding capacity to avidin, and it localizes well with high tumour-to-normal tissue ratios early post-injection using the two-step method, but compared to 111In-biotin it is unstable. We conclude that the stability of the product in serum needs to be improved prior to in-vivo applications.

Animals↗
PubMed1998

Strategies to reduce renal radioactivity levels of antibody fragments.

Antibody fragments such as Fab and single-chain Fv fragments possess many advantages over intact antibodies as vehicles to deliver radioactivity for diagnostic and therapeutic applications. However, radiolabled antibody fragments exhibited high and persistent localization of the radioactivity in the kidney, which compromises diagnostic accuracy and therapeutic effectiveness. Recent studies indicated that the persistent localization of renal radioactivity would be originated from the re-absorption of glomerularly-filtered radiolabeled antibody fragments, followed by the retention of the radiometabolites generated after degradation in the lysosomal compartment of the renal cells. Two major approaches have been performed to reduce the renal radioactivity levels of antibody fragments. One is to block the reabsorption of radiolabeled antibody fragments themselves at the proximal tubular cells from the luminal fluid by administration of basic amino acids such as L-lysine. The other approach is to decrease the residence time of the radiometabolites within the lysosomal compartments of the renal cells by introducing a cleavable linkage between antibody fragments and radiometabolites of rapid urinary excretion. Another approach to reduce renal radioactivity levels of antibody fragments may be to release radiolabeled compound of urinary excretion from glomerularly-filtered antibody fragments before they are reabsorbed into the renal cells by the action of brush border enzymes present on the lumen of the renal proximal cells. In this paper, recent studies of the three approaches to reduce the renal radioactivity levels of antibody fragments are briefly reviewed.

Antibodies, Monoclonal↗
PubMed1997

A novel radioiodination reagent for protein radiopharmaceuticals with L-lysine as a plasma-stable metabolizable linkage to liberate m-iodohippuric acid after lysosomal proteolysis.

Radiochemical design of polypeptides using metabolizable linkages would be attractive to enhance target-selective localization of radioactivity for diagnostic and therapeutic nuclear medicine. However, while use of ester bonds as the linkage allows selective release of the designed radiometabolite from covalently conjugated polypeptides after lysosomal proteolysis in nontarget tissues, low plasma stability of ester bonds causes a decrease in radioactivity levels of the target. In pursuit of new metabolizable linkages that provide stable attachment of radiolabels with polypeptide in plasma while facilitating rapid and selective release of designed radiometabolites of rapid urinary excretion in lysosomes, a new radioiodination reagent with L-lysine as the metabolizable linkage to liberate m-iodohippuric acid (L-HML) was designed and synthesized. Stabilities of the metabolizable linkage in serum and cleavabilities of the linkage in lysosomal proteolysis in hepatic cells were investigated after conjugation of [131I]-L-HML with galactosyl-neoglycoalbumin (NGA). For comparison, a radioiodination reagent with an ester bond to release m-iodohippuric acid (MIH) was conjugated with NGA under similar conditions. When incubated in human serum, [131I]-L-HML-NGA liberated less than 3% of the initial radioactivity after 24 h, whereas [125I]MIH-NGA released more than 60% of its radioactivity during the same interval. In biodistribution studies, [131I]-L-HML-NGA demonstrated radioactivity elimination from murine liver at a rate and excretion route similar to [125I]MIH-NGA. Analyses of murine urine after injection of [131I]-L-HML-NGA indicated a single radioactivity peak at fractions identical to those of m-iodohippuric acid. Biodistribution studies of radioiodinated NGAs with D-lysine or cadaverine as the linkages demonstrated a delayed elimination rate from murine liver with significantly higher radioactivity being excreted in the feces at 24 h postinjection. Thus, L-HML is the first reagent that allows stable attachment of radiolabel with polypeptide in serum while facilitating selective release of a radiometabolite with rapid urinary excretion from covalently conjugated polypeptides after lysosomal proteolysis at a rate similar to that of ester bonds. Thus, L-HML is potentially useful for the radioiodination of polypeptides for diagnostic and therapeutic purposes.

Albumins↗
PubMed1996

Reassessment of diethylenetriaminepentaacetic acid (DTPA) as a chelating agent for indium-111 labeling of polypeptides using a newly synthesized monoreactive DTPA derivative.

Previous studies on indium-111 (111In) labeling of polypeptides and peptides using cyclic diethylenetriaminepentaacetic dianhydride (cDTPA) as a bifunctional chelating agent (BCA) have indicated that DTPA might be a useful BCA for 111In labeling of polypeptides at high specific activities when DTPA can be incorporated without inducing intra- or intermolecular cross-linking. To investigate this hypothesis, a monoreactive DTPA derivative with a maleimide group as the peptide binding site (MDTPA) was designed and synthesized. A monoclonal antibody (OST7, IgG1) was used as a model polypeptide, and conjugation of MDTPA with OST7, 111In radiolabeling of MDTPA-OST7, and the stability of 111In-MDTPA-OST7 were investigated using cDTPA and benzyl-EDTA derivatives as references. SDS-PAGE analysis demonstrated that while cDTPA induced intramolecular cross-linking, no such undesirable side reactions were observed with MDTPA. MDTPA generated 111In-labeled OST7 with high radiochemical yields at higher specific activities than those produced using cDTPA and benzyl-EDTA derivatives as the BCAs. Incubation of each 111In-labeled OST7 in human serum indicated that MDTPA generated 111In-labeled OST7 of much higher and a little lower stability than those derived from cDTPA and benzyl-EDTA derivatives, respectively. These findings indicated that the low in vivo stability of cDTPA-conjugated antibody reported previously is not attributable to low stability of 111In-DTPA but to formation of intramolecular cross-linking during cDTPA conjugation reactions. The present study also indicated that MDTPA and its precursor, the tetra-tert-butyl derivative of DTPA, would be useful BCAs for 111In radiolabeling of polypeptides that have rapid blood clearance with high specific activities.

Chelating Agents↗
PubMed1996

Comparison of pleuropneumonectomy and limited surgery for lung cancer with pleural dissemination.

The role of surgery in the management of lung cancer with pleural dissemination is controversial. We performed a retrospective analysis of our patients with lung cancer and pleural dissemination who were treated surgically. Between 1973 and 1993, 1,206 patients with lung cancer underwent pulmonary resection at Kanazawa University Hospital. Among them, 40 (3.3%) had pleural dissemination without pleural effusion. The 1-, 3-, and 5-year survival rates for 38 patients (except 2 patients undergoing exploratory thoracotomy alone) were 51.5%, 19.4%, and 19.4%, respectively. The 1-year survival rate in the 10 patients who underwent pleuropneumonectomy was only 20%, and 9 of these patients died within 18 months postoperatively (1 patient has survived for 25 months). In contrast, the 1-, 3-, and 5-year survival rates for the 14 patients who underwent resection of the primary tumor plus parietal pleurectomy were 85.1%, 35.5%, and 35.5%, respectively, a significantly better outcome (P < 0.01). Seven patients are still alive (the longest survival time is 65 months with the disease). The average survival time in the seven fatal cases was 18 months. In patients with lung cancer accompanied by pleural dissemination, it is quite possible that local excision plus pleurectomy will be justified.

Adenocarcinoma↗
PubMed1996

Stability of a metabolizable ester bond in radioimmunoconjugates.

Ester bonds have been used as metabolizable linkages to reduce radioactivity levels in non-target tissues following the administration of antibodies labeled with metallic radionuclides. In this radiochemical design of antibodies, while the ester bonds should be cleaved rapidly in non-target tissues, high stability of the ester bonds in plasma is also required to preserve target radioactivity levels. To assess the structural requirements to stabilize the ester bond, a new benzyl-EDTA-derived bifunctional chelating agent with an ester bond, (1-[4-[4-(2- maleimidoethoxy)succinamido]benzyl]ethylenediamine-N,N,N',N' -tetraacetic acid; MESS-Bz-EDTA), was developed. MESS-Bz-EDTA was coupled with a thiolated monoclonal antibody (OST7, IgG1) prepared by reducing its disulfide bonds to introduce the ester bond close and proximal to the antibody molecule. For comparison, 1-[4-(5- maleimidopentyl)aminobenzyl]ethylenediamine-N,N,N',N'-tetraacetic acid (EMCS-Bz-EDTA) and meleimidoethyl 3-[131I]iodohippurate (MIH) was coupled to OST7 under the same conjunction chemistry. When incubated in 50% murine plasma or a buffered-solution of neutral pH, OST7-MESS-Bz-EDTA-111In rapidly released the radioactivity, and more than 95% of the initial radioactivity was liberated after a 24 h incubation in both solutions, due to a cleavage of the ester bond. On the other hand, only about 20% of the radioactivity was released from OST7-MIH-131I in both solutions during the same incubation period. In mice biodistribution studies, while a slightly faster radioactivity clearance from the blood with less radioactivity levels in the liver and kidneys was observed with OST7-MIH-131I than with OST7-EMCS-Bz-EDTA-111In, OST7-MESS-Bz-EDTA-111In indicated radioactivity clearance from the blood much faster than and almost comparable to that of OST7-MIH-131I and succinamidobenzyl-EDTA-111In, respectively. These findings as well as previous findings on radiolabeled antibodies with ester bonds suggested that while an introduction of an ester bond close to an antibody molecule stabilized the ester bond against esterase access, chemical structures of the linkages and radiolabels attached to the ester bonds play a significant role in the chemical stability of the ester bond. This may explain the different stability of the ester bonds in radioimmunoconjugates so far reported.

Animals↗
PubMed1996

[Protein- and peptide-derived radiopharmaceuticals].

Recent development of radiochemistry has provided various reagent that allow stable attachment of radiolabels to proteins in vivo. The advent of genetic and protein engineering have generated proteins and peptides with reduced or no immunogenicity or more favorable distribution characteristics. However, localization of radioactivity in nontarget tissues still constitutes a problem to be resolved for accurate diagnosis and effective therapy using the radiopharmaceuticals. Recent studies have indicated that radiometabolites after lysosomal proteolysis of proteins play a critical role in the radioactivity levels in nontarget tissues. Furthermore, radiochemical design of polypeptides that liberates radiometabolites of rapid urinary excretion after lysosomal proteolysis in nontarget tissues has facilitated rapid radioactivity elimination from nontarget tissues to urine. From these findings, we believe a new era of protein- and peptide-derived radiopharmaceuticals much more suitable for diagnostic and therapeutic applications will be opened soon.

Animals↗
PubMed1996

[Significance of 5'-deoxy-5-fluorouridine (5'-DFUR) administration before surgery for advanced gastric and colonic cancers--activity of pyrimidine nucleoside phosphorylase (PyNPase) and serum immunosuppressive acidic protein (IAP)].

We administered preoperatively 5'-deoxy-5-fluorouridine (5'-DFUR) for treatment of advanced gastric and colonic cancers, and measured pyrimidine nucleoside phosphorylase (PyNPase) in the excised tumor sample and serum immunosuppressive acidic protein (serum IAP), which is an index of the immunity of host-bearing cancer, while studying its direct antitumor effect and improved immunity. Patients with 24 advanced gastric cancers and 36 colonic cancers were randomly divided into a preoperatively administered group and a non-administered group. In the preoperatively administered group, 5'-DFUR (1,200 mg/day) was orally administered on preoperative days 7 approximately 14. After collecting samples (about 0.5 g) from adjacent normal tissues with tumor within 30 minutes after extirpation of tumor and freezing those less than -20 degrees C, the PyNPase level was measured as soon as possible. Moreever, serum IAP levels at pre-administration in the administered group and on admission in the non-administered group were measured. Those in the administered group were measured again on the operative day. No decreasing tendency of PyNPase was generally found in cases with gastric colonic cancers, and no significant difference in stage-II was not either. However, a decreasing tendency in tumor activity was found by pre-administration. Moreover, there was significant improvement in the serum IAP level in cases with gastric and colonic cancers by pre-operative administration of 5'-DFUR. This tendency was also found in advanced colonic cancer with Dukes-C by Dukes's classification. In conclusion, it was suggested that the pre-operative administration of 5'-DFUR for treatment of advanced gastric and colonic cancers has a favorable influence for prognosis because the tumor region was retarded by the high PyNPase activity according to the severity of tumors and elevating tendency of the immune response in host.

Administration, Oral↗
PubMed1995

Results of surgical treatment of pulmonary metastases.

From 1970 to 1993, 155 thoracotomies for metastatic lung tumors were performed on 113 patients in the Department of Surgery, Kanazawa University School of Medicine. Overall 30-day mortality amounted to 0.9% (1/113). The cumulative 3- and 5-year survival rates were 39.4% and 29.1%, respectively. The overall median survival was 24 months. The 5-year survival rate for carcinoma was 37.2% and for sarcoma it was 14.5% (P < 0.01). The other significant predictors of better long-term survival with metastatic lung tumors were solitary lesions, disease-free interval (DFI) > 24 months, and tumor size < or = 20 mm in diameter. There was no significant difference in survival based on the method of pulmonary resection. Repeat thoracotomy for recurrent metastases was performed in 27 patients, whose 5-year survival rate after the first lung resection was 35.5%. For bilateral pulmonary metastases, we recently performed simultaneous bilateral thoracotomy via median sternotomy on 25 patients and transsternal simultaneous bilateral thoracotomy on 8 patients. The latter procedure provides a wide operative field and better survival. We conclude that resection of metastatic lung tumors is safe and effective, and that repeat thoracotomy is warranted in selected patients with recurrent pulmonary metastases.

Adolescent↗
PubMed1995

Radiolabeled metabolites of proteins play a critical role in radioactivity elimination from the liver.

We have recently reported that the behavior of radiolabeled metabolites in the liver appears to be responsible for the hepatic radioactivity levels after administration of protein radiopharmaceuticals. To better understand the role played by radiolabeled metabolites in hepatic radioactivity levels, two benzyl-EDTA derivatives rendering different radiolabeled metabolites, 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-Bz-EDTA) and 1-[p-(5-maleimidopentyl)aminobenzyl]ethylenediaminetetraacetic acid (ECMS-Bz-EDTA), were selected as bifunctional chelating agents (BCAs), and 111In labeling of galactosyl-neoglycoalbumin (NGA) and mannosyl-neoglycoalbumin (NMA) was performed. Biodistribution of radioactivity in mice and subcellular distribution of radioactivity in hepatocytes were then compared. After accumulation in hepatic parenchymal cells, NGA-EMCS-Bz-EDTA-111In rendered a faster elimination rate of radioactivity from the liver than NGA-SCN-Bz-EDTA-111In. Although each 111In-NMA exhibited a delayed elimination rate of radioactivity from the liver compared to the 111In-NGA counterpart, NMA-EMCS-Bz-EDTA-111In showed faster elimination rate of radioactivity than NMA-SCN-Bz-EDTA-111In. Analyses of radioactivity excreted in feces and urine and remaining in the liver indicated that both BCAs rendered mono-amino acid adducts as the major radiolabeled metabolites (cysteine-EMCS-Bz-EDTA-111In and lysine-SCN-Bz-EDTA-111In), which were generated in both cell types of the liver within 1 h postinjection. Subcellular distribution of radioactivity indicated that the radioactivity was copurified with lysosomes. These results demonstrate that although in vivo stability of radiometal chelates is essential, the biological properties of the radiolabeled metabolites generated after lysosomal proteolysis in hepatocytes play a critical role in radioactivity elimination from the liver.

Animals↗
PubMed1995

[Two cases of chondrosacoma of rib].

Chondrosarcoma of rib origin is rare in Japan. We treated two cases of chondrosarcoma of rib origin. Case 1: A 68-year-old man with anterior chest wall mass and chest pain was underwent aspiration biopsy in Inami General Hospital. The histological examination showed Class V. Operation was done in our department and the histological diagnosis was chondrosarcoma. The tumor was 30 x 20 x 20 mm in size arising from the left fourth rib. The defect of bony chest wall was repaired with a double layer of Marlex mesh. His postoperative course was uneventful. Case 2: 66-year-old man noticed a tumor in left anterior part of the chest 7 months ago. He was underwent incisional biopsy and the histological diagnosis was chondrosarcoma. Radical resection was performed. The tumor was 70 x 50 x 50 mm in size arising from the left rib. His postoperative course was uneventful.

Aged↗
PubMed1994

Maleimidoethyl 3-(tri-n-butylstannyl)hippurate: a useful radioiodination reagent for protein radiopharmaceuticals to enhance target selective radioactivity localization.

In pursuit of radiolabeled monoclonal antibodies (mAbs) with rapid urinary excretion of radioactivity from nontarget tissues, radioiodinated mAbs releasing a m-iodohippuric acid from the mAbs in nontarget tissues were designed. A novel reagent, maleimidoethyl 3-(tri-n-butylstannyl)hippurate (MIH), was synthesized by reacting N-(hydroxyethyl)maleimide with N-Boc-glycine before coupling with N-succinimidyl 3-(tri-n-butylstannyl)benzoate (ATE). MIH possessed a maleimide group for mAb conjugation and a butylstannyl moiety for high-yield and site-specific radioiodination, and the two functional groups were linked via an ester bond to release m-iodohippuric acid. To investigate the fate of radiolabels after lysosomal proteolysis, hepatic parenchymal cells were used as a model nontarget tissue and 131I-labeled MIH was conjugated with galactosyl-neoglycoalbumin (NGA). Further conjugation of [131I]MIH with a mAb against osteogenic sarcoma (OST7) after reduction of its disulfide bonds was followed up. In murine biodistribution studies, [131I]MIH-NGA exhibited rapid accumulation in the liver followed by radioactivity elimination from the liver at a rate that was identical to and faster than those of 131I-labeled NGA via direct iodination ([131I]NGA) and [131I]ATE-labeled NGA, respectively. While [131I]NGA indicated high radioactivity levels in the murine neck, stomach, and blood, such increases in the radioactivity count were not detectable by the administration of either [131I]MIH-NGA or [131I]ATE-NGA. At 6 h postinjection of [131I]MIH-NGA, 80% of the injected radioactivity was recovered in the urine. Analyses of urine samples indicated that m-iodohippuric acid was the sole radiolabeled metabolite. In biodistribution studies using [131I]-MIH-OST7 and [131I]ATE-OST7, while both 131I-labeled OST7s registered almost identical radioactivity levels in the blood up to 6 h postinjection, the former demonstrated a lower radioactivity level than [131I]ATE-OST7 in nontarget tissues throughout the experiment. Such chemical and biological characteristics of MIH would enable high target/nontarget ratios in diagnostic and therapeutic nuclear medicine using mAbs and other polypeptides.

Albumins↗