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1.
In recent years, much effort has been concentrated on the use of Β-emitting radionuclides for the treatment of various cancers. The reports suggested the application of186Re and153Sm as radiotherapeutic radionuclides for the treatment of palliative widespread skeletal métastases, whereas166Ho was suggested as an agent for radiation synovectomy. Hence, a study on the production of186Re,153Sm, and166Ho radionuclides was carried out by neutron activation of the appropriate target materials using a Pakistan Atomic Research Reactor (PARR-1) at a neutrons flux of 1 x 104 n/cm2 s. These radionuclides were then converted to appropriate radiopharmaceuticals for their use on animals and patients. The targets of natural Re (metal), natural Sm2O3, enriched Sm2O3 (99.06%), Sm(NO3)3 (solid), Sm(NO3)3 (liquid), and Ho2O3 were irradiated in the PARR-1. After irradiation, the purity of these radionuclides were checked by a multichannel analyzer, Canberra series 85 (MCA) coupled with HPGe detector and then measured in radioisotope calibrator Capintec ionization chamber model CRC-5RH. The effect of the irradiation time and amount of target material was investigated on the production yields of the radionuclides. The results showed an increase in the specific activity of Re with an increase in the irradiation time from 1 to 72 h, whereas a decrease in the specific activity was observed with increase in the amount of Re from 10 to 100 mg. Similar results were obtained for153Sm and166Ho radionuclides. The results further indicated that the specific activity of powder target was much less than the liquid targets for153Sm. Their conversion to the appropriate radiotherapeutic radiopharmaceuticals were also carried out by investigating the experimental conditions and acceptable quality of186Re-HEDP and153Sm-EDTMP complexes were prepared. These complexes were then used on animals and patients which showed good performance.  相似文献   

2.
An exclusive labeling of high affinity sites of IgG and its F(ab′)2 fragments with 99mTc was accomplished. Antibody was first labeled in 0.1 M acetate buffer at pH 4.5, using stannous chloride as a reducing agent. Thus, high capacity, low affinity sites and low capacity, high affinity sites were both labeled. These 99mTc complexes were stable at pH 4.5 and 7.0; however, they became destabilized at pH 8.2 and 9.0. Transchelation of 99mTc to DTPA took place at the higher pH values and leveled off at 54% 99mTc-F(ab′)2 and 73% 99mTc-IgG. These results indicate that the majority of 99mTc bound to the low affinity sites was transchelated to the high affinity sites rather than to DTPA since low affinity sites account for 84% of total F(ab′)2 sites and 76% of IgG sites. Biodistribution data in mice at 2.5 h postinjection were consistent with this hypothesis in that tissue concentrations of 111In-DTPA-F(ab′)2 were similar to the reequilibrated 99mTc-F(ab′)2 but were much higher than that of the unequilibrated 99mTc-F(ab′)2.  相似文献   

3.
We previously reported that microSPECT/CT imaging with 111In-labeled pertuzumab detected decreased HER2 expression in human breast cancer (BC) xenografts in athymic mice associated with response to treatment with trastuzumab (Herceptin). Our aim was to extend these results to PET/CT by constructing F(ab′)2 of pertuzumab modified with NOTA chelators for complexing 64Cu. The effect of the administered mass (5–200 µg) of 64Cu-NOTA-pertuzumab F(ab′)2 was studied in NOD/SCID mice engrafted with HER2-positive SK-OV-3 human ovarian cancer xenografts. Biodistribution studies were performed in non-tumor bearing Balb/c mice to predict radiation doses to normal organs in humans. Serial PET/CT imaging was conducted on mice engrafted with HER2-positive and trastuzumab-sensitive BT-474 or trastuzumab-insensitive SK-OV-3 xenografted mice treated with weekly doses of trastuzumab. There were no significant effects of the administered mass of 64Cu-NOTA-pertuzumab F(ab′)2 on tumor or normal tissue uptake. The predicted total body dose in humans was 0.015 mSv/MBq, a 3.3-fold reduction compared to 111In-labeled pertuzumab. MicroPET/CT images revealed specific tumor uptake of 64Cu-NOTA-pertuzumab F(ab′)2 at 24 or 48 h post-injection in mice with SK-OV-3 tumors. Image analysis of mice treated with trastuzumab showed 2-fold reduced uptake of 64Cu-NOTA-pertuzumab F(ab′)2 in BT-474 tumors after 1 week of trastuzumab normalized to baseline, and 1.9-fold increased uptake in SK-OV-3 tumors after 3 weeks of trastuzumab, consistent with tumor response and resistance, respectively. We conclude that PET/CT imaging with 64Cu-NOTA-pertuzumab F(ab′)2 detected changes in HER2 expression in response to trastuzumab while delivering a lower total body radiation dose compared to 111In-labeled pertuzumab.  相似文献   

4.
Athymic mice with and without circulating CA 125 antigen were injected with 0.1–100μg of 131I-labeled OC 125 F(ab′)2 antibody fragment. Both the blood clearance of 131I activity and the change in serum CA 125 were monitored over 24 h. Influence of CA 125 on blood pool activity could be avoided only at the 100 βg dose. In patient studies, circulating CA 125 levels decreased for the first 2 h after injection of OC 125 F(ab′)2 but generally returned to preinjection levels shortly thereafter. In vitro binding studies using the sera from patients injected with 131I-labeled OC 125 F(ab′)2 suggest that circulating CA 125 could interfere with the tumor uptake of the labeled antibody.  相似文献   

5.
Radioimmunotherapy (RIT) for treatment of hematologic malignancies has primarily employed monoclonal antibodies (Ab) labeled with 131I or 90Y which have limitations, and alternative radionuclides are needed to facilitate wider adoption of RIT. We therefore compared the relative therapeutic efficacy and toxicity of anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model. Biodistribution studies showed that both 90Y- and 177Lu-anti-murine CD45 Ab conjugates (DOTA-30F11) targeted hematologic tissues, as at 24 hours 48.8±21.2 and 156±14.6% injected dose per gram of tissue (% ID/g) of 90Y-DOTA-30F11 and 54.2±9.5 and 199±11.7% ID/g of 177Lu-DOTA-30F11 accumulated in bone marrow (BM) and spleen, respectively. However, 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit: 60% of mice treated with 300 µCi 90Y-DOTA-30F11 lived over 180 days after therapy, and mice treated with 100 µCi 90Y-DOTA-30F11 had a median survival 66 days. 90Y-anti-CD45 RIT was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, 90Y was more effective than 177Lu for anti-CD45 RIT of AML in this murine leukemia model.  相似文献   

6.
A new mouse monoclonal antibody that recognizes α- and β-heavy chains of human atrial and ventricular myosin and β-heavy chain of human slow skeletal muscle myosin was obtained. The 125I- and 111In-labelled antibody, and its F(ab′)2 and Fab fragments localize in isoproterenol induced infarcted rat heart, with the F(ab′)2 fragment showing the highest uptake. Comparison with 99mTc-pyrophosphate uptake in infarcted dog heart, induced by selective obstruction of a coronary artery, suggest that the 111In-labelled F(ab′)2 localizes specifically in infarcted myocardium only.  相似文献   

7.
Radioiodinated BB5-G1, a parathyroid-specific monoclonal antibody, and its F(ab′)2 and Fab fragments were characterized using a nude mouse model system. Blood clearance studies indicated that the most slowly clearing species was the 125I-BB5-G1 intact antibody, while the most rapidly clearing one was the 125I-Fab fragment. 125I-F(ab′)2 retained its capacity to localize in the human parathyroid tissue implants with the uptake at 24 h being similar to that observed with the intact antibody. Poor localization was observed with the Fab fragment. These results suggest that BB5-G1 or its F(ab′)2 fragment may be useful for parathyroid imaging.  相似文献   

8.

Introduction

Samarium-153 (153Sm) styrene divinylbenzene microparticles were developed as a surrogate for Yttrium-90 (90Y) microspheres in liver radioembolization therapy. Unlike the pure beta emitter 90Y, 153Sm possess both therapeutic beta and diagnostic gamma radiations, making it possible for post-procedure imaging following therapy.

Methods

The microparticles were prepared using commercially available cation exchange resin, Amberlite IR-120 H+ (620–830 μm), which were reduced to 20–40 μm via ball mill grinding and sieve separation. The microparticles were labelled with 152Sm via ion exchange process with 152SmCl3, prior to neutron activation to produce radioactive 153Sm through 152Sm(n,γ)153Sm reaction. Therapeutic activity of 3 GBq was referred based on the recommended activity used in 90Y-microspheres therapy. The samples were irradiated in 1.494 x 1012 n.cm-2.s-1 neutron flux for 6 h to achieve the nominal activity of 3.1 GBq.g-1. Physicochemical characterisation of the microparticles, gamma spectrometry, and in vitro radiolabelling studies were carried out to study the performance and stability of the microparticles.

Results

Fourier Transform Infrared (FTIR) spectroscopy of the Amberlite IR-120 resins showed unaffected functional groups, following size reduction of the beads. However, as shown by the electron microscope, the microparticles were irregular in shape. The radioactivity achieved after 6 h neutron activation was 3.104 ± 0.029 GBq. The specific activity per microparticle was 53.855 ± 0.503 Bq. Gamma spectrometry and elemental analysis showed no radioactive impurities in the samples. Radiolabelling efficiencies of 153Sm-Amberlite in distilled water and blood plasma over 48 h were excellent and higher than 95%.

Conclusion

The laboratory work revealed that the 153Sm-Amberlite microparticles demonstrated superior characteristics for potential use in hepatic radioembolization.  相似文献   

9.
Radiolabeled antibodies for cancer therapy are being investigated in clinical trials in more than 30 centers. 131Iodine-labeled antibody (Ab) therapy of solid tumors has produced few responses when given alone. When given in conjunction with chemotherapy and external beam therapy in hepatoma patients, objective responses have occurred. Because of the short range of 131I, 90Y and 186Re are being studied and objective responses have occurred in patients without the addition of other therapies. 131I-labeled Ab therapy of lymphoma, a radioresponsive tumor, has produced a much higher objective response rate than in other solid tumors. Regional RIT has not been shown to offer a definite advantage over the intravenous route. Tumor doses have generally been less than 2000 cGy per treatment with some tumors receiving higher doses. The bone marrow is the dose-limiting organ for RIT and marrow cryopreservation with subsequent reinfusion may prove useful.  相似文献   

10.
《Process Biochemistry》2007,42(5):812-819
Dual fluorescence confocal laser scanning microscopy has been used to visualise the binding of a fluorescently labelled polyclonal ovine anti-fluorescein F(ab′)2 antibody to immobilised fluorescein. The fluorescent ligand was immobilised on a Streamline quartz base agarose matrix; a resin used industrially for expanded bed chromatography, using two different fluorescein initial concentrations in order to obtain two batches of immunogen-affinity adsorbent with different immobilised ligand densities. The fluorescein specific F(ab′)2 were purified from anti-fluorescein serum pepsin digest by adsorption on immobilised antigen chromatographic resin, followed by conjugation to the fluorescent probe Alexa Fluor 660. The dual fluorescence signals from the immobilised antigen and the immuno-specific F(ab′)2 were used to map the progressive depth of the bound F(ab′)2 layer within individual adsorbent beads. In addition, the labelled anti-fluorescein F(ab′)2 was diluted to identical antigen binding activity concentrations in crude serum digest and in blank buffer and the resulting fluorescence intensity profiles were comparatively assessed for any detectable differences in binding patterns that might be caused by processing the more complex mixture of crude serum digests. It was observed that the relative immobilised ligand utilisation was higher when using the immuno-adsorbent with lower immobilised antigen density. Furthermore, the progression of the adsorbed F(ab′)2 front inside the immuno-adsorbent beads displayed closer agreement with the postulates of the shrinking core mechanism (SCM) when the immuno-adsorbent with lower immobilised antigen was used. The confocal images did not reveal any differences between the depth of the adsorption fronts of crude serum digest and pre-purified F(ab′)2 samples.  相似文献   

11.
The pharmacokinetics of 131I-labeled OC 125 F(ab′)2 antibody fragment were investigated in athymic mice bearing OVCAR-3 ovarian carcinoma xenografts, a model in which the CA 125 antigen is present in serum. Nine antibody doses between 0.1 and 650 μg were studied. Optimal tumor to normal tissue ratios were obtained at 100–200 μg of F(ab′)2. At most antibody doses, the pre-injection level of circulating CA 125 appeared to influence the localization of 131I activity in tumor, liver and spleen.  相似文献   

12.
Experimental procedures are described for the radiolocalization of human tumors by murine monoclonal antibodies (MAb) in animal model systems. Visualization of tumor xenografts was clearer in nude mice as compared to experimentally immunosuppressed mice due to the higher viability of the tumors in nude mice. MAb localization in tumor tissue was greatly enhanced when F(ab′)2 fragments rather than intact antibody molecules were used. Although tumors could be visualized with either 131I-, 123I- or 111In-labeled MAb fragments without using background subtraction, tumor-to-background ratios of radioactivity were highest for 131I-labeled fragments. 131I-labeled F(ab′)2 fragments of eight MAb against human colorectal carcinoma, melanoma or lung carcinoma localized specifically only in those tumors that bound the MAb in vitro and not in unrelated tumors. Radiolabeled fragments of MAb with other specificities (anti-hepatitis virus MAb) did not localize in tumors. All MAb that inhibited tumor growth in nude mice effectively localized these tumors by γ-scintigraphy. On the other hand, some MAb were effective in localizing tumors but ineffective in inhibiting their growth. The ability of the specific radiolabeled F(ab′)2 fragments to localize in tumor grafts correlated significantly with MAb binding affinity and density of antigenic sites on tumor cells together, but not with either in vitro binding parameter alone. Thus, Scatchard analysis of MAb binding to tumor cells may be an effective means to screen for MAb with tumor radiolocalization potential.  相似文献   

13.
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   

14.
The biodistributions of 111In-BB5-G1 and 111In-F(ab′)2 were compared with the biodistributions of the corresponding 125I-labeled molecules. For BB5-G1 intact antibody, the relative uptake of the 111In- and 125I-labeled molecules in human parathyroid tissue implants was similar at 24 h, but by 96 h the uptake of the 111In-BB5-G1 %ID/g was four times greater than that observed with the 125I-labeled antibody. For the F(ab′)2 fragments, the relative parathyroid uptake of the two preparations was similar at all times tested. The uptake by the clearance organs was significantly higher when the 111In-labeled molecules were used. Imaging results suggest that 111In-BB5-G1 or 111In-F(ab′)2 may be a useful radiopharmaceutical for parathyroid radioimmunodetection.  相似文献   

15.
Two methods were investigated for the no-carrier-added synthesis of N-succinimidyl 4-[18F]fluorobenzoate (S[18F]FB). The first, an attempted nucleophilic aromatic substitution by [18F]fluoride on N-succinimidyl 4-nitrobenzoate was unsuccessful. The second method involved three steps; [18F]fluoride for trimethylammonium substitution on 4-formyl-N,N,N-trimethylanilinium triflate, oxidation to 4-[18F]fluorobenzoic acid, followed by reaction with N-hydroxysuccinimide and dicyclohexylcarbodiimide to form S[18F]FB. Total synthesis and purification time was 100 min and the overall radiochemical yield was 25% (decay corrected). A monoclonal antibody F(ab′)2 fragment could be labeled in 40–60% yield by reaction with S[18F]FB for 15–20 min. The tissue distribution in normal mice and in vitro tumor binding of the antibody F(ab′)2 labeled by reaction with S[18F]FB were comparable to those observed for the fragment after radioiodination using N-succinimidyl 4-[125I]iodobenzoate.  相似文献   

16.
Small cell lung cancer (SCLC) is an aggressive tumor and prognosis remains poor. Therefore, the development of more effective therapy is needed. We previously reported that high levels of an anti-c-kit antibody (12A8) accumulated in SCLC xenografts. In the present study, we evaluated the efficacy of two antibodies (12A8 and 67A2) for radioimmunotherapy (RIT) of an SCLC mouse model by labeling with the 90Y isotope.

Methods

111In- or 125I-labeled antibodies were evaluated in vitro by cell binding, competitive inhibition and cellular internalization assays in c-kit-expressing SY cells and in vivo by biodistribution in SY-bearing mice. Therapeutic efficacy of 90Y-labeled antibodies was evaluated in SY-bearing mice upto day 28 and histological analysis was conducted at day 7.

Results

[111In]12A8 and [111In]67A2 specifically bound to SY cells with high affinity (8.0 and 1.9 nM, respectively). 67A2 was internalized similar to 12A8. High levels of [111In]12A8 and [111In]67A2 accumulated in tumors, but not in major organs. [111In]67A2 uptake by the tumor was 1.7 times higher than for [111In]12A8. [90Y]12A8, but not [90Y]67A2, suppressed tumor growth in a dose-dependent manner. Tumors treated with 3.7 MBq of [90Y]12A8, and 1.85 and 3.7 MBq of [90Y]67A2 (absorbed doses were 21.0, 18.0 and 35.9 Gy, respectively) almost completely disappeared approximately 2 weeks after injection, and regrowth was not observed except for in one mouse treated with 1.85 MBq [90Y]67A2. The area of necrosis and fibrosis increased depending on the RIT effect. Apoptotic cell numbers increased with increased doses of [90Y]12A8, whereas no dose-dependent increase was observed following [90Y]67A2 treatment. Body weight was temporarily reduced but all mice tolerated the RIT experiments well.

Conclusion

Treatment with [90Y]12A8 and [90Y]67A2 achieved a complete therapeutic response when SY tumors received an absorbed dose greater than 18 Gy and thus are promising RIT agents for metastatic SCLC cells at distant sites.  相似文献   

17.
The effect of para vs meta substitution on the biological behavior of an intact antibody and an F(ab′)2 fragment was investigated. Paired-label studies were performed using 81C6 IgG and OC 125 F(ab′)2 labeled using the N-succinimidyl esters of both p-[125I]- and m-[131I]iodobenzoate as well as with the potential catabolites, p-[125I]- and m-[131I]iodobenzoic acid. In all 3 studies, up to 55% lower uptake of 131I in thyroid and stomach was observed, suggesting that the m-substituted species were more inert to dehalogenation in vivo.  相似文献   

18.
The β emitting isotopes 186Re and 188Re are logical choices on which to base therapeutic radiopharmaceuticals that might be expected to be analogous to diagnostic radiopharmaceuticals based on 99mTc. However, the chemistry of rhenium is sufficiently different from that of technetium so that the development of Re radiopharmaceuticals often cannot be predicated on the known chemistry and biological behavior of 99mTc radiopharmaceuticals. The relevant chemical differences involve the greater stability of the higher oxidation states of Re (and thus the greater tendency of reduced Re radiopharmaceuticals to undergo re-oxidation to perrhenate), and the greater substitution inertness of reduced Re complexes. These differences are illustrated (1) in the preparation and use of 186Re (Sn)-HEDP and 99mTc(Sn)-HEDP diphosphonate radiopharmaceuticals designed, respectively, for palliative therapy and diagnosis of metastatic cancer to bone, and (2) in the preparation and biodistribution of tr-[186Re(DMPE)2Cl2]+ and [186Re(DMPE)3]+, analogs to the potential myocardial perfusion imaging agents tr-[99mTc(DMPE)2Cl2]+ and [99mTc(DMPE)3]+. [HEDP = (1-hydroxyethylidene)diphosphonate; DMPE = 1,2-bis(dimethylphosphino)ethane].  相似文献   

19.
The effects of rabbit anti-HLA-DR and anti-β2-microglobulin (anti-β2m) antibodies on three different Fc-receptor-mediated cell functions of peripheral blood mononuclear leukocytes were studied. Both IgG and F(ab′)2 fragments of anti-HLA-DR antibodies inhibited the cytotoxicity against a monolayer of antibody-sensitized sheep erythrocytes (plaque formation) whereas no effect was observed on the cytotoxicity against antibody-sensitized chicken erythrocytes in suspension (51Cr release), or on EA-rosette formation. On the other hand, all the three functions were inhibited by the IgG fraction of anti-β2m antibodies but not by the corresponding F(ab′)2 fragments. The results demonstrate that the plaque-forming cells (PFC) carry HLA-DR-like antigens. Furthermore, a closer association exists between the HLA-DR-like antigens and the Fc receptors than between the β2m molecules and the Fc receptors on the PFC. The results further support our earlier investigations suggesting that the PFC are of monocytic origin.  相似文献   

20.
A nonagglutinating derivative of wheat germ agglutinin has been prepared that binds to platelets and precipitates an antibody to the lectin. Platelets treated with this inactive derivative released serotonin when exposed to bivalent F(ab′)2, but not monovalent Fab, fragments of the lectin antibody. Bridging of platelet-bound Fab by an antibody again induced secretion. The F(ab′)2 or Fab fragments plus IgG, without the derivative, did not induce secretion. This secretion was not affected by indomethacin showing a direct activation of platelets. Platelets treated with con A followed by F(ab′)2 to con A did not secrete. In addition, lentil lectin failed to release platelet serotonin. The receptors of the lectin derivative are mobile on the platelet surface and their redistribution may lead to secretion.  相似文献   

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