Comparative study of<Superscript>99m</Superscript>TcN (NOEt)<Subscript>2</Subscript> and<Superscript>99m</Superscript>Tc-MIBI imaging in mice bearing Ehrlich ascites tumor

Objective To evaluate and compare the ability to detect tumor by bis (N-ethoxy-N-ethyl dithiocarbamato) nitrido^99mTc(V) [^99mTcN(NOEt)₂] and^99mTc hexakis-2- methoxyisobutyl isonitrile [^99mTc-MIBI]. Methods ^99mTcN(NOEt)₂ was prepared and quality control was performed using ascending thin-layer chromatography. Four mice bearing Ehrich ascites tumor cells underwent whole body planar imaging at 30 min, 2 h and 4 h after injection of^99mTc-MIBI or^99mTcN(NOEt)₂. ROIs were drawn around the tumor, head, chest, and contralateral limbs in whole body planar images, and ratios of radioactivity in tumor in head (T/H), chest (T/C), and contralateral limbs (T/L) were calculated. The mice of^99mTcN (NOEt)₂ group were killed, then blood was collected, and the tumor and organs were excised, weighed and the radioactivity was measured. Results ^99mTcN(NOEt)₂ was stable after 4h at the room temperature.^99mTcN(NOEt)₂ was delivered to the tumor selectively and efficiently.^99mTcN(NOEt)₂ was found to provide excellent tumor-to-nontumor contrast for all the tissue except the abdomen. The T/L ratios increased to their maximums (4.87) at 2 h after injection. There was significant difference between the^99mTcN(NOEt)₂ imaging group and^99mTc-MIBI imaging group. In vitro the radioactivity ratios per unit weight of tumor to blood, muscle, skeleton, lung, heart, and spleen were much higher than those of tumor to liver, instestine. Conclusion In mice bearing Ehrich ascites tumor,^99mTcN(NOEt)₂ exhibits a set of features essential for a good tracer for tumor imaging, including a rapid washout from blood, high uptake rate in tumor tissue, prolonged retention and high tumor-to-nontumor uptake ratio. The imaging quality of^99mTcN(NOEt)₂ was superior to that of^99mTc-MIBI. These features indicate that^99mTcN(NOEt)₂ may be a better tracer to detect tumor than^99mTc-MIBI.     

In vivo99mTc-HYNIC-annexin V imaging of early tumor apoptosis in mice after single dose irradiation

Background

Apoptosis is a major mode of hematological tumor death after radiation. Early detection of apoptosis may be beneficial for cancer adaptive treatment. ^99mTc-HYNIC-annexinV has been reported as a promising agent for in vivo apoptosis imaging. The purpose of this study is to evaluate the feasibility of in vivo^99mTc-HYNIC-annexinV imaging of radiation- induced apoptosis, and to investigate its correlation with radiosensitivity.

Methods

Ten days after inoculation of tumor cells in the right upper limbs, the mice were randomly divided into two groups. The imaging group (4 mice each level, 4 dose levels) was injected with 4-8 MBq ^99mTc-HYNIC-annexinV 24 hours after irradiation and imaged 1 hr post-injection, and the mice were sacrificed immediately after imaging for biodistribution analysis of annexin V. The observation group (4 mice each level, 2 dose levels) was only observed for tumor regression post-radiation. The number of apoptotic cells in a tumor was estimated with TUNEL assay.

Results

The ^99mTc-HYNIC-annexin V uptake in E14 lymphoma significantly increased as the radiation dose escalated from 0 to 8 Gy, and significantly correlated with the number of TUNEL-positive cells (r = 0.892, P < 0.001). The Annexin-V uptake and the number of TUNEL-positive cells in El4 lymphoma were significantly greater than those in S180 sarcoma. With 8 Gy, S180 sarcoma tumor showed scanty apoptosis and less shrinkage while El4 lymphoma showed remarkable apoptosis and complete remission.

Conclusion

⁹⁹mTc-HYNIC-annexinV in vivo imaging is a feasible method to detect early radiation-induced apoptosis in different tumors, and might be predictive for radiation sensitivity.     

Determination of tumor-related factors of influence on the uptake of the monoclonal antibody 323/A3 in experimental human ovarian cancer

The epithelial glycoprotein 40 (EGP40) is an important target in the clinic for radioimmunolocalization and monoclonal antibody (MAb)-mediated therapy of cancer. We determined which tumor-related factors (including antigen distribution and density, vascularization and perfusion) were involved in the uptake of the anti-EGP40 MAb 323/A3 in 4 different human ovarian cancer xenografts grown s.c. in nude mice. The reactivity pattern of 323/A3 in all xenografts in vitro was similar and showed a strong and homogeneous distribution of the EGP40 antigen. FMa xenografts, however, showed the highest uptake of 323/A3 in vivo, which was 5.5-, 6.2- and 10.0-fold higher than that in OVCAR-3, Ov.Pe and Ov.Sh xenografts, respectively. FMa xenografts contained 2.1- to 3.5-fold more antigen per gram protein when compared with the antigen content of the other xenografts. FMa and Ov.Sh xenografts demonstrated a better vascularization pattern, whereas Ov.Pe and OVCAR-3 xenografts were moderately to poorly vascularized. FMa xenografts were also better perfused, as was shown by a 1.6- to 1.8-fold higher uptake of the ^99mTc-labeled blood flow marker hexamethylpropyleneamine oxime (HMPAO). The tumor uptake of the non-specific MAb E48 was 2.2- to 11.2-fold lower when compared with that of 323/A3, but the sequence of uptake was similar (FMa > OVCAR-3 = Ov.Pe > Ov.Sh), indicating the lowest extravasation of MAbs in Ov.Sh xenograft tissue. Since both the antigen content and the perfusion appeared to be important factors of influence on the tumor uptake of 323/A3, attempts were made to manipulate these determinants to improve the tumor uptake. Neither γ-interferon nor 5-fluorouracil were able to increase EGP40 expression in human ovarian cancer cells in vitro. Treatment of tumor-bearing mice with the calcium-antagonist flunarizine did not result in an improved perfusion, although a slight increase in the initial tumor uptake of 323/A3 was observed in Ov.Sh-bearing mice. Our results illustrate the relative contribution of various tumorrelated factors that determine the usefulness of a MAb for imaging and therapy of cancer. Int. J. Cancer 71:237–245, 1997. © 1997 Wiley-Liss, Inc.     

Imaging integrin αvβ3 positive glioma with a novel RGD dimer probe and the impact of antiangiogenic agent (Endostar) on its tumor uptake

Integrin α_vβ₃ has been recognized to play an important role in angiogenesis, tumor growth and metastasis. It will be of interest to apply this promising target for tumor imaging and visualization of tumor angiogenesis in vivo. In this study, a novel integrin α_vβ₃ targetting imaging probe, ^99mTc-HYNIC-E[c(RGDfK)]₂, was used to investigate the glioma uptake in vitro and in vivo before and after treatment with an antiangiogenic agent, endostar. The results indicated that U87MG glioma cells have high expression of integrin α_vβ₃ and special uptake of ^99mTc-HYNIC-E[c(RGDfK)]₂ both in cell line and in tumor xenograft. The endostatin analogue endostar can inhibit the expression of integrin α_vβ₃ receptors in both U87MG cells in vitro and glioma tissues, which suggested that integrin pathway may play a role in antiangiogenic effect of Endostar. ^99mTc-HYNIC-E[c(RGDfK)]₂ may be a promising molecular imaging probe for integrin α_vβ₃ positive tumor imaging and open up the possibility to establish an molecular imaging modality for assessment of tomor antiangiogenic therapy.     

Studies on the Distribution and Radioimmunoimaging of 99m↑Tc-Labeled 5-Fluorouracil Loaded Immunological Nanoparticles in Tissues and Human Gastric Carcinoma Xenografts

Objective To explore the method of preparation of ^99mTc labeled Anti-VEGF McAb 5-FU loaded polylactic acid nanoparticles (^99mTc-5-Fu-Ab-NPs), and investigate the biological distribution of the nanoparticles in human gastric carcinoma xenografts. Methods Anti-VEGF monoclonal antibodyes (MCAB) in 5-FU-Ab-NPs were labeled with ^99mTc using a modified Schwarz method. After isolation of the ^99mTc-5-FU-Ab-NPs using a Sephadex G-250 column, the labeling percentage and radiochemical purity were determined using paper chromatography. The immunocompetence of the ^99mTc-5-FU-Ab-NPs as tumor markers was determined using ELISA and immunohistochemistry. ^99mTc-5-FU-Ab-NPs (experimental group), ^99mTc-labelled murine multiclonal IgG loaded polylactic acid and nanoparticles (control group) were injected via the tail vein into SCID mice bearing human gastric carcinoma. A radio-immunity ECT image was developed at 2 and 6 h after the injection. Following the ECT imaging, the mice were sacrificed, their tissue and tumor radioactivity distribution determined, and percentage of the injected-dose per gram (%ID/g) and tumor/nontumor (T/NT) ratio calculated. High performance liquid chromatography (HPLC) was used to determine the 5-FU concentration in the tumor tissue and blood in the mice of both groups. Results The percentage of ^99mTc-5-FU-Ab-NPs labeling was 90%∼95%. There was no obvious decrease in the antibody activity before and after labeling. The radio-immuno-imaging (RII) showed that the tumor image had developed 2 h after injection of the ^99mTc-5-FU-Ab-NPs, and with time it was clearer at the 6th hour following the injection. The %ID/g of the tumor tissue at both 2 h and 6 h after the injection was significantly higher compared to the control group. The tumor %ID/g and the tumor to blood activity ratio (TB) of the experimental group at 6 h following the injection increased compared to that at 2 h, and at the same time, 5-FU concentration in the tumor of the experimental group continuously increased over time, and showed a significant difference compared to the 5-FU concentration in the tumor of the control group. Conclusion The ^99mTc-5-FU-Ab-NPs prepared in this study are adequate to meet the demands of the RII, and the immune targeting ability of the anti-VEGF MCAB is reliable. Six hours after injection, the ^99mTc-5-FU-Ab-NPs showed a relatively high specific concentration shadow in the human gastric carcinoma xenografts. This work was supported by the grants as follows: The Problems-Tackling Program in Science and Technology of Guangzhou City, China (No.2003 Z 3-E0381); National Foundation of Natural Science, China (No.30670951); Guangdong Foundation of Natural Science, Guangdong, China (No.06021322); The Problems-Tackling Program in Science and Technology of Guangdong Province, China (No.2005 B31211002).     

STUDIES OF ~(99m)Tc LABELLED MONOCLONAL ANTIBODY 3H11

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Evaluation of a HER2-targeting affibody molecule combining an N-terminal HEHEHE-tag with a GGGC chelator for <Superscript>99m</Superscript>Tc-labelling at the C terminus

Affibody molecules are a class of small (ca.7 kDa) robust scaffold proteins with high potential as tracers for radionuclide molecular imaging in vivo. Incorporation of a cysteine-containing peptide-based chelator at the C terminus provides an opportunity for stable labelling with the radionuclide ^99mTc. The use of a GGGC chelator at the C terminus has provided the lowest renal radioactivity retention of the previously investigated peptide-based chelators. Previously, it has also been demonstrated that replacement of the His₆-tag with the negatively charged histidine-glutamate-histidine-glutamate-histidine-glutamate (HEHEHE)-tag permits purification of affibody molecules by immobilized metal ion affinity chromatography (IMAC) and provides low hepatic accumulation of radioactivity of conjugates site-specifically labelled at the C terminus using several different nuclides. We hypothesized that the combination of a HEHEHE-tag at the N terminus and a GGGC chelator at the C terminus of an affibody molecule would be a favourable format permitting IMAC purification and providing low uptake in excretory organs. To investigate this hypothesis, a (HE)₃-Z_HER2:342-GGGC affibody molecule was generated. It could be efficiently purified by IMAC and stably labelled with ^99mTc. ^99mTc-(HE)₃-Z_HER2:342-GGGC preserved specific binding to HER2-expressing cells. In NMRI mice, hepatic uptake of ^99mTc-(HE)₃-Z_HER2:342-GGGC was lower than the uptake of the control affibody molecules, ^99mTc-Z_HER2:2395-VDC and ^99mTc-Z_HER2:342-GGGC. At 1 and 4 h after injection, the renal uptake of ^99mTc-(HE)₃-Z_HER2:342-GGGC was 2–3-fold lower than uptake of ^99mTc-Z_HER2:2395-VDC, but it was substantially higher than uptake of ^99mTc-Z_HER2:342-GGGC. Further investigation indicated that a fraction of ^99mTc was chelated by the HEHEHE-tag which caused a higher accumulation of radioactivity in the kidneys. Thus, a combination of a HEHEHE-tag and the GGGC chelator in targeting scaffold proteins was found to be undesirable in the case of ^99mTc labelling due to a partial loss of site-specificity of nuclide chelation.     

Randomized Comparison of Intra-arterial Versus Intravenous Infusion of ACNU for Newly Diagnosed Patients with Glioblastoma

The purpose of the present study was to assess the ability of technetium-99m-tetrofosmin (^99mTc-TF) to predict tumor malignancy and to compare its uptake with that of thallium-201 (²⁰¹Tl), technetium-99m-hexakis-2-methoxyisobutyl isonitrile (^99mTc-MIBI) and fluorine-18-fluorodeoxyglucose (¹⁸F-FDG) in brain tumors. ^99mTc-TF single-photon emission computed tomography (SPECT) imaging was performed in 22 patients with brain tumors and 3 healthy controls. Some of the patients underwent ²⁰¹Tl (n = 12) and ^99mTc-MIBI SPECT (n = 14) and ¹⁸F-FDG positron emission tomography (PET) (n = 12). The radioactivity ratio of tumor to contralateral normal tissue (T/N) and the ratio of tumor to contralateral white matter (T/WM) were calculated in SPECT and PET images, respectively. In healthy controls, ^99mTc-TF uptake was seen only in scalp, in the choroid plexus and pituitary gland, but not in normal cerebral parenchyma. TF T/N in low grade gliomas (2.8 ± 0.4) was significantly lower than that in high grade gliomas (22.5 ± 29.8) and malignant non-gliomas (8.3 ± 2.8) without overlap of values (p = 0.003 and p = 0.014, respectively). TF T/N was significantly correlated with MIBI T/N ( = 0.92, p = 0.001), Tl T/N ( = 0.72, p = 0.017), and FDG T/WM ( = 0.65, p = 0.031). There was an excellent agreement between TF T/N and MIBI T/N values on linear regression analysis (MIBI T/N = –0.63 + 0.97 × TF T/N). These preliminary results indicate that SPECT imaging with ^99mTc-TF may be useful for the non-invasive grading of brain tumors. They also suggest that ^99mTc-TF and ^99mTc-MIBI may accumulate in brain tumors by a similar mechanism or in relation to a similar process of tumor cell proliferation.     

A CLINICAL STUDY FOR EVALUATING EARLY RADIOTHERAPY EFFECT IN PATIENTS WITH BRAIN TUMOR USING ^99Tc^m-HL91 SPECT

Radiotherapy is one of the main methods in brain tumor therapy. Early and accurate evaluation to the curative effect can not only help therapeutist to institute impersonal radiotherapy program, but also reduce injury and expense owing to excess radiotherapy. Therefore, it is important to assess the effect of such therapy as soonas possible. We used 99Tcm-HL91 (a new generation agent for imaging hypoxia tissue) SPECT imaging to evaluate the early effect of radiotherapy in patients with brain…     

Sodium/iodide symporter gene transfection increases radionuclide uptake in human cisplatin-resistant lung cancer cells

The sodium/iodide symporter (NIS) is involved in iodide uptake and has been used for the diagnosis and treatment of thyroid cancer. Transfection of the NIS gene in A549 human lung cancer cells can induce radioactive iodine (¹³¹I) and radioactive technetium (^99mTc) uptake. The aim of the present study was to assess the role of NIS in ^99mTc and ¹³¹I uptake by the A549/DDP human cisplatin-resistant lung cancer cell line. To do so, recombinant adenovirus, adenovirus-enhanced green fluorescent protein-human NIS (Ad-eGFP-hNIS) and Ad-eGFP-rat NIS (Ad-eGFP-rNIS) vectors were established. These vectors were transfected into A549/DDP cells and xenograft tumors in nude mice. Assessment of ^99mTc and ¹³¹I uptake was performed. Results showed that the transfection efficiency of Ad-eGFP-hNIS and Ad-eGFP-rNIS in A549/DDP cells was at least 90 % in all experiments, and that the uptake ability of ^99mTc and ¹³¹I was highly enhanced (14–18 folds for ^99mTc, and 12–16 folds for ¹³¹I). However, the radionuclide concentration in transfected NIS genes’ A549/DDP cells reached a plateau within 30–60 min, indicating that NIS transport led rapidly to ^99mTc and ¹³¹I saturation in cells. In xenograft tumor models, uptake of ^99mTcO₄ ^? was obviously higher in the hNIS and rNIS groups compared with controls. In conclusion, these results support the hypothesis that A549/DDP cells can effectively uptake ^99mTc and ¹³¹I when transfected with the hNIS and rNIS gene. The rNIS or hNIS gene could be used as an effective method for the effective delivery of radioactive products to specific tissues for imagery and/or treatment.     

Pentavalent technetium-99m dimercaptosuccinic acid [<Superscript>99m</Superscript>Tc-(V)DMSA] brain scintitomography—a plausible non-invasive depicter of glioblastoma proliferation and therapy response

The biological behavior and prognosis of gliomas depend largely on cellular proliferation, resistance to chemotherapy, and metastatic potential. Proliferative propensity has significant implications on patient management but its assessment requires tissue sampling; the non-invasive estimation of brain tumor proliferation represents therefore a major goal. Pentavalent technetium-99 m dimercapto-succinic acid [^99mTc-(V)DMSA] is a tumor-seeking radiotracer displaying affinity for gliomas; its intracellular accumulation is directly linked to cell proliferation. We performed a tomographic ^99mTc-(V)DMSA brain scan in a 35-year-old male baring a recurrent glioblastoma multiforme, to depict its proliferative disposition. The patient had been diagnosed 14 months earlier and had been submitted to surgery, followed by adjuvant radiotherapy and temozolomide-based chemotherapy. On clinical suspicion of recurrence 5 months later, magnetic resonance imaging (MRI) revealed a lesion at the site of preceded surgery, which was treated by imatinib mesylate. No improvement was ascertained the following months and radiographic assessment verified tumor progression. Scintitomography revealed avid radiotracer uptake in the entirety of the lesion (the distribution of radioactivity closely conforming to the morphological tumor boundaries), an indication that the neoplasm demonstrated no substantial proliferation decline in response to imatinib. The patient deceased a few weeks later. Mounting in vivo and in vitro evidence indicates that ^99mTc-(V)DMSA is a credible non-invasive proliferation depicter, its cellular accumulation linked closely to phosphate uptake and kinase pathway activation. A potential role in patient management, prognosis estimation, and therapy response monitoring could occur for this tracer.     

The role of technetium‐99m methoxyisobutyl isonitrile scintigraphy in predicting the therapeutic effect of chemotherapy against nasopharyngeal carcinoma

BACKGROUND:

The authors prospectively evaluated the correlation between technetium‐99m methoxyisobutyl isonitrile (^99mTc‐MIBI) accumulation in tumors and response to induction chemotherapy in patients with nasopharyngeal carcinoma (NPC).

METHODS:

Eighty‐six patients with locally advanced NPC underwent single‐photon emission computed tomography 15 minutes after an intravenous injection of 740 megabecquerels (20 mCi) ^99mTc‐MIBI before chemotherapy. The tumor uptake ratio (TUR) was calculated. Two weeks after the second cycle of combined chemotherapy with 5‐fluorouracil (5‐FU) and cisplatin (DDP), the tumor response rate was evaluated. The correlation between ^99mTc‐MIBI accumulation in tumors and response to chemotherapy with 5‐FU/DDP was examined.

RESULTS:

Positive accumulation of ^99mTc‐MIBI in tumors was observed in 76 patients (88.4%). The tumor response was a complete response (CR) in 8 patients, a partial response (PR) in 68 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. The response rate (CR and PR) to 5‐FU/DDP chemotherapy in patients who had positive ^99mTc‐MIBI accumulation (tumor uptake ratio [TUR] >1.1) was higher than that in patients who had negative ^99mTc‐MIBI accumulation (TUR ≤1.1; 98.7% vs 10%; P < .001).

CONCLUSIONS:

Patients with negative ^99mTc‐MIBI accumulation were resistant to 5‐FU/DDP chemotherapy. ^99mTc‐MIBI imaging in patients with NPC was capable of predicting tumor response to chemotherapy with 5‐FU/DDP and can help in the selection of patients for induction chemotherapy. Cancer 2011. © 2010 American Cancer Society.     

Characterization of the Attenuation of Breast Cancer Bone Metastasis in Mice by Zoledronic Acid Using 99mTc bone Scintigraphy

Metastatic breast cancer often metastasizes to bone. The purposes of the study were (1) to evaluate the use of ^99mTc-MDP bone scintigraphy for detection of metastatic bone lesions, and (2) to determine the efficacy of zoledronic acid in mice with breast cancer bone metastasis. All tumor-bearing mice were analyzed with radionuclide bone scintigraphy, X-ray, and histological analysis. The metastatic bone tissue was also harvested and analyzed by western blotting and real-time qPCR. Interestingly, zoledronic acid significantly decreased both the tumor burden and the incidence of bone metastasis in mice. In addition, histomorphometric, stereological, and molecular biology analyses demonstrated that zoledronic acid may function to inhibit breast cancer cell growth in the bone microenvironment and regulate the function of osteoblasts and osteoclasts in tumor-bearing mice. Finally, the attenuation of breast cancer bone metastasis using zoledronic acid can be accurately characterized by ^99mTc bone scintigraphy in mice.     

The influence of tumor oxygenation on <Superscript>18</Superscript>F-FDG (Fluorine-18 Deoxyglucose) uptake: A mouse study using positron emission tomography (PET)

Background

This study investigated whether changing a tumor's oxygenation would alter tumor metabolism, and thus uptake of ¹⁸F-FDG (fluorine-18 deoxyglucose), a marker for glucose metabolism using positron emission tomography (PET).

Results

Tumor-bearing mice (squamous cell carcinoma) maintained at 37°C were studied while breathing either normal air or carbogen (95% O₂, 5% CO₂), known to significantly oxygenate tumors. Tumor activity was measured within an automatically determined volume of interest (VOI). Activity was corrected for the arterial input function as estimated from image and blood-derived data. Tumor FDG uptake was initially evaluated for tumor-bearing animals breathing only air (2 animals) or only carbogen (2 animals). Subsequently, 5 animals were studied using two sequential ¹⁸F-FDG injections administered to the same tumor-bearing mouse, 60 min apart; the first injection on one gas (air or carbogen) and the second on the other gas. When examining the entire tumor VOI, there was no significant difference of ¹⁸F-FDG uptake between mice breathing either air or carbogen (i.e. air/carbogen ratio near unity). However, when only the highest ¹⁸F-FDG uptake regions of the tumor were considered (small VOIs), there was a modest (21%), but significant increase in the air/carbogen ratio suggesting that in these potentially most hypoxic regions of the tumor, ¹⁸F-FDG uptake and hence glucose metabolism, may be reduced by increasing tumor oxygenation.

Conclusion

Tumor ¹⁸F-FDG uptake may be reduced by increases in tumor oxygenation and thus may provide a means to further enhance ¹⁸F-FDG functional imaging.

     

Localization of human breast tumors grafted in nude mice with a monoclonal antibody directed against a defined cell surface antigen of human mammary epithelial cells

Summary A mouse monoclonal antibody (BLMRL-HMFG-Mc5) prepared against a defined cell surface antigen of human mammary epithelial cells, non-penetrating glycoprotein (NPGP), was used in imaging and distribution studies in athymic nude mice grafted with human breast tumors. Forin vivo tissue distribution studies,¹²⁵I-labeled monoclonal antibody was injected into nude mice carrying simulated metastases of human tumors (breast and colon carcinomas). After 22–24 hr the amount of radioactivity per gram of tissue was 3–4 times higher in the breast tumor than in liver, brain, lung, muscle, or spleen. In contrast, colon carcinoma tissue, grafted and treated likewise, did not show higher accumulation of radioactivity relative to other tissues. At 4 days, the incorporation in breast tumors remained almost as high, while the circulating radioactive tracer and the incorporation in tissues other than breast had fallen significantly.In tumor imaging studies, breast tumor masses as small as 4 mm in diameter were clearly localized on a whole body scan using¹³¹I-labeled BLMRL-HMFG-Mc5 antibodies with a High-Purity germanium gamma camera. Normalization of¹³¹I-distribution to that of^99mTc-pertechnetate increased the specificity of this imaging methodology. The quantitative density of¹³¹I-label was 2–3 fold higher over the breast tumor than over comparable areas of the mouse. No positive localization images were obtained for similar implants of colon and lung carcinomas or melanomas after injections of¹³¹I-labeled BLMRL-HMFG-Mc5. Localization of human breast tumors in this model can be achieved with¹³¹I-labeled anti-breast epithelial monoclonal antibodies.Abbreviations NPGP non-penetrating glycoprotein - CEA carcinoembryonic antigen     

头颈部肿瘤99mTc-MIBI阳性显像的临床研究

Objective： To investigate the diagnostic potential value of ^99Tc-MIBI imaging in head and neck tumors. Methods： Ninety-one patients with malignant and benign head and neck lesions were subjected to ^99mTc-MIBI tomography, and 20 healthy volunteers served as control group. Results： The overall sensitivity,specificity, accuracy and positive predictive accuracy of early/delay ^99mTc-MIBI imaging in diagnosis of head and neck malignant tumors were 78.7%/72.3%, 72.1%/88.4%, 75.6%/80.0% and 75.5%/87.2% respectively. The results of ^99mTc-MIBI Imaging in diagnosis of nasopharyngeal cancer and sinonasal non-Hodgkin＇s lymphoma were more satisfactory than those in maxillary sinus cancer. In distinguishing recurrent/residual nasopharyngeal carcinoma and sinonasal non-Hodgkin＇s lymphoma, ^99mTc-MIBI scintigraphy was superior to CT/MRI. Conclusion： ^99mTc-MIBI imaging is a promising useful tool in identifying head and neck tumor, and it has a special value to evaluate the local invasion and metastasis involved.     

Post-lumpectomy intracavitary retention and lymph node targeting of <Superscript>99m</Superscript>Tc-encapsulated liposomes in nude rats with breast cancer xenograft

Liposomes are recognized drug delivery systems with tumor-targeting capability. In addition, therapeutic or diagnostic radionuclides can be efficiently loaded into liposomes. This study investigated the feasibility of utilizing radiotherapeutic liposomes as a new post-lumpectomy radiotherapy for early-stage breast cancer by determining the locoregional retention and systemic distribution of liposomes radiolabeled with technetium-99m (^99mTc) in an orthotopic MDA-MB-231 breast cancer xenograft nude rat model. To test this new brachytherapy approach, a positive surgical margin lumpectomy model was set up by surgically removing the xenograft and deliberately leaving a small tumor remnant in the surgical cavity. Neutral, anionic, and cationic surface-charged fluorescent liposomes of 100 and 400 nm diameter were manufactured and labeled with ^99mTc-BMEDA. Locoregional retention and systemic distribution of ^99mTc-liposomes injected into the post-lumpectomy cavity were determined using non-invasive nuclear imaging, ex vivo tissue gamma counting and fluorescent stereomicroscopic imaging. The results indicated that ^99mTc-liposomes were effectively retained in the surgical cavity (average retention was 55.7 ± 24.2% of injected dose for all rats at 44 h post-injection) and also accumulated in the tumor remnant (66.9 ± 100.4%/g for all rats). The majority of cleared ^99mTc was metabolized quickly and excreted into feces and urine, exerting low radiation burden on vital organs. In certain animals ^99mTc-liposomes significantly accumulated in the peripheral lymph nodes, especially 100 nm liposomes with anionic surface charge. The results suggest that post-lumpectomy intracavitary administration of therapeutic radionuclides delivered by 100-nm anionic liposome carrier is a potential therapy for the simultaneous treatment of the surgical cavity and the draining lymph nodes of early-stage breast cancer.     

Miniaturized antibodies for imaging membrane type‐1 matrix metalloproteinase in cancers

Since membrane type‐1 matrix metalloproteinase (MT1‐MMP) plays pivotal roles in tumor progression and metastasis and holds great promise as an early biomarker for malignant tumors, a method of evaluating MT1‐MMP expression levels would be valuable for molecular biological and clinical studies. Although we have previously developed a ^99mTc‐labeled anti‐MT1‐MMP monoclonal IgG (^99mTc‐MT1‐mAb) as an MT1‐MMP imaging probe by nuclear medical techniques for this purpose, slow pharmacokinetics were a problem due to its large molecular size. Thus, in this study, our aim was to develop miniaturized antibodies, a single chain antibody fragment (MT1‐scFv) and a dimer of two molecules of scFv (MT1‐diabody), as the basic structures of MT1‐MMP imaging probes followed by in vitro and in vivo evaluation with an ¹¹¹In radiolabel. Phage display screening successfully provided MT1‐scFv and MT1‐diabody, which had sufficiently high affinity for MT1‐MMP (K_D = 29.8 and 17.1 nM). Both ¹¹¹In labeled miniaturized antibodies showed higher uptake in MT1‐MMP expressing HT1080 cells than in non‐expressing MCF7 cells. An in vivo biodistribution study showed rapid pharmacokinetics for both probes, which exhibited >20‐fold higher tumor to blood radioactivity ratios (T/B ratio), an index for in vivo imaging, than ^99mTc‐MT1‐mAb 6 h post‐administration, and significantly higher tumor accumulation in HT1080 than MCF7 cells. SPECT images showed heterogeneous distribution and ex vivo autoradiographic analysis revealed that the radioactivity distribution profiles in tumors corresponded to MT1‐MMP‐positive areas. These findings suggest that the newly developed miniaturized antibodies are promising probes for detection of MT1‐MMP in cancer cells.     

Methotrexate (MTX) concentration in tumors following low-dose MTX

Summary Methotrexate (MTX) is a folate analog competitive with reduced folates for cellular transport and metabolism. Since the normal plasma folate concentration is only 10^-8 M, we tested the possibility that there may be a saturable uptake of MTX by proliferating tumor tissue at plasma MTX concentrations of only 10^-7 to 10^-6 M. Patients with advanced malignancies, refractory to accepted therapy, were given low-dose oral MTX (30–60 mg/m² total dose in four to eight divided doses). Tumor tissue was biopsied 18–24 h after the last oral dose of MTX. The concentrations of MTX and its polyglutamated derivatives were measured in these samples. Forty-eight percent of the drug in the tumor samples was present as a polyglutamated derivative.Partially supported by American Cancer Society grant ACS CH-228 (BAK) and American Society of Clinical Oncology grant (NJW) BAK is a Scholar of the Leukemia Society of America     

Role of 99mTc‐glucoheptonic acid brain single photon emission computed tomography in differentiation of recurrent brain tumour and post‐radiation gliosis

Blood?brain barrier imaging of brain tumours is fast attracting interest now that it has been demonstrated that disruption of the blood?brain barrier is essential for uptake of all tumour‐seeking agents. The aim of the present study was to differentiate recurrent tumour from post‐radiation gliosis using ^99mtechnetium‐glucoheptonate (^99mTc‐GHA) as a tumour‐seeking agent. Brain single photon emission computed tomography (SPECT) with ^99mTc‐GHA was performed in 73 patients with primary malignant brain tumours after radiotherapy, and the results were correlated with the clinical behaviour of the disease on follow up. The SPECT was suggestive of recurrent tumour in 55 patients. The clinical course was consistent with recurrence in 51 of the 55 patients. The clinical course was consistent with radiation necrosis in the remaining 21 patients, which included 17 patients with a negative SPECT and four patients with a positive SPECT study. Mean GHA index in recurrent tumour and post‐radiation gliosis was 7.04 ± 4.35 and 1.88 ± 1.70, respectively (P = 0.0001). Mean GHA index in high‐grade and low‐grade glioma was 7.78 ± 4.73 and 3.15 ± 2.44, respectively (P = 0.001). ^99mTechnetium‐glucoheptonate brain SPECT is a sensitive and reliable diagnostic modality to differentiate recurrent tumour from post‐radiation gliosis.