In vivo monitoring of intranuclear p27 protein expression in breast cancer cells during trastuzumab (Herceptin) therapy

IntroductionTrastuzumab, a humanized antibody directed against the Her2 receptor, induces the expression of p27^kip1, an intranuclear cyclin-dependent kinase inhibitor in some breast cancer cells. The aim of this study was to develop a radioimmunoconjugate (RIC) to monitor trastuzumab-induced p27^kip1 protein up-regulation in vivo.Materials and MethodsAnti-p27^kip1 IgG was purified, and conjugated to diethylenetriaminopentaacetate, to allow radiolabeling with ¹¹¹In for in vivo detection. Then tat peptide (GRKKRRQRRRPPQGYG), containing a nuclear localization sequence (underlined), was conjugated to the Fc-domain of IgG, using NaIO₄ oxidation of carbohydrates and the resulting Schiff base stabilized with NaCNBH₃. The conjugate was radiolabeled with ¹¹¹In, yielding [¹¹¹In]-anti-p27^kip1-tat. ¹¹¹In labeling efficiency, purity and p27^kip1 binding were measured. Trastuzumab-induced p27^kip1 up-regulation was assessed in a panel of breast cancer cell lines by Western blot analysis. Uptake and retention of [¹¹¹In]-anti-p27^kip1-tat were measured in MDA-MB-361 and SKBr3 cells after exposure to trastuzumab. Uptake of [¹¹¹In]-anti-p27^kip1-tat was determined at 72 h postintravenous injection in MDA-MB-361 xenografts in athymic mice treated with trastuzumab or saline.Results[¹¹¹In]-anti-p27^kip1-tat was synthesized to 97% purity. The RIC was able to bind to p27^kip1 protein and internalized in the cells and was transported to the nuclei of MDA-MB-361 cells. The level of p27^kip1 protein in MDA-MB-361 cells was increased after exposure to clinically relevant doses of trastuzumab for 3 days. Trastuzumab-mediated induction of p27^kip1 was not associated with increased cellular uptake or nuclear localization of [¹¹¹In]-anti-p27^kip1-tat (6.53±0.61% vs. 6.98±1.36% internalized into trastuzumab-treated vs. control cells, respectively). However, retention of [¹¹¹In]-anti-p27^kip1-tat at 72 h was increased approximately twofold (13.5±1.3% vs. 6.6±0.6% of internalized [¹¹¹In]-anti-p27^kip1-tat was retained in trastuzumab-treated vs. control cells, respectively; P=.016). Immunohistochemistry showed up-regulation of p27^kip1 in trastuzumab-treated xenografts. Tumour uptake of [¹¹¹In]-anti-p27^kip1-tat was significantly higher in trastuzumab-treated compared to control animals (6.5±0.9 vs. 4.8±0.1 %ID/g at 72 h postinjection, respectively; P=.0065).Conclusion[¹¹¹In]-Anti-p27^kip1-tat may be useful for monitoring changes in the expression of the intranuclear protein, p27^kip1. Up-regulation of p27^kip1 resulted in increased retention of [¹¹¹In]-anti-p27^kip1-tat in cells treated with trastuzumab. Modest, but statistically significantly higher, retention was also observed in tumours in mice treated with trastuzumab. Since responsiveness to trastuzumab correlated to up-regulation of p27^kip1, it may be possible to use [¹¹¹In]-anti-p27^kip1-tat to guide treatment with Herceptin and other drugs which alter p27^kip1 expression.     

HER2-positive breast cancer: 18F-FDG PET for early prediction of response to trastuzumab plus taxane-based neoadjuvant chemotherapy

Purpose

To investigate the value of ¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET/CT) to predict a pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in women with human epidermal growth factor receptor 2 (HER2)-positive breast cancer.

Material and methods

Fifty-seven consecutive women with HER2-positive breast cancer, treated with trastuzumab plus taxane-based NAC, were prospectively included. Maximum Standardized Uptake Value of the primary tumor and axillary nodes were measured at baseline (PET₁.SUV_max) and after the first course of NAC (PET₂.SUV_max). Tumor metabolic volumes were assessed to determine Total Lesion Glycolysis (TLG). The tumor metabolic response (ΔSUV_max and ΔTLG) was calculated.

Results

In univariate analysis, negative hormonal receptor status (p?=?0.04), high tumor grade (p?=?0.03), and low tumor PET ₂ .SUV_max (p?=?0.001) were predictive of pCR. Tumor ΔSUV_max correlated with pCR (p?=?0.03), provided that tumors with low metabolic activity at baseline were excluded. ΔTLG did not correlate with pCR. In multivariate analysis, tumor PET₂.SUV_max?<?2.1 was the best independent predictive factor (Odds ratio =14.3; p?=?0.004) with both negative and positive predictive values of 76 %. Although the metabolic features of the primary tumor did not depend on hormonal receptor status, both the baseline metabolism and early response of axillary nodes were higher if estrogen receptors were not expressed (p?=?0.01 and p?=?0.03, respectively).

Conclusion

In HER2-positive breast cancer, very low tumor residual metabolism after the first cycle of NAC (SUV_max?<?2.1) was the main predictor of pCR. These results should be further explored in multicenter studies and incorporated into the design of clinical trials.     

(111)In-labeled trastuzumab (Herceptin) modified with nuclear localization sequences (NLS): an Auger electron-emitting radiotherapeutic agent for HER2/neu-amplified breast cancer.

The cytotoxicity and tumor-targeting properties of the anti-HER2/neu monoclonal antibody trastuzumab modified with peptides (CGYGPKKKRKVGG) harboring the nuclear localization sequence ([NLS] italicized) of simian virus 40 large T-antigen and radiolabeled with (111)In were evaluated. METHODS: Trastuzumab was derivatized with sulfosuccinimidyl-4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC) for reaction with NLS-peptides and labeled with (111)In using diethylenetriaminepentaacetic acid (DTPA). The immunoreactivity of (111)In-NLS-trastuzumab was determined by its ability to displace the binding of trastuzumab to SK-BR-3 human breast cancer (BC) cells. Cellular uptake and nuclear localization were evaluated in SK-BR-3, MDA-MB-361, and MDA-MB-231 BC cells, expressing high, intermediate, or very low levels of HER2/neu, respectively, by cell fractionation and confocal microscopy. Biodistribution and nuclear uptake were compared in athymic mice bearing MDA-MB-361 xenografts. The cytotoxicity of (111)In-trastuzumab and (111)In-NLS-trastuzumab was studied by clonogenic assays, and DNA damage was assessed by probing for phosphorylated histone H2AX (gammaH2AX) foci. RESULTS: The dissociation constant for binding of (111)In-NLS-trastuzumab to SK-BR-3 cells was reduced <3-fold compared with that of (111)In-trastuzumab, demonstrating relatively preserved receptor-binding affinity. The receptor-mediated internalization of (111)In-trastuzumab in SK-BR-3, MDA-MB-361, and MDA-MB-231 cells increased significantly from 7.2% +/- 0.9%, 1.3% +/- 0.1%, and 0.2% +/- 0.05% to 14.4% +/- 1.8%, 6.3% +/- 0.2%, and 0.9% +/- 0.2% for (111)In-NLS-trastuzumab harboring 6 NLS-peptides, respectively. NLS-trastuzumab localized in the nuclei of BC cells, whereas unmodified trastuzumab remained surface-bound. Conjugation of (111)In-trastuzumab to NLS-peptides did not affect its tissue biodistribution but promoted specific nuclear uptake in MDA-MB-361 xenografts (2.4-2.9 %ID/g [percentage injected dose per gram] for (111)In-NLS-trastuzumab and 1.1 %ID/g for (111)In-trastuzumab). (111)In-NLS-trastuzumab was 5- and 2-fold more potent at killing SK-BR-3 and MDA-MB-361 cells than (111)In-trastuzumab, respectively, whereas toxicity toward MDA-MB-231 cells was minimal. (111)In-NLS-trastuzumab was 6-fold more effective at killing SK-BR-3 cells than unlabeled trastuzumab. Formation of gammaH2AX foci occurred in a greater proportion of BC cells after incubation with (111)In-NLS-trastuzumab compared with (111)In-trastuzumab or unlabeled trastuzumab. CONCLUSION: NLS-peptides routed (111)In-trastuzumab to the nucleus of HER2/neu-positive human BC cells, rendering the radiopharmaceutical lethal to the cells through the emission of nanometer-micrometer range Auger electrons. The greater cytotoxic potency of (111)In-NLS-trastuzumab compared with unlabeled trastuzumab in vitro and its favorable tumor-targeting properties in vivo suggest that it could be an effective targeted radiotherapeutic agent for HER2/neu-amplified BC in humans.     

Radiolabelling of poly(histidine) derivatized biodegradable microspheres with the 188Re tricarbonyl complex [188Re(CO)3(H2O)3]+

OBJECTIVES: Many radiopharmaceuticals have been studied as radiation synovectomy agents. In this study, we developed a new potential agent for radiation synovectomy: poly(lactic acid)-histidine (PLA-his) microspheres radiolabelled with [188Re(CO)3(H2O)3]+. METHODS: The reaction conditions for the chelation of [188Re(CO)3(H2O)3]+ and the radiolabelling of PLA microspheres were optimized and the stabilities for both steps tested in vitro. RESULTS: The chelation efficiency of [188Re(CO)3(H2O)3]+ reached 93.12 +/- 1.82% with >95% radiochemical purity once the colloidal and free 188Re were removed by a small Sep-Pak column (Plus QMA). More than 90% of radioactivity stayed in the [188Re(CO)3(H2O)3]+ form over 5 h. The radiolabelling efficiency of PLA-his microspheres with [188Re(CO)3(H2O)3]+ was above 92%. After 3 days incubation at 37 degrees C in calf serum, more than 80% of the radioactivity was still bound to the microspheres. CONCLUSION: Such microspheres are potentially useful as a radiation synovectomy agent for the treatment of chronically inflamed arthritic joints. Furthermore, they might be valuable in cancer brachytherapy.     

An alternative approach to the preparation of (188)Re radiopharmaceuticals from generator-produced [(188)ReO(4)](-): efficient synthesis of (188)Re(V)-meso-2,3-dimercaptosuccinic acid

A new efficient approach for the preparation of (188)Re radiopharmaceuticals starting from [(188)ReO(4)](-), produced at a carrier-free level through the (188)W/(188)Re generator system, is described. The reaction procedure was based on the combined action of different reagents and has been applied in detail to the preparation of the therapeutic agent (188)Re(V)-DMSA (H(2)DMSA [meso-2,3-dimercaptosuccinic acid]). The most efficient combination required the use of SnCl(2), oxalate ions, and gamma-cyclodextrin. These were reacted with [(188)ReO(4)](-) and H(2)DMSA to afford the final radiopharmaceutical in high radiochemical purity, at room temperature, and in weakly acidic solution. The role played by the various reagents in the reaction was investigated. It was found that SnCl(2) behaved as the actual reducing agent, whereas oxalate and gamma-cyclodextrin greatly enhanced the ease of reduction of [(188)ReO(4)](-) through the action of two hypothetical mechanisms. In the first step of the reaction, oxalate ions gave rise to the formation of Re(VII) complexes with the concomitant expansion of the coordination sphere of the metal. This process strongly favored the electron transfer between Sn(2+) and Re(+7) centers, giving rise to intermediate reduced rhenium complexes. These species were further stabilized by the formation of transient host-guest aggregates with gamma-cyclodextrin and finally converted into (188)Re(V)-DMSA through simple replacement of the coordinated ligands by H(2)DMSA.     

A comparative study of 188Re(V)-meso-DMSA and 188Re(V)-rac-DMSA: preparation and in vivo evaluation in nude mice xenografted with a neuroendocrine tumor

Dimercaptosuccinic acid (DMSA) exists in meso and racemic (rac) forms. Unlike a meso isomer, rac-2,3-DMSA is very soluble in water, strongly acidic solutions and organic solvents. Despite these differences, rac-2,3-DMSA has not been studied as a radiopharmaceutical. In this study, ¹⁸⁸Re complexes with diastereomeric DMSA were prepared to compare the properties of ¹⁸⁸Re(V)-rac-DMSA with those of ¹⁸⁸Re(V)-meso-DMSA in in vitro and in vivo models.

Methods

rac-2,3-DMSA was synthesized and radiolabeled with ¹⁸⁸Re. The biodistribution and gamma camera imaging of ¹⁸⁸Re(V)-meso-DMSA and ¹⁸⁸Re(V)-rac-DMSA were performed in nude mice subcutaneously implanted with PC-12 cell lines.

Results and conclusions

Both ¹⁸⁸Re(V)-meso-DMSA and ¹⁸⁸Re(V)-rac-DMSA showed excellent radiochemical purity and stability at room temperature. Compared with ¹⁸⁸Re(V)-meso-DMSA, ¹⁸⁸Re(V)-rac-DMSA needed a higher concentration of rac-DMSA and metabisulfite for maximum yields. ¹⁸⁸Re(V)-meso-DMSA showed high labeling efficiency at pH 2, whereas ¹⁸⁸Re(V)-rac-DMSA showed maximum yields at pH 5. The tumor uptake of ¹⁸⁸Re(V)-rac-DMSA was 3.5 times higher than that of ¹⁸⁸Re(V)-meso-DMSA at 1 h (P<.01). Gamma camera images showed that ¹⁸⁸Re(V)-rac-DMSA was more selectively localized than ¹⁸⁸Re(V)-meso-DMSA at the tumor region in a xenograft model. These results demonstrate that ¹⁸⁸Re(V)-rac-DMSA may have better potential than ¹⁸⁸Re(V)-meso-DMSA as a therapeutic agent against neuroendocrine tumors.     

In vitro cytotoxicity of 211At-labeled trastuzumab in human breast cancer cell lines: effect of specific activity and HER2 receptor heterogeneity on survival fraction

INTRODUCTION: Radioimmunotherapy with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab is a promising strategy for treating HER2-positive breast and ovarian carcinoma patients. The objective of this study was to determine the cytotoxic effectiveness of trastuzumab labeled with the 7.2-h half-life alpha-particle emitter 211At. METHODS: Experiments were performed on SKBr-3, BT-474 and the transfected MCF7/HER2-18 human breast carcinoma cell lines. Intrinsic radiosensitivity was determined after exposure to external beam irradiation. The cytotoxicity of 211At-labeled trastuzumab was measured by clonogenic assays. The distribution of HER2 receptor expression on the cell lines was measured using fluorescence-activated cell sorting. A pharmacokinetic (PK)/microdosimetric model was established to assess the effects of specific activity (SA), HER2 receptor expression and absorbed dose on survival fraction (SF). RESULTS: With external beam irradiation, the 2-Gy SF for BT-474, SKBr-3 and MCF7/HER2-18 cells was 0.78, 0.53 and 0.64 Gy, respectively. Heterogeneous HER2 expression was observed, with a subpopulation of cells lacking measurable receptor (14.5%, SKBr-3; 0.34%, MCF-7/HER2; 1.73%, BT-474). When plotted as a function of activity concentration, SF curves were biphasic and inversely proportional to SA; however, when the model was applied and absorbed doses calculated, the SF curve was monoexponential independent of SA. Thus, the PK model was able to demonstrate the effects of competition between cold and labeled mAb. These studies showed that the relative biological effectiveness of 211At-labeled trastuzaumab was about 10 times higher than that of external beam therapy. CONCLUSION: These in vitro studies showed that 211At-labeled trastuzumab mAb is an effective cytotoxic agent for the treatment of HER2-positive tumor cells. The SA of the labeled mAb and the homogeneity of HER2 receptor expression are important variables influencing the efficiency of cell killing.     

Rhenium-188: availability from the (188)W/(188)Re generator and status of current applications

Rhenium-188 is one of the most readily available generator derived and useful radionuclides for therapy emitting β(-) particles (2.12 MeV, 71.1% and 1.965 MeV, 25.6%) and imageable gammas (155 keV, 15.1%). The (188)W/(188)Re generator is an ideal source for the long term (4-6 months) continuous availability of no carrier added (nca) (188)Re suitable for the preparation of radiopharmaceuticals for radionuclide therapy. The challenges associated with the double neutron capture route of production of the parent (188)W radionuclide have been a major impediment in the progress of application of (188)Re. Tungsten-188 of adequate specific activity can be prepared only in 2-3 of the high flux reactors operating in the World. Several useful technologies have been developed for the preparation of clinical grade (188)W/(188)Re generators. Since the specific activity of (188)W used in the generator is relatively low 185 GBq( < 5 Ci)/g], the eluted (188)ReO(4)(-) can have low radioactive concentration often insufficient for radiopharmaceutical preparation. However, several efficient post elution concentration techniques have been developed that yield clinically useful (188)ReO(4)(-) solutions. Rhenium-188 has been used for the preparation of therapeutic radiopharmaceuticals for the management of diseases such as bone metastasis, rheumatoid arthritis and primary cancers. Several early phase clinical studies using radiopharmaceuticals based on (188)Re-labeled phosphonates, antibodies, peptides, lipiodol and particulates have been reported. This article reviews the availability and use of (188)Re including a discussion of why broader use of (188)Re has not progressed as expected as a popular radionuclide for therapy.     

188Re-DTPA-DG致MCF-7乳腺癌细胞凋亡实验研究

目的研究不同放射性浓度^188Re-DTPA-脱氧葡萄糖（DG）对人MCF-7乳腺癌细胞凋亡的影响及其作用机制.方法用流式细胞仪检测^188Re-DTPA-DG处理后MCF-7乳腺癌细胞的凋亡.将人MCF-7乳腺癌细胞分成3组：^188Re-DTPA-DG实验组、^188ReO-4对照组和生理盐水组.其中前2组分3个不同放射性浓度组：37、55.5、74kBq/ml.结果^188Re-DTPA-DG、^188ReO-4均能导致肿瘤细胞发生凋亡,实验组与^188ReO-4对照组及生理盐水组在不同放射性浓度下差异均有显著性（P＜0.01）,随着放射性浓度增加,凋亡程度增大;^188Re-DTPA-DG较^188ReO-4更易诱导凋亡发生.结论^188Re-DTPA-DG能导致肿瘤细胞凋亡,并且与放射性浓度相关;其机制可能是辐射导致DNA严重损伤,使细胞周期发生阻滞.     

188Re(Ⅴ)-DMSA药盒制备及其质量评估

目的研制188Re(Ⅴ)-二巯基丁二酸(DMSA)标记配方并制备药盒,评价药盒的质量.方法酸性环境下,SnCl2·2H2O还原高价态ReO4-为Ⅴ价,并与DMSA反应,制备药盒,以高压液相色谱仪(HPLC)测定该药盒的标记率、标记物的体外稳定性、药盒的稳定性,并与99Tcm(Ⅴ)-DMSA在小鼠体内分布比较.结果药盒标记率为100%,标记物室温放置24 h后标记率＞97%;药盒置-20和4℃条件下3个月后,标记率＞95%;188Re(Ⅴ)-DMSA与99Tcm(Ⅴ)-DMSA在小鼠体内分布相似,在骨骼高浓聚,经肾脏排泄.结论188Re(Ⅴ)-DMSA药盒性能优良.     

99mTc(V)DMSA quantitatively predicts 188Re(V)DMSA distribution in patients with prostate cancer metastatic to bone

Rhenium-188 dimercaptosuccinic acid complex [188Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent 99mTc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if 99mTc(V)DMSA could be used to predict tumour and kidney retention of 188Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of 99mTc(V)DMSA and 188Re(V)DMSA. This would determine whether a scan with 99mTc(V) DMSA could be used to identify patients for whom 188Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in 188Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent 99mTc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq 99mTc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq 188Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the 188Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on 188Re scans than on 99mTc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for 188Re than for 99mTc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were seen between 99mTc and 188Re scans, and kidney-to-background ratios on 188Re scans were not higher than on 99mTc scans. These differences are insufficient to infer that they are due to a real difference in biodistribution, and they may be due only to different physical imaging characteristics. Thus 99mTc(V)DMSA scans are predictive of 188Re(V)DMSA biodistribution and could be used to estimate tumour and renal dosimetry and assess suitability of patients for 188Re(V)DMSA treatment.     

99mTc(V)DMSA quantitatively predicts 188Re(V)DMSA distribution in patients with prostate cancer metastatic to bone

Rhenium-188 dimercaptosuccinic acid complex [¹⁸⁸Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent ^99mTc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if ^99mTc(V)DMSA could be used to predict tumour and kidney retention of ¹⁸⁸Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of ^99mTc(V)DMSA and ¹⁸⁸Re(V)DMSA. This would determine whether a scan with ^99mTc(V)DMSA could be used to identify patients for whom ¹⁸⁸Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in ¹⁸⁸Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent ^99mTc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq ^99mTc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq ¹⁸⁸Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the ¹⁸⁸Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on ¹⁸⁸Re scans than on ^99mTc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for ¹⁸⁸Re than for ^99mTc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were seen between ^99mTc and ¹⁸⁸Re scans, and kidney-to-background ratios on ¹⁸⁸Re scans were not higher than on ^99mTc scans. These differences are insufficient to infer that they are due to a real difference in biodistribution, and they may be due only to different physical imaging characteristics. Thus ^99mTc(V)DMSA scans are predictive of ¹⁸⁸Re(V)DMSA biodistribution and could be used to estimate tumour and renal dosimetry and assess suitability of patients for ¹⁸⁸Re(V)DMSA treatment.     

[188Re(CO)3(H2O)3]+间接标记免疫磁性纳米微粒的实验研究

目的探讨标记单克隆抗体磁性纳米微粒的实验条件。方法以[二（2-吡啶甲基）-氨基]-乙酸（PADA）作为双功能螯合剂，将[^188Re（CO）3（H2O）3]^＋间接标记到耦联了单克隆抗体的磁性纳米微粒。结果[^188Re（CO）3（H2O）3]^＋间接标记免疫磁性纳米微粒的标记率大于80％，在小牛血清和生理盐水中48h后稳定性仍能保持在90％以上。结论使用PADA作为双功能螯合剂，[^188Re（CO）3（H2O）3]^＋间接标记免疫磁性纳米微粒的标记率高，稳定性好，适于进一步体内研究。     

Preparation of (188Re) Re-AEDP and its biodistribution studies.

The synthesis of the Re (V) complex and preparation of 188Re-AEDP are described using 188Re which was obtained from the alumina-based 188W/188Re generator. Dependence of the radiolabeling yields of 188Re-AEDP on reducing agent concentration, AEDP concentration, pH and addition of carrier was examined. In the case of optimum conditions, the radiolabeling yields of 188Re-AEDP were 92-93% for carrier-free 188Re and 95-98% for carrier-added 188Re. The stability of 188Re-AEDP at pH approximately 6 was studied and it is found that the carrier has a significant effect on the stability of 188Re-AEDP. The biodistribution of carrier-free and carrier-added 188Re-labelled compounds in rats was also measured. The results show that 188Re (carrier-added)-AEDP is a potential bone palliation radiopharmaceutical due to its high skeletal uptake, rapid blood clearance and relatively low soft tissue absorption.     

钼靶X线在早期乳腺癌诊断中的临床应用价值

乳腺癌患者的生存期和病理分期有密切关系,乳腺癌的早期诊断和治疗。是提高乳腺癌患者生存率和降低死亡率的关键,钼靶X线是国际公认的检测早期乳腺癌的有效方法。     

The 188Re(III)-EDTA complex--a multipurpose starting material for the preparation of relevant 188Re complexes under mild conditions.

An easy and gentle method for the preparation of 188Re(V) complexes with bidentate and tetradentate ligands is described starting from the precursor complex 188Re(III)-EDTA. That complex is prepared at room temperature in acidic solution and reacts by a combined re-oxidation/ligand exchange reaction with appropriate ligands like DMSA or ECD (DMSA = dimercapto succinic acid, ECD = L,L-ethylene dicysteine diethyl ester) or en, tau, and cyclam (en = ethylene diamine, tau = 1,4,8,11-tetraazaundecane, cyclam = 1,4,8,11-tetraazacyclo-tetradecane) to the 188Re(V)-oxo- and dioxocomplexes, respectively. The chelates were unambiguously identified by chromatographic comparison with spectroscopically characterised samples or known 99mTc-kit reconstitutions. The reaction succeeds under mild conditions (room temperature, short time, neutral or weak basic solutions) with high yields and has potential for labelling of sensitive biomolecules with 188Re.     

The efficacy of tucatinib-based therapeutic approaches for HER2-positive breast cancer

Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in approximately 15%–20%of breast cancer cases.HER2 is a member of the epidermal growth factor receptor (EGFR) family with tyrosinase kinase activity,and its overexpression is linked to poor prognosis and shorter progression-free survival (PFS) and overall survival(OS).Among various treatment options,HER2-targeting monoclonal antibodies and tyrosine kinase inhibitors(TKIs) have mostly been applied in recent decades to treat...     

In vivo prediction of response to antiestrogen treatment in estrogen receptor-positive breast cancer.

In metastatic breast cancer, the estrogen receptor (ER) is a well-known prognostic factor predictive of response to hormonal treatment in most, but not all, patients. Recently, a receptor-specific radioligand for in vivo imaging of the ER in breast cancer patients was developed: (123)I-labeled cis-11beta-methoxy-17alpha-iodovinyl-estradiol (Z-(123)I-MIVE). It showed high sensitivity and specificity for the in vivo detection of ER-positive breast cancer. The aim of this study was to determine whether Z-(123)I-MIVE scintigraphy is able to predict response or resistance to antiestrogen therapy in patients with metastatic ER-positive breast carcinoma. METHODS: Twenty-three patients with first metastases of their breast cancer and positive Z-(123)I-MIVE scintigraphy were included and treated with tamoxifen, 40 mg/d. Scintigraphy was repeated, on average, 4 wk later. The results of these scintigraphies were compared with the clinical outcome. RESULTS: On baseline scintigraphy, 21 of 23 patients had clear uptake and 2 of 23 patients had faint uptake of Z-(123)I-MIVE. After initiation of antiestrogen treatment, 17 of 21 patients with clear uptake on baseline scintigraphy showed complete blockade of ER activity on the Z-(123)I-MIVE scintigraphy. Four of 21 patients showed mixed or no ER blockade. All patients with faint baseline uptake or mixed or no ER blockade after tamoxifen showed progressive disease despite antiestrogen treatment. Patients with clear baseline uptake and complete ER blockade after tamoxifen had a significantly longer progression-free interval (mean +/- SEM, 14.4 +/- 1.6 vs. 1.8 +/- 0.8 mo; P < 0.01). CONCLUSION: Z-(123)I-MIVE scintigraphy seems to be a useful tool to predict response or resistance to antiestrogen treatment in ER-positive metastatic breast cancer patients and to depict nonresponders before the clinical manifestation of progression.     

Treatment of HER2-positive breast carcinomatous meningitis with intrathecal administration of α-particle-emitting At-labeled trastuzumab

IntroductionCarcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of α-particle emitting ²¹¹At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM.MethodsAthymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 μCi ²¹¹At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 μCi ²¹¹At-labeled trastuzumab or saline. In Experiment 3, animals received 28 μCi ²¹¹At-labeled trastuzumab, 30 μCi ²¹¹At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study.ResultsIn Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 μCi ²¹¹At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 μCi ²¹¹At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with ²¹¹At-labeled TPS3.2 and ²¹¹At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the ²¹¹At-trastuzumab-treated groups.ConclusionIntrathecal ²¹¹At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM.     

乳腺癌76例钼靶X线诊断分析

本文选择我院2002年1月～2003年5月间,经手术病理证实且具备完整临床及钼靶X线资料的76例乳腺癌病例,结合文献进行回顾性分析,结果报告如下.