Pharmacokinetics and radiation dosimetry of ^(99m)Tc-3PRGD_2 in healthy individuals:A pilot study

99mTc-3PRGD2 is a new SPECT radiotracer for several tumor imaging with high uptake where integrinαvβ3 is highly expressed.This pilot study was to assess the safety,biodistribution and radiation dosimetry of 9,mTc-3PRGD2 in healthy volunteers.The 10 healthy male volunteers were injected with 99mTc-3PRGD2（786.7±55.8 MBq,19.1-24.2 mCi）.Baseline measurements of vital signs,laboratory safety tests and 12-lead electrocardiogram were recorded before and after injection.Blood and urine samples were collected and radiation counts were obtained at various time points.Whole-body scans and ROIs of identified organs were used for visual analysis and estimating the radiation dosimetry.No adverse reactions were found during the study.99mTc-3PRGD2 exhibited a rapid clearance from the blood with less than 45%of the initial dosage at 10 min after injection and gradual increasing radioactivity in urine with（52.9±6）%of original dose at 1440 min.The whole-body imaging showed high radioactive accumulation in bladder.And the highest 99mTc-3PRGD2 uptake was found in the kidneys(3.50×10-2 mSv/MBq).The 99mTc-3PRGD2 exhibited good pharmacokinetic properties and little radiation burden.This study showed that 99mTc-3PRGD2 would be a safe and attractive SPECT agent in clinic applications.

^(99m)Tc-3P_4 -RGD_2 radiotracers for SPECT/CT of esophageal tumor

In recent years,several RGD(Arg-Gly-Asp)-based radiotracers have already been successfully tested in human for the visualization of integrin αvβ3,demonstrating its feasibility in tumor diagnosis.In this paper,we evaluated the 99mTc-3P4-RGD2 single photon emission computed tomography/computerized tomography(SPECT/CT)in patients suffering from space occupying disease of esophagus.40 patients(34 males and 6 female;mean age: 58.3 years) with a suspected space occupying lesion of esophagus were included,thus finally obtaining their definite pathologic diagnosis(malignant,n=32;benign,n=8).All patients underwent endoscopic,barium esophagography and SPECT/CT imaging preoperatively.The chest SPECT was performed at 4 h after administration of99mTc-3P4-RGD2 with a dose of 939±118 MBq.The diagnosis precision,sensitivity and specificity among these methods were compared.The relationship between radioactive uptake and clinical pathological stage of esophageal carcinoma was discussed by calculating the tumor to normal esophagus(T/N).Meanwhile,the integrin αvβ3 expression was assessed immunohistochemically in postoperative esophageal tissues.31 patients were diagnosed as esophageal carcinoma;and 1,leiomyosarcoma;and 6.leimyoma;and 2,esophageal tuberculosis.The accuracy,sensitivity and specificity of barium esophagography,endoscopic and SPECT/CT imaging are 92.5/93.8/87.5%,97.5/96.9/100%,and 90/90.6/87.5%,respectively.Abnormal accumulation of radiotracer in 29 malignant lesions is observed.The SPECT/CT imaging displayed the region of radioactive uptake and lesions matched extremely with the T/N ratio from 1.31 to 2.79(mean 2.04).A case with pulmonary metastases and a case with mediastinal lymph node metastases were found which were missed by barium esophagography and endoscopic.The99mTc-3P4-RGD2 uptake of the esophageal carcinoma masses had no relevance to the tumor pathologic classification(P>0.05).There was a significant positive correlation between T/N ratio and positive cell percentage of integrin αvβ3(r=0.976),demonstrating the certain clinical potential in the diagnosis of esophageal carcinoma.

A pilot study on ^(99m)Tc-3PRGD2 scintigraphy in diagnosis of brain glioma

The 99mTc-3PRGD2 targeted SPECT/CT scanning was of significance in detecting differentiated glioma.In this work,the diagnostic value of 99mTc-3PRGD2 scintigraphy in brain glioma was evaluated by the ten clinically verified brain glioma patients after obtaining informed consent.The patients first accepted X-ray imaging to localize the detecting regions before administrating with 99mTc-3PRGD2 at a mean radioactivity of 849±115 MBq via single intravenous bolus injection 2 h prior to SPECT/CT imaging.Tumor samples for detectingαvβ3 were collected by surgical operations two weeks after the scintigraphy.The results of CT and SPECT scanning were merged and compared.The correlation between tumor occupation（T/N ratio） andαvβ3 expression level were analyzed.The T/N ratios in brain glioma were proportionally correlated to av(33 positive cell percentage（R2=0.9253,p<0.05）.This study primarily evaluated the clinical application of 99mTc-3PRGD2 SPECT scintigraphy on brain glioma.The more pathological types and detecting strategies covering a large amount of samples would aid to clarify the potentials.

Synthesis and preliminary biological evaluation of the derivatives of O^6-benzylguanine as inactivators of O^6-alkylguanine-DNA alkyltransferase

A series of new O6-BG derivatives （14-21,23-30） were synthesized as inactivators of O6-Alkylguanine-DNA alkyltransferase （AGT）, and their ability to inhibit AGT was preliminary evaluated by MTT with O6-BG as the control. The result suggested compound 30 displayed a higher activity than O6-BG.

Tumor targeting of ^(125)I-labeled anti-EGFR monoclonal antibody LA22 in HT-29 human colon cancer

Epidermal growth factor receptor (EGFR) plays a critical role in proliferation, apoptosis, angiogenesis, invasiveness and distant metastasis of tumors. In this study, the tumor targeting properties of anti-EGFR monoclonal antibody (mAb) LA22 in a colon cancer mouse model are evaluated. The results from flow cytometry assay and immunofluorescent staining clearly showed that HT-29 human colon cancer cells were EGFR positive, and the binding of mAb LA22 to the HT-29 cell surface was specific. The saturation binding experiment of 125I-LA22 to HT-29 cells revealed that LA22 possessed moderate affinity to EGFR with the Kd value calculated to be 3.28±0.76 nM. The in vivo γ imaging demonstrated the specific accumulation of 125I-LA22 in HT-29 tumor xenografts. The specific tumor targeting properties of mAb LA22 make it a good candidate for tumor targeted radioimmunotherapy of EGFR-positive tumors when it is labeled with therapeutic nuclides, such as 131I, 177Lu, or 90Y.

Synthesis of a Novel Chiral Trihydroxamic Acid Containing L-Pro-L-Ala-L-Ala-β-(HO)Ala-OMe Unit

An N-hydroxyl peptide unit of H-L-Pro-L-Ala-L-Ala-β-（BnO）Ala-OMe was synthesized by stepwise chain building method in solution. Then, based on nitrilotriacetic acid backbone and this N-hydroxyl peptide unit, a novel chiral tripodal ligand P as an analogue of desferrichrome, has been synthesized. In neutral pH, ligand P formed stable tri（hydroxamato）- iron（Ⅲ） complexes which showed a maximum absorptiota （∑max=2750 M^-lcm^-1） at 422 nm in UV-Vis spectra. The characteristic absorption spectra are similar to those of natural trihydroxamate-type siderophores.

Arab/c/opste N^(6)-methyladenosine reader CPSF30-L recognizes FUE signals to control polyadenylation site choice in liquid-like nuclear bodies

The biological functions of the epitranscriptomic modification N^(6)-methyladenosine(m^(6)A)in plants are not fully understood.CPSF30-L is a predominant isoform of the polyadenylation factor CPSF30 and consists of CPSF30-S and an m^(6)A-binding YTH domain.Little is known about the biological roles of CPSF30-L and the molecular mechanism underlying its m^(6)A-binding function in alternative polyadenylation.Here,we charac-terized CPSF30-L as an Arabidopsis m^(6)A reader whose m^(6)A-binding function is required for the floral tran-sition and abscisic acid(ABA)response.We found that the m^(6)A-binding activity of CPSF30-L enhances the formation of liquid-like nuclear bodies,where CPSF30-L mainly recognizes m*A-modified far-upstream elements to control polyadenylation site choice.Deficiency of CPSF30-L lengthens the 3'untranslated region of three phenotypes-related transcripts,thereby accelerating their mRNA degradation and leading to late flowering and ABA hypersensitivity.Collectively,this study uncovers a new molecular mechanism for m^(6)A-driven phase separation and polyadenylation in plants.

First-in-human pilot study of an integrinα6-targeted radiotracer for SPECT imaging of breast cancer

Dear Editor,The molecular classification has been playing a crucial role in the precise theranostics of cancer.Compared with the invasive biopsy,the in vivo noninvasive detection of biomarkers by nuclear imaging possesses advantages due to tumor heterogeneity.As one member of the integrin family,integrinα6 subunit combines the integrinβ1 orβ4 subunit to form integrinα6β1 orα6β4 heterodimers,which function to promote the migration,invasion,and survival of tumor cells,leading to increased metastasis,poor prognosis,and reduced survival.Therefore,the in vivo imaging of integrinα6 expression could play an important role in the treatment planning and prognosis prediction.

A novel peptide-based probe^(99m)Tc-PEG_(6)-RD-PDP2 for the molecular imaging of tumor PD-L2 expression

Tumor-related PD-L2 expression is associated with the clinical efficacy of PD-1/PD-L1 blockade therapy.PD-L2-specific imaging can help selecting patients for appropriate immunotherapy.In this study,a PD-L2-targeting peptide(PDP2)was screened by the one-bead one-compound combinatorial library approach.Using the retro-inverso D-peptide of PDP2(RD-PDP2)and PEGylation strategies,we developed a novel Tc-99m-labeled PD-L2-targeting peptide as a SPECT tracer(^(99m)Tc-PEG_(6)-RD-PDP2)for imaging of tumor PD-L2 expression.The radiolabeling yield of ^(99m)Tc-PEG_(6)-RD-PDP2 was greater than 95%by the standard HYNIC/tricine/TPPTS labeling procedure.^(99m)Tc-PEG_(6)-RD-PDP2 displayed high PD-L2-binding specificity both in vitro and in vivo.SPECT/CT imaging with^(99m)Tc-PEG_(6)-RD-PDP2 showed that the A549-PD-L2tumors were clearly visualized,whereas the signals in PD-L2-negative A549 tumors were much lower.In vivo blocking study suggested that the tumor uptake of^(99m)Tc-PEG_(6)-RD-PDP2 was PD-L2 specifically mediated.^(99m)Tc-PEG_(6)-RD-PDP2 is a promising SPECT probe for the non-invasive imaging of tumor PD-L2expression and has a great potential in guiding the anti-PD-1 or anti-PD-L1 immunotherapy of cancer.