scholarly journals Synthesis and Preclinical Evaluation of 68Ga-MALAT-1 ASO for PET Imaging of MALAT-1 expressing Tumours

2020 ◽  
Author(s):  
Zhen-Feng Liu ◽  
Jun Yang ◽  
Qianni Ye ◽  
Min Yang ◽  
Dong-hui Pan ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Malignant Tumors ◽  
Radiochemical Yield ◽  
Cell Uptake ◽  
Log P ◽  
Pharmacokinetic Studies ◽  
Specific Uptake ◽  
Pet Scans

Abstract Background: MALAT-1 (Metastasis-Associated Lung Adenocarcinoma Transcript 1) is a large long nuclear noncoding RNA (lncRNA) that is overexpressed in an array of cancers. In this study, we designed a range of positron probes for MALAT-1 to evaluate its distribution, pharmacokinetics, and to explore whether the probe can be used for the imaging of malignant tumors with high MALAT-1 expression in vivo. Methods: 68Ga labelling of MALAT-1 antisense oligonucleotides (68Ga–MALAT-1 ASO) was synthesized by the conjugation of MALAT-1 NOTA-ASO and 68Ga3+. Purity was assessed by radio-HPLC. Pharmacokinetic studies and cell uptake were assessed. The biodistribution and metabolism of 68Ga–MALAT-1 ASO in normal ICR and MHCC-LM3 xenograft-bearing nude mice were studied. Results: 68Ga–MALAT-1 ASO was obtained at a radiochemical yield of 98% from a 10 min synthesis with 100 ± 50 MBq/nmol activity and > 99% purity once synthesized. The Log P was -2.53±0.19. The tracer displayed excellent stability in vitro. 68Ga–MALAT-1 ASO showed satisfactory binding ability to MHCC-LM3 cells; the biodistribution of 68Ga-MALAT-1 ASO in MHCC-LM3 tumour-bearing mice showed high levels of uptake (3.04 ± 0.11%ID/g). Micro-PET scans demonstrated the tumor specific uptake of 68Ga-MALAT-1 ASO in mouse models. Conclusions: We conclude that 68Ga labelling of MALAT-1 ASO is a convenient approach to label tumors overexpressing MALAT-1.

scholarly journals Long noncoding RNA SNHG1 promotes TERT expression by sponging miR-18b-5p in breast cancer

2021 ◽  
Author(s):  
yujuan Kang ◽  
Lin Wan ◽  
Qin Wang ◽  
Yanling Yin ◽  
Jiena Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
Positive Role ◽  
Nucleolar Rna ◽  
Human Malignant Tumors ◽  
Tert Expression

Abstract Background: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a positive role in the progression of human malignant tumors. However, the molecular mechanism of SNHG1 remains elusive in breast cancer. Results: LncRNA SNHG1 was upregulated and had a positive relationship with poor prognosis according to bioinformatics analysis. Silencing SNHG1 inhibited tumorigenesis in breast cancer both in vitro and in vivo. Mechanistically, SNHG1 functioned as a ceRNA to promote TERT expression by sponging miR-18b-5p. Moreover, miR-18b-5p acted as a tumor repressor in breast cancer. Finally, E2F1, a transcription factor, enhanced SNHG1 transcription.Conclusions: Our results provide a comprehensive understanding of the oncogenic mechanism of lncRNA SNHG1 in breast cancer. Importantly, we identified a novel E2F1–SNHG1–miR-18b-5p–TERT axis, which may be a potential therapeutic target for breast cancer.

scholarly journals Evaluation of Radioiodinated Fluoronicotinamide/Fluoropicolinamide-Benzamide Derivatives as Theranostic Agents for Melanoma

2020 ◽  
Vol 21 (18) ◽  
pp. 6597
Author(s):  
Chao-Cheng Chen ◽  
Yang-Yi Chen ◽  
Yi-Hsuan Lo ◽  
Ming-Hsien Lin ◽  
Chih-Hsien Chang ◽  
...  
Keyword(s):  
Absorbed Dose ◽  
Radiochemical Yield ◽  
Amelanotic Melanoma ◽  
In Vivo Studies ◽  
Log P ◽  
Theranostic Agent ◽  
Biodistribution Studies ◽  
Theranostic Agents

Malignant melanoma is the most harmful type of skin cancer and its incidence has increased in this past decade. Early diagnosis and treatment are urgently desired. In this study, we conjugated picolinamide/nicotinamide with the pharmacophore of 131I-MIP-1145 to develop 131I-iodofluoropicolinamide benzamide (131I-IFPABZA) and 131I-iodofluoronicotiamide benzamide (131I-IFNABZA) with acceptable radiochemical yield (40 ± 5%) and high radiochemical purity (>98%). We also presented their biological characteristics in melanoma-bearing mouse models. 131I-IFPABZA (Log P = 2.01) was more lipophilic than 131I-IFNABZA (Log P = 1.49). B16F10-bearing mice injected with 131I-IFNABZA exhibited higher tumor-to-muscle ratio (T/M) than those administered with 131I-IFPABZA in planar γ-imaging and biodistribution studies. However, the imaging of 131I-IFNABZA- and 131I-IFPABZA-injected mice only showed marginal tumor uptake in A375 amelanotic melanoma-bearing mice throughout the experiment period, indicating the high binding affinity of these two radiotracers to melanin. Comparing the radiation-absorbed dose of 131I-IFNABZA with the melanin-targeted agents reported in the literature, 131I-IFNABZA exerts lower doses to normal tissues on the basis of similar tumor dose. Based on the in vitro and in vivo studies, we clearly demonstrated the potential of using 131I-IFNABZA as a theranostic agent against melanoma.

scholarly journals Long noncoding RNA SNHG1 promotes TERT expression by sponging miR-18b-5p in breast cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yujuan Kang ◽  
Lin Wan ◽  
Qin Wang ◽  
Yanling Yin ◽  
Jiena Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
Inhibitory Effect ◽  
Positive Role ◽  
Breast Cancer Growth ◽  
Tert Expression

Abstract Background Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a positive role in the progression of human malignant tumors. However, the molecular mechanism of SNHG1 remains elusive in breast cancer. Results LncRNA SNHG1 was upregulated and had a positive relationship with poor prognosis according to bioinformatics analysis in pan-cancer including breast cancer. Silencing SNHG1 inhibited tumorigenesis in breast cancer both in vitro and in vivo. Mechanistically, SNHG1 functioned as a competing endogenous RNA (ceRNA) to promote TERT expression by sponging miR-18b-5p in breast cancer. miR-18b-5p acted as a tumor repressor in breast cancer. Moreover, the combination of SNHG1 knockdown and TERT inhibitor administration showed a synergistic inhibitory effect on breast cancer growth in vivo. Finally, E2F1 as a transcription factor, binding to SNHG1 promoter and enhanced SNHG1 transcription in breast cancer. Conclusions Our results provide a comprehensive understanding of the oncogenic mechanism of lncRNA SNHG1 in breast cancer. Importantly, we identified a novel E2F1–SNHG1–miR-18b-5p–TERT axis, which may be a potential therapeutic target for breast cancer. Our results also provided a potential treatment for breast cancer when knockdown SNHG1 and TERT inhibitor administration simultaneously.

scholarly journals Long Noncoding RNA SNHG1 Promotes TERT Expression by Sponging miR-18b-5p in Breast Cancer

2021 ◽  
Author(s):  
Yujuan Kang ◽  
Lin Wan ◽  
Qin Wang ◽  
Yanling Yin ◽  
Jiena Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transcription Factor ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
The Cancer Genome Atlas ◽  
Luciferase Reporter ◽  
Tert Expression

Abstract Background: Long noncoding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) plays a positive role in the progression of human malignant tumors. However, the molecular mechanism of SNHG1 remains elusive in breast cancer. Methods: The Cancer Genome Atlas data were used to examine the differential expression of SNHG1 in tumor and normal tissues, as well as the relationship between SNHG1 expression and prognosis. Oncogenic role of SNHG1 in breast cancer was studied both in vitro and in vivo. Animal experiments along with colony counting kit-8, colony formation, wound healing, and Transwell invasion assays were used to verify that SNHG1 was an oncogene in breast cancer. Furthermore, reverse transcription-polymerase chain reaction, western blotting analysis, subcellular RNA fractionation, and dual-luciferase reporter assay were performed to prove the competing endogenous RNA (ceRNA) mechanism of SNHG1, miR-18b-5p, and telomerase reverse transcriptase (TERT). Finally, chromatin immunoprecipitation was performed to confirm that the transcription factor E2F1 could enhance SNHG1 transcription.Results: LncRNA SNHG1 was upregulated and had a positive relationship with poor prognosis according to bioinformatics analysis. Silencing SNHG1 inhibited tumorigenesis in breast cancer both in vitro and in vivo. Mechanistically, SNHG1 functioned as a ceRNA to promote TERT expression by sponging miR-18b-5p. Moreover, miR-18b-5p acted as a tumor repressor in breast cancer. Finally, E2F1, a transcription factor, enhanced SNHG1 transcription.Conclusions: Our results provide a comprehensive understanding of the oncogenic mechanism of lncRNA SNHG1 in breast cancer. Importantly, we identified a novel E2F1–SNHG1–miR-18b-5p–TERT axis, which may be a potential therapeutic target for breast cancer.

scholarly journals H-CRRETAWAC-OH, a Lead Structure for the Development of Radiotracer Targeting Integrinα5β1?

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Roland Haubner ◽  
Simone Maschauer ◽  
Jürgen Einsiedel ◽  
Iris E. Eder ◽  
Christine Rangger ◽  
...  
Keyword(s):  
Specific Binding ◽  
Radiochemical Yield ◽  
Human Melanoma ◽  
Cell Uptake ◽  
Preclinical Research ◽  
M Cell ◽  
Biodistribution Studies ◽  
Uptake Studies

Imaging of angiogenic processes is of great interest in preclinical research as well as in clinical settings. The most commonly addressed target structure for imaging angiogenesis is the integrinαvβ3. Here we describe the synthesis and evaluation of [18F]FProp-Cys*-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys*-OH, a radiolabelled peptide designed to selectively target the integrinα5β1. Conjugation of 4-nitrophenyl-(RS)-2-[18F]fluoropropionate provided [18F]FProp-Cys*-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys*-OH in high radiochemical purity (>95%) and a radiochemical yield of approx. 55%. In vitro evaluation showedα5β1binding affinity in the nanomolar range, whereas affinity toαvβ3andαIIbβ3was >50 μM. Cell uptake studies using human melanoma M21 (αvβ3-positive andα5β1-negative), human melanoma M21-L (αvβ3-negative andα5β1-negative), and human prostate carcinoma DU145 (αvβ3-negative andα5β1-positive) confirmed receptor-specific binding. The radiotracer was stable in human serum and showed low protein binding. Biodistribution studies showed tumour uptake ranging from 2.5 to 3.5% ID/g between 30 and 120 min post-injection. However, blocking studies and studies using mice bearingα5β1-negative M21 tumours did not confirm receptor-specific uptake of [18F]FProp-Cys*-Arg-Arg-Glu-Thr-Ala-Trp-Ala-Cys*-OH, although this radiopeptide revealed high affinity and substantial selectivity toα5β1in vitro. Further experiments are needed to study the in vivo metabolism of this peptide and to develop improved radiopeptide candidates suitable for PET imaging ofα5β1expression in vivo.

Long noncoding RNA Linc01296 promotes hepatocellular carcinoma development through regulation of the miR-26a/PTEN axis

2020 ◽  
Vol 401 (3) ◽  
pp. 407-416 ◽  
Author(s):  
Libin Zhang ◽  
Jing Hu ◽  
Menghui Hao ◽  
Liang Bu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Lines ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Malignant Tumors ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Migration And Invasion

AbstractLong noncoding RNA 01296 (Lnc01296) is dysregulated in malignant tumors. However, the detailed effect of Linc01296 on hepatocellular carcinoma (HCC) remains largely unknown. In this study, we identified the biological role of Linc01296 in HCC. The levels of Linc01296 in HCC tissues and a panel of cell lines were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of Linc01296 on HCC progression were explored using a Cell Counting Kit-8 (CCK-8), flow cytometry, migration and Transwell invasion assays. The interactions among Linc01296, miR-26a and PTEN were determined using luciferase, RNA immunoprecipitation (RIP) and Western blot assays. Tumor xenograft models were utilized to confirm the in vivo functional roles of Linc01296 in HCC development. Linc01296 expression was increased in both HCC tissue samples and cell lines. Knockdown of Linc01296 suppressed HCC cell processes, such as proliferation, migration and invasion, and enhanced apoptosis in vitro; these effects were reversed by a miR-26a mimic or PTEN overexpression. Furthermore, knockdown of Linc01296 suppressed HCC growth in vivo. These findings indicated that Linc01296 is involved in HCC progression via regulating miR-26a/PTEN.

The Role of nitro (NO2-), chloro (Cl), and fluoro (F) Substitution in the Design of Antileishmanial and Antichagasic Compounds

2020 ◽  
Vol 21 ◽  
Author(s):  
Boniface Pone ◽  
Ferreira Igne Elizabeth
Keyword(s):  
Chagas Disease ◽  
Mammalian Cells ◽  
Neglected Tropical Diseases ◽  
New Drugs ◽  
Pharmacokinetic Studies ◽  
Scientific Publications ◽  
Antitrypanosomal Activity ◽  
Chemical Groups

: Neglected tropical diseases (NTDs) are responsible for over 500,000 deaths annually and are characterized by multiple disabilities. Leishmaniasis and Chagas disease are among the most severe NTDs, and are caused by the Leishmania sp, and Trypanosoma cruzi, respectively. Glucantime, pentamidine and miltefosine are commonly used to treat leishmaniasis, whereas nifurtimox, benznidazole are current treatments for Chagas disease. However, these treatments are associated with drug resistance, and severe side effects. Hence, the development of synthetic products, especially those containing N02, F, or Cl, which chemical groups are known to improve the biological activity. The present work summarizes the information on the antileishmanial and antitrypanosomal activity of nitro-, chloro-, and fluoro-synthetic derivatives. Scientific publications referring to halogenated derivatives in relation to antileishmanial and antitrypanosomal activities were hand searched in databases such as SciFinder, Wiley, Science Direct, PubMed, ACS, Springer, Scielo, and so on. According to the literature information, more than 90 compounds were predicted as lead molecules with reference to their IC50/EC50 values in in vitro studies. It is worth to mention that only active compounds with known cytotoxic effects against mammalian cells were considered in the present study. The observed activity was attributed to the presence of nitro-, fluoro- and chloro-groups in the compound backbone. All in all, nitro and h0alogenated derivatives are active antileishmanial and antitrypanosomal compounds and can serve as baseline for the development of new drugs against leishmaniasis and Chagas disease. However, efforts on in vitro and in vivo toxicity studies of the active synthetic compounds is still needed. Pharmacokinetic studies, and the mechanism of action of the promising compounds need to be explored. The use of new catalysts and chemical transformation can afford unexplored halogenated compounds with improved antileishmanial and antitrypanosomal activity.

68Ga-labeled HBED-CC Variant of uPAR Targeting Peptide AE105 Compared with 68Ga-NODAGA-AE105

2019 ◽  
Vol 18 (9) ◽  
pp. 1289-1294 ◽  
Author(s):  
Kusum Vats ◽  
Rohit Sharma ◽  
Haladhar D. Sarma ◽  
Drishty Satpati ◽  
Ashutosh Dash
Keyword(s):  
Solid Phase ◽  
Evaluation Studies ◽  
Radiochemical Yield ◽  
In Vivo Evaluation ◽  
Peptide Conjugates ◽  
Biodistribution Studies ◽  
Target Organs ◽  
U87mg Tumor

Aims: The urokinase Plasminogen Activator Receptors (uPAR) over-expressed on tumor cells and their invasive microenvironment are clinically significant molecular targets for cancer research. uPARexpressing cancerous lesions can be suitably identified and their progression can be monitored with radiolabeled uPAR targeted imaging probes. Hence this study aimed at preparing and evaluating two 68Ga-labeled AE105 peptide conjugates, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 as uPAR PET-probes. Method: The peptide conjugates, HBED-CC-AE105-NH2 and NODAGA-AE105-NH2 were manually synthesized by standard Fmoc solid phase strategy and subsequently radiolabeled with 68Ga eluted from a commercial 68Ge/68Ga generator. In vitro cell studies for the two radiotracers were performed with uPAR positive U87MG cells. Biodistribution studies were carried out in mouse xenografts with the subcutaneously induced U87MG tumor. Results: The two radiotracers, 68Ga-NODAGA-AE105 and 68Ga-HBED-CC-AE105 that were prepared in >95% radiochemical yield and >96% radiochemical purity, exhibited excellent in vitro stability. In vivo evaluation studies revealed higher uptake of 68Ga-HBED-CC-AE105 in U87MG tumor as compared to 68Ga-NODAGAAE105; however, increased lipophilicity of 68Ga-HBED-CC-AE105 resulted in slower clearance from blood and other non-target organs. The uPAR specificity of the two radiotracers was ascertained by significant (p<0.05) reduction in the tumor uptake with a co-injected blocking dose of unlabeled AE-105 peptide. Conclusion: Amongst the two radiotracers studied, the neutral 68Ga-NODAGA-AE105 with more hydrophilic chelator exhibited faster clearance from non-target organs. The conjugation of HBED-CC chelator (less hydrophilic) resulted in negatively charged 68Ga-HBED-CC-AE105 which was observed to have high retention in blood that decreased target to non-target ratios.

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