Development of peptides specifically modulating the activity of KLK2 and KLK3

2008 ◽  
Vol 389 (6) ◽  
Author(s):  
Hannu Koistinen ◽  
Ale Närvänen ◽  
Miikka Pakkala ◽  
Can Hekim ◽  
Johanna M. Mattsson ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
First Generation ◽  
Tumor Imaging ◽  
Prostatic Epithelium ◽  
Poorly Differentiated ◽  
Binding Peptides ◽  
The Stability ◽  
Tumor Growth And Invasion

Abstract The prostate produces several proteases, the most abundant ones being kallikrein-related peptidase 3 (KLK3, PSA) and KLK2 (hK2), which are potential targets for tumor imaging and treatment. KLK3 expression is lower in malignant than in normal prostatic epithelium and it is further reduced in poorly differentiated tumors, in which the expression of KLK2 is increased. KLK3 has been shown to inhibit angiogenesis, whereas KLK2 may mediate tumor growth and invasion by participating in proteolytic cascades. Thus, it may be possible to control prostate cancer growth by modulating the proteolytic activity of KLK3 and KLK2. We have developed peptides that very specifically stimulate the activity of KLK3 or inhibit that of KLK2. Using these peptides we have established peptide-based methods for the determination of enzymatically active KLK3. The first-generation peptides are unstable in vivo and are rapidly cleared from the circulation. Currently we are modifying the peptides to make them suitable for in vivo applications. We have been able to considerably improve the stability of KLK2-binding peptides by cyclization. In this review we summarize the possible roles of KLK3 and KLK2 in prostate cancer and then concentrate on the development of peptides that modulate the activity of these proteases.

In vitro and in vivo evaluation of first-generation carbosilane arene Ru(II)-metallodendrimers in advanced prostate cancer

2019 ◽  
Vol 113 ◽  
pp. 229-235 ◽  
Author(s):  
Marta Maroto-Diaz ◽  
Natalia Sanz del Olmo ◽  
Laura Muñoz-Moreno ◽  
Ana M. Bajo ◽  
M. José Carmena ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
First Generation ◽  
In Vivo Evaluation

scholarly journals PET Radiopharmaceuticals for Imaging Integrin Expression: Tracers in Clinical Studies and Recent Developments

2014 ◽  
Vol 2014 ◽  
pp. 1-17 ◽  
Author(s):  
Roland Haubner ◽  
Simone Maschauer ◽  
Olaf Prante
Keyword(s):  
Nuclear Medicine ◽  
First Generation ◽  
Integrin Expression ◽  
Rgd Peptides ◽  
Recent Developments ◽  
Interesting Approach ◽  
Complex Chemistry ◽  
Pet Radiopharmaceuticals

Noninvasive determination of integrin expression has become an interesting approach in nuclear medicine. Since the discovery of the first18F-labeled cyclic RGD peptide as radiotracer for imaging integrinαvβ3expression in vivo, there have been carried out enormous efforts to develop RGD peptides for PET imaging. Moreover, in recent years, additional integrins, includingα5β1andαvβ6, came into the focus of pharmaceutical radiochemistry. This review will discuss the tracers already evaluated in clinical trials and summarize the preliminary outcome. It will also give an overview on recent developments to further optimize the first-generation compounds such as [18F]Galacto-RGD. This includes recently developed18F-labeling strategies and also new approaches in68Ga-complex chemistry. Furthermore, the approaches to develop radiopharmaceuticals targeting integrinα5β1andαvβ6will be summarized and discussed.

Targeted molecular imaging of prostate cancer using tumor endothelium homing Arg-Arg-Leu peptides

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14582-14582 ◽  
Author(s):  
D. O. Henry ◽  
S. C. Chen ◽  
M. K. Wong
Keyword(s):  
Prostate Cancer ◽  
Near Infrared ◽  
Tumor Imaging ◽  
Specific Binding ◽  
Time Lapse ◽  
Human Prostate ◽  
Animal Imaging ◽  
Tumor Endothelium ◽  
Unique Cell

14582 Background: Tumor endothelial cells express a specific and unique cell surface signature. We have previously reported on the discovery of tumor endothelial cell (TDEC) binding peptides that possess the amino acid sequence Arg-Arg-Leu (RRL). We now show specific binding of this synthetic peptide to both surgically resected and experimental human prostate adenocarcinoma tumors thereby allowing for tumor imaging. Methods and Results: Cryosections from human lung, colon, renal, breast and prostate cancers were immunohistochemically processed to reveal the relationship of RRL-peptide staining in relation to Factor VIII labeled tumor vasculature. The RRL-peptide tightly co-localizes onto tumor endothelium within human prostate adenocarcinomas, and did not stain the tumor cells proper. Alexa 680, 800 are two near-infrared dyes that can be conjugated to RRL peptide and which emit at a wavelength unquenched by biologic tissue, thus permitting whole animal imaging. Intravenous administration of RRL-peptide-Alexa chimera to human PC3 prostate tumor bearing mice or TRAMP (transgenic prostate cancer) mice results in the fluorescent visualization of tumors within the intact animal through the prolonged intra-tumor retention of the RRL-dye complex as compared to controls. Direct time-lapse intravital microscopy of such tumors show real-time tumor vascular binding of the RRL peptide. Whole animal imaging revealed the tumor and did not show an appreciable image signal at any other site or organ. Conclusion: The RRL peptide homes to prostate vasculature and is useful for the specific detection of experimental prostate tumors in vivo. Further development of the RRL-peptide into a drug delivery and imaging agent is underway. No significant financial relationships to disclose.

In Vitro Studies on Physiological and Chemical Stability of New LE404-Derivatives with Extended Half-Life

Drug Research ◽  
2018 ◽  
Vol 68 (09) ◽  
pp. 514-520
Author(s):  
Stephanie Zergiebel ◽  
Andreas Seeling
Keyword(s):  
Pharmacokinetic Parameters ◽  
Lead Structure ◽  
Lack Of Information ◽  
Gastrointestinal Fluid ◽  
In Vivo Tests ◽  
Dopamine And Serotonin Receptors ◽  
The Stability

AbstractDibenzoazecines are a class of potential neuroleptics with high affinity to dopamine and serotonin receptors. The efficacy and high therapeutic range has already been demonstrated in vivo with the lead structure 7-methyl-5,6,7,8,9,14-hexahydrodibenzo[d,g]azecin-3-ol (LE404) and selected derivatives. There is a variety of new synthesized structurally different dibenzoazecine derivatives with the aim to improve pharmacokinetic parameters, all of which contain the lead structure LE404. For a multitude of these substances is still a lack of information, inclusive of stability, physicochemical parameters, pharmacokinetics and metabolism. Therefore, the present study investigated the stability properties of 17 new azecine derivatives, including esterase cleavage, stability in simulated gastrointestinal fluid, stability at different pH-values and determination of octanol/water-partition coefficients. These findings, in correlation to the properties and efficacy of the already in vivo tested substances, will be useful for safety and efficacy in further in vivo tests.

scholarly journals A Pretargeted Imaging Strategy for EGFR Positive Colorectal Carcinoma via the Modulation of Tz-radioligand Pharmacokinetics

2020 ◽  
Author(s):  
Lin Qiu ◽  
Hui Tan ◽  
Qingyu Lin ◽  
Zhan Si ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Tumor Imaging ◽  
Molecular Probes ◽  
Ideal Situation ◽  
Imaging Results ◽  
Imaging Strategy ◽  
Xenograft Mice ◽  
The Stability ◽  
In Vitro Stability

Abstract Objective: Previously, we successfully developed a pretargeted imaging strategy (Atezolizumab-TCO/99mTc-HYNIC-PEG11-Tz), which is a powerful tool for evaluating Programmed Cell Death Ligand-1 (PD-L1) expression in xenograft mice tumor models. However, the surplus unclicked 99mTc-HYNIC-PEG11-Tz is cleared somewhat sluggishly through the intestines. This is certainly not an ideal situation for imaging for colorectal cancer (CRC). In order to shift the excretion of the Tz-radioligand to the renal system, we have sought to develop a novel Tz-radioligand by adding a polypeptide linker between HYNIC and PEG11. Methods: Pretargeted molecular probes 99mTc-HYNIC-Polypeptide-PEG11-Tz and Cetuximab-TCO were synthesized. The stability of 99mTc-HYNIC-Polypeptide-PEG11-Tz was evaluated in vitro, and its blood pharmacokinetic test was performed in vivo. In vitro ligation reactivity of 99mTc-HYNIC-Polypeptide-PEG11-Tz towards Cetuximab-TCO was tested. The biodistribution and imaging of 99mTc-HYNIC-Polypeptide-PEG11-Tz was performed to observe the clear pathway of this novel Tz-radioligand. Pretargeted biodistribution of three different accumulation intervals was performed to determine the optimal pretargeted interval time. Comparison of pretargeted (Cetuximab-TCO 48 h/99mTc-HYNIC-PEG11-Tz 6 h) and (Cetuximab-TCO 48 h/99mTc-HYNIC-Polypeptide-PEG11-Tz 6 h) imagings was performed to show the effect of the two Tz-radioligands with different excretion pathway on tumor imaging. Results: 99mTc-HYNIC-Polypeptide-PEG11-Tz showed favorable in vitro stability and rapid blood clearance in mice. SEC-HPLC revealed almost complete reaction between Cetuximab-TCO and 99mTc-HYNIC-Polypeptide-PEG11-Tz in vitro, with the 8:1 Tz-to-mAb reaction providing a conversion yield of 87.83 ± 3.27%. The biodistribution and imaging of 99mTc-HYNIC-Polypeptide-PEG11-Tz demonstrated that the Tz-radioligand was cleared through kidneys. After allowing 24 h, 48 h and 72 h for accumulation of Cetuximab-TCO in HCT116 tumor, pretargeted biodistribution revealed the tumor-to-blood ratio was 0.83 ± 0.13, 1.40 ± 0.31, and 1.15 ± 0.21, respectively. Both pretargeted (Cetuximab-TCO 48 h/99mTc-HYNIC-PEG11-Tz 6 h) and (Cetuximab-TCO 48 h/99mTc-HYNIC-Polypeptide-PEG11-Tz 6 h) imaging delineated the HCT116 tumor clearly. However, pretargeted imaging strategy using Cetuximab-TCO/99mTc-HYNIC-Polypeptide-PEG11-Tz could be used for diagnosing CRC since the surplus unclicked 99mTc-HYNIC-Polypeptide-PEG11-Tz is cleared through urinary system and produces low abdominal uptake background. Conclusion: We developed a novel pretargeted imaging strategy (Cetuximab-TCO/99mTc-HYNIC-Polypeptide-PEG11-Tz) for imaging CRC since the surplus unclicked 99mTc-HYNIC-Polypeptide-PEG11-Tz produces low abdominal uptake background, which broadens the application scope of pretargeted imaging strategy.

Preparation and Preliminary Evaluation of 68 Ga-Acridine: An Attempt to Study the Potential of Radiolabeled DNA Intercalator as a PET Radiotracer for Tumor Imaging

2020 ◽  
Vol 20 (13) ◽  
pp. 1538-1547 ◽  
Author(s):  
Subhajit Ghosh ◽  
Tapas Das ◽  
Shishu K. Suman ◽  
Haladhar D. Sarma ◽  
Ashutosh Dash
Keyword(s):  
Radiochemical Purity ◽  
Tumor Imaging ◽  
Raji Cell ◽  
Biological Behavior ◽  
Preliminary Evaluation ◽  
Dna Intercalator ◽  
Tumor Accumulation ◽  
The Stability

Introduction: Acridine is a well-known DNA intercalator and thereby gets easily inserted within DNA. As uncontrolled rapid cell division is one of the primary characteristics of the tumors, it is expected that acridine or its suitable derivatives will have preferential accumulation in the tumorous lesions. Therefore, an attempt was made to radiolabel an acridine derivative with 68Ga and study the potential of the 68Ga-acridine complex as a PET agent for tumor imaging. Methods: 9-aminoacridine was coupled with p-NCS-benzyl-DOTA to render it suitable for labeling with 68Ga. The purified acridine-DOTA conjugate was radiolabeled with 68Ga, eluted from a 68Ge/68Ga radionuclide generator. Various radiolabeling parameters were optimized and the stability of the radiolabeled preparation was studied. The biological behavior of the 68Ga-acridine complex was studied both in vitro and in vivo using Raji cell line and fibrosarcoma tumor bearing Swiss mice, respectively. Results: 68Ga-acridine complex was obtained with ~100% radiochemical purity under the optimized reaction conditions involving incubation of 2mg/mL of ligand at 100°C for 30 minutes. The complex maintained a radiochemical purity of >95% in normal saline and >65% in human blood serum at 3h post-incubation. In vitro cellular study showed (3.2±0.1)% uptake of the radiotracer in the Raji cells. Biodistribution study revealed significant tumor accumulation [(11.41±0.41)% injected activity in per gram] of the radiotracer within 1h postadministration along with uptake in other non-target organs such as, blood, liver, GIT kidney etc. Conclusion: The present study indicates the potential of 68Ga-acridine as a PET agent for imaging of tumorous lesions. However, further detailed evaluation of the agent is warranted to explore its actual potential.

S100A3 Suppression Inhibits In Vitro and In Vivo Tumor Growth and Invasion of Human Castration-resistant Prostate Cancer Cells

Urology ◽  
2015 ◽  
Vol 85 (1) ◽  
pp. 273.e9-273.e15 ◽  
Author(s):  
Minyong Kang ◽  
Hye Sun Lee ◽  
Young Ju Lee ◽  
Woo Suk Choi ◽  
Yong Hyun Park ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Castration Resistant Prostate Cancer ◽  
Prostate Cancer Cells ◽  
Castration Resistant ◽  
Tumor Growth And Invasion

scholarly journals LncRNA AC245100.4 binds HSP90 to promote the proliferation of prostate cancer

Epigenomics ◽  
2020 ◽  
Vol 12 (15) ◽  
pp. 1257-1271
Author(s):  
Rongjun Cui ◽  
Chi Liu ◽  
Ping Lin ◽  
Hui Xie ◽  
Wei Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Counting ◽  
Chaperone Function ◽  
In Vivo Assays ◽  
Iκb Kinase ◽  
Rna Immunoprecipitation ◽  
The Stability

Aim: To investigate the role and mechanisms of AC245100.4 in prostate cancer. Materials & methods: The expression and location of AC245100.4 were examined using real-time PCR and  in situ hybridization. Cell Counting Kit-8, clone formation, flow cytometry and in vivo assays were conducted to determine the role of AC245100.4. RNA antisense purification with mass spectrometry and RNA immunoprecipitation were performed to identify proteins that bind to AC245100.4. Western blotting was performed to quantify the expression of protein. Results: AC245100.4 expression was upregulated in prostate cancer and mainly located in the cytoplasm. Knockdown of AC245100.4 inhibited proliferation of prostate cancer. Mechanistically, AC245100.4 bound to HSP90 and altered its chaperone function, increased the stability of IκB kinase and activated the NFκB signaling pathway. Conclusion: AC245100.4 promotes the proliferation of prostate cancer via binding of HSP90.

scholarly journals PCa dynamics with neuroendocrine differentiation and distributed delay

2021 ◽  
Vol 18 (6) ◽  
pp. 8577-8602
Author(s):  
Leo Turner ◽  
◽  
Andrew Burbanks ◽  
Marianna Cerasuolo
Keyword(s):  
Prostate Cancer ◽  
Mathematical Models ◽  
Sufficient Conditions ◽  
Distributed Delay ◽  
Neuroendocrine Differentiation ◽  
Delay Distribution ◽  
Delay Dynamical System ◽  
Neuroendocrine Transdifferentiation ◽  
The Stability

<abstract><p>Prostate cancer is the fifth most common cause of death from cancer, and the second most common diagnosed cancer in men. In the last few years many mathematical models have been proposed to describe the dynamics of prostate cancer under treatment. So far one of the major challenges has been the development of mathematical models that would represent <italic>in vivo</italic> conditions and therefore be suitable for clinical applications, while being mathematically treatable. In this paper, we take a step in this direction, by proposing a nonlinear distributed-delay dynamical system that explores neuroendocrine transdifferentiation in human prostate cancer <italic>in vivo</italic>. Sufficient conditions for the existence and the stability of a tumour-present equilibrium are given, and the occurrence of a Hopf bifurcation is proven for a uniform delay distribution. Numerical simulations are provided to explore differences in behaviour for uniform and exponential delay distributions. The results suggest that the choice of the delay distribution is key in defining the dynamics of the system and in determining the conditions for the onset of oscillations following a switch in the stability of the tumour-present equilibrium.</p></abstract>

scholarly journals Long noncoding RNA LINC00261 suppresses prostate cancer tumorigenesis through upregulation of GATA6-mediated DKK3

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Yang Li ◽  
Hai Li ◽  
Xin Wei
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Prostate Cancer Progression ◽  
Aberrant Expression

Abstract Background Prostate cancer is one of the leading causes of cancer death in males. Recent studies have reported aberrant expression of lncRNAs in prostate cancer. This study explores the role of LINC00261 in prostate cancer progression. Methods The differentially expressed genes, transcription factors, and lncRNAs related to prostate cancer were predicted by bioinformatics analysis. Prostate cancer tissue samples and cell lines were collected for the determination of the expression of LINC00261 by reverse transcription quantitative polymerase chain reaction. The binding capacity of LINC00261 to the transcription factor GATA6 was detected by RIP, and GATA6 binding to the DKK3 promoter region was assessed by ChIP. In addition, luciferase reporter system was used to verify whether LINC00261 was present at the DKK3 promoter. After gain- and loss-of function approaches, the effect of LINC00261 on prostate cancer in vitro and in vivo was assessed by the determination of cell proliferation, invasion and migration as well as angiogenesis. Results LINC00261, GATA6, and DKK3 were poorly expressed in prostate cancer. LINC00261 could inhibit transcriptional expression of DKK3 by recruiting GATA6. Overexpression of LINC00261 inhibited prostate cancer cells proliferation, migration, and invasion as well as angiogenesis, which could be reversed by silencing DKK3. Furthermore, LINC00261 could also suppress the tumorigenicity of cancer cells in vivo. Conclusions Our study demonstrates the inhibitory role of LINC00261 in prostate cancer progression, providing a novel biomarker for early detection of prostate cancer.

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