scholarly journals In vivo and ex vivo imaging of nociceptor expression and activity

2019 ◽  
Vol 11 (2) ◽  
pp. 3-3
Author(s):  
Marie MULIER ◽  
Joris VRIENS ◽  
Thomas VOETS
Keyword(s):  
Ex Vivo ◽  
Ex Vivo Imaging ◽  
Expression And Activity

Tumor Targeted Nanoparticles Improve Therapeutic Index of BCL2 and MCL1 dual inhibition

Blood ◽  
2020 ◽  
Author(s):  
Neeta Bala Tannan ◽  
Mandana T Manzari ◽  
Laurie Herviou ◽  
Mariana da Silva Ferreira ◽  
Connor J Hagen ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Therapeutic Index ◽  
Drug Dose ◽  
Hematological Toxicity ◽  
Bcl2 Family ◽  
Fold Reduction ◽  
Tumor Killing ◽  
Toxic Drugs ◽  
Ex Vivo Imaging

Cancer and normal cells utilize multiple anti-apoptotic BCL2 proteins to prevent cell death. Therapeutic targeting of multiple BCL2 family proteins enhances tumor killing, but is also associated with increased systemic toxicity. Here, we demonstrate that the dual targeting of MCL1 and BCL2 proteins, using the small molecules S63845 and venetoclax, induces durable remissions in mice harboring human DLBCL tumors but is accompanied by hematological toxicity and weight loss. To mitigate these toxicities, we encapsulated S63845 or venetoclax into nanoparticles targeting P-selectin that is enriched in tumor endothelial cells. In vivo and ex vivo imaging demonstrated preferential targeting of the nanoparticles to lymphoma tumors over vital organs. Mass-spectrometry analyses after nanoparticle drug administration confirmed tumor enrichment of the drug while reducing plasma levels. Furthermore, nanoparticle encapsulation allowed 3.5 to 6.5-fold reduction in drug dose, induced sustained remissions and minimized toxicity. Our results support the development of nanoparticles to deliver BH3 mimetic combinations in lymphoma and in general for toxic drugs in cancer therapy.

In-vivo near-infrared optical imaging of growing osteosarcoma cell lesions xenografted in mice: dual-channel quantitative evaluation of volume and mineralization

2011 ◽  
Vol 52 (9) ◽  
pp. 978-988 ◽  
Author(s):  
Hitoshi Nakayama ◽  
Tomoyuki Kawase ◽  
Kazuhiro Okuda ◽  
Larry F Wolff ◽  
Hiromasa Yoshie
Keyword(s):  
Optical Imaging ◽  
Near Infrared ◽  
Imaging Technique ◽  
Ex Vivo ◽  
Acquisition Time ◽  
Osteosarcoma Cell ◽  
Dual Channel ◽  
Nir Imaging ◽  
Ex Vivo Imaging

Background In a previous study using a rodent osteosarcoma-grafted rat model, in which cell-dependent mineralization was previously demonstrated to proportionally increase with growth, we performed a quantitative analysis of mineral deposit formation using 99mTc-HMDP and found some weaknesses, such as longer acquisition time and narrower dynamic ranges (i.e. images easily saturated). The recently developed near-infrared (NIR) optical imaging technique is expected to non-invasively evaluate changes in living small animals in a quantitative manner. Purpose To test the feasibility of NIR imaging with a dual-channel system as a better alternative for bone scintigraphy by quantitatively evaluating mineralization along with the growth of osteosarcoma lesions in a mouse-xenograft model. Material and Methods The gross volume and mineralization of osteosarcoma lesions were evaluated in living mice simultaneously with dual-channels by NIR dye-labeled probes, 2-deoxyglucose (DG) and pamidronate (OS), respectively. To verify these quantitative data, retrieved osteosarcoma lesions were then subjected to ex-vivo imaging, weighing under wet conditions, microfocus-computed tomography (μCT) analysis, and histopathological examination. Results Because of less scattering and no anatomical overlapping, as generally shown, specific fluorescence signals targeted to the osteosarcoma lesions could be determined clearly by ex-vivo imaging. These data were well positively correlated with the in-vivo imaging data ( r > 0.8, P < 0.02). Other good to excellent correlations ( r > 0.8, P < 0.02) were observed between DG accumulation and tumor gross volume and between OS accumulation and mineralization volume. Conclusion This in-vivo NIR imaging technique using DG and OS is sensitive to the level to simultaneously detect and quantitatively evaluate the growth and mineralization occuring in this type of osteosarcoma lesions of living mice without either invasion or sacrifice. By possible mutual complementation, this dual imaging system might be useful for accurate diagnosis even in the presence of overlapping tissues.

scholarly journals The Opportunities and Use of Imaging to Measure Target Engagement

2019 ◽  
Vol 25 (2) ◽  
pp. 127-136
Author(s):  
Juliana Maynard ◽  
Philippa Hart
Keyword(s):  
Ex Vivo ◽  
Clinical Success ◽  
Receptor Occupancy ◽  
Accurate Information ◽  
Target Engagement ◽  
Drug Molecule ◽  
Drug Discovery And Development ◽  
Ex Vivo Imaging

Lack of efficacy and poor safety outcomes are deemed to be the greatest causes of clinical failure of novel therapeutics. The use of biomarkers that give accurate information on target engagement, providing confidence that pharmacological activity in the target organ is being achieved, is key in optimizing clinical success. Without a measurement of target engagement, it can be very difficult to discern the basis for any lack of efficacy of a drug molecule within the pharmaceutical industry. Target engagement can be measured in both an in vitro and in vivo setting, and in recent years imaging measurements have been used frequently in drug discovery and development to assess target engagement and receptor occupancy in both human and animal models. From this perspective, we assess and look at the advancements in both in vivo and ex vivo imaging to demonstrate the enormous potential that imaging has as an application to provide a greater understanding of target engagement with a correlative therapeutic impact.

scholarly journals Highly Potent GalNAc-Conjugated Tiny LNA Anti-miRNA-122 Antisense Oligonucleotides

Pharmaceutics ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 817
Author(s):  
Tsuyoshi Yamamoto ◽  
Yahiro Mukai ◽  
Fumito Wada ◽  
Chisato Terada ◽  
Yukina Kayaba ◽  
...  
Keyword(s):  
Antisense Oligonucleotides ◽  
Ex Vivo ◽  
The Body ◽  
Locked Nucleic Acid ◽  
Imaging Studies ◽  
Phosphodiester Bond ◽  
Chemically Modified ◽  
Ex Vivo Imaging ◽  
Mirna Targeting

The development of clinically relevant anti-microRNA antisense oligonucleotides (anti-miRNA ASOs) remains a major challenge. One promising configuration of anti-miRNA ASOs called “tiny LNA (tiny Locked Nucleic Acid)” is an unusually small (~8-mer), highly chemically modified anti-miRNA ASO with high activity and specificity. Within this platform, we achieved a great enhancement of the in vivo activity of miRNA-122-targeting tiny LNA by developing a series of N-acetylgalactosamine (GalNAc)-conjugated tiny LNAs. Specifically, the median effective dose (ED50) of the most potent construct, tL-5G3, was estimated to be ~12 nmol/kg, which is ~300–500 times more potent than the original unconjugated tiny LNA. Through in vivo/ex vivo imaging studies, we have confirmed that the major advantage of GalNAc over tiny LNAs can be ascribed to the improvement of their originally poor pharmacokinetics. We also showed that the GalNAc ligand should be introduced into its 5′ terminus rather than its 3′ end via a biolabile phosphodiester bond. This result suggests that tiny LNA can unexpectedly be recognized by endogenous nucleases and is required to be digested to liberate the parent tiny LNA at an appropriate time in the body. We believe that our strategy will pave the way for the clinical application of miRNA-targeting small ASO therapy.

Multicolor core/shell silicananoparticles for in vivo and ex vivo imaging

Nanoscale ◽  
2012 ◽  
Vol 4 (3) ◽  
pp. 824-830 ◽  
Author(s):  
Enrico Rampazzo ◽  
Federico Boschi ◽  
Sara Bonacchi ◽  
Riccardo Juris ◽  
Marco Montalti ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Core Shell ◽  
Ex Vivo Imaging

scholarly journals Supramolecular Encapsulation of Small-Ultra Red Fluorescent Proteins in Virus-Like Nanoparticles for Non-Invasive In Vivo Imaging Agents

2020 ◽  
Author(s):  
Fabian C. Herbert ◽  
Olivia Brohlin ◽  
Tyler Galbraith ◽  
Candace Benjamin ◽  
Cesar A. Reyes ◽  
...  
Keyword(s):  
In Vivo Imaging ◽  
Fluorescent Protein ◽  
Fluorescent Proteins ◽  
Ex Vivo ◽  
Imaging Agents ◽  
Non Invasive ◽  
Red Fluorescent Proteins ◽  
Ex Vivo Imaging

<div> <div> <div> <p>Icosahedral virus-like particles (VLPs) derived from bacteriophages Qβ and PP7 encapsulating small-ultra red fluorescent protein (smURFP) were produced using a versatile supramolecualr capsid dissassemble-reassemble approach. The generated fluorescent VLPs display identical structural properties to their non-fluorescent analogs. Encapsulated smURFP shows indistinguishable photochemical properties to its unencapsulated counterpart, exhibits outstanding stability towards pH, and produces bright in vitro images following phagocytosis by macrophages. In vivo imaging allows biodistribution to be imaged at different time points. Ex vivo imaging of intravenously administered encapsulated smURFP reveleas localization in the liver and </p> </div> </div> <div> <div> <p>kidneys after 2 h blood circulation and substantial elimination constructs as non-invasive in vivo imaging agents. </p> </div> </div> </div>

Abstract 480: ACE2 Independent Pathways of Angiotensin 1-7 Formation in the Murine Kidney

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Oliver Domenig ◽  
Arndt Manzel ◽  
Johannes Stegbauer ◽  
Susan Gurley ◽  
Marlies Antlanger ◽  
...  
Keyword(s):  
Renal Cortex ◽  
Enzyme Inhibitors ◽  
Ex Vivo ◽  
Renin Angiotensin System ◽  
Therapeutic Interventions ◽  
Minor Role ◽  
Local Formation ◽  
Alternative Pathways ◽  
Expression And Activity

Fluid balance, salt retention and tissue remodeling is hormonally regulated by the Renin-Angiotensin-System. The sophisticated enzyme network serially cleaves peptide hormones generating various effector hormones including the vasoconstrictor Angiotensin 1-8 and its counterbalancing downstream metabolite Angiotensin 1-7. LC-MS/MS based analysis of kidney and plasma of ACE2 knockout mice revealed unchanged Angiotensin 1-7 concentrations compared to wild type animals pointing to alternative pathways of Angiotensin 1-7 formation and suggesting a minor role for ACE2 in the formation of Angiotensin 1-7 in vivo. Moreover, we observed a decrease in the Angiotensin 1-8/Angiotensin 1-10 ratio in ACE2KO-mice indicating a changed conversion rate from Angiotensin 1-10 to Angiotensin 1-8. We analyzed Angiotensin 1-7 metabolism in kidney homogenates by spiking natural substrates in the absence and presence of specific enzyme inhibitors. The metabolism of ex vivo spiked Angiotensins in kidney homogenates in presence and absence of the Prolyl-Carboxypepdidase (PCP) and Prolyl-Endopeptidase (PEP) Inhibitor ZPP and the ACE2-Inhibitor MLN-4760 revealed stronger contribution of PCP and PEP to Angiotensin 1-7 formation than ACE2. Analyzing the formation of Angiotensin 1-8 from Angiotensin 1-10 in renal cortex and medulla homogenates of WT and ACE2KO mice in the absence and presence of an ACE-Inhibitor confirmed our observations on endogenous peptide levels and the ratio between Angiotensin 1-8 and Angiotensin 1-10 in plasma, revealing a reduced ACE activity in the renal cortex of ACE2KO. Our study raises questions concerning the relevance of renal ACE2 for the local formation of Angiotensin 1-7. Moreover, the reduced ACE expression and activity in renal cortex might be a physiologically and therefore phenotype relevant consequence of the knockdown of ACE2 in these mice. The possible crosstalk between ACE and ACE2 expression and activity might give rise to further studies addressing the underlying mechanisms and might be important for our understanding of RAS dynamics in regard to therapeutic interventions.

In vivo and ex vivo Imaging with Ultrahigh Resolution Full-Field OCT

2005 ◽  
Author(s):  
Kate Grieve ◽  
Gael Moneron ◽  
Wilfrid Schwartz ◽  
Claude Boccara ◽  
Arnaud Dubois
Keyword(s):  
Ex Vivo ◽  
Ultrahigh Resolution ◽  
Full Field ◽  
Ex Vivo Imaging
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