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.

scholarly journals Targeting melanoma’s MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Matthew J. Sale ◽  
Emma Minihane ◽  
Noel R. Monks ◽  
Rebecca Gilley ◽  
Frances M. Richards ◽  
...  
Keyword(s):  
Cell Death ◽  
Patient Outcomes ◽  
Tumour Growth ◽  
Therapeutic Index ◽  
Synthetic Lethal ◽  
Bcl2 Family ◽  
Family Activity ◽  
Pathway Inhibition ◽  
Tumour Cell Death

AbstractBRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-XL expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-XL inhibitors is stronger in CRC, correlating with a low MCL1:BCL-XL ratio; indeed the MCL1:BCL-XL ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-XL inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.

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>

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

scholarly journals Reduced Contraction of Blood Clots in Venous Thromboembolism Is a Potential Thrombogenic and Embologenic Mechanism

TH Open ◽  
2018 ◽  
Vol 02 (01) ◽  
pp. e104-e115 ◽  
Author(s):  
Alina Peshkova ◽  
Dmitry Malyasyov ◽  
Roman Bredikhin ◽  
Giang Le Minh ◽  
Izabella Andrianova ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Ex Vivo ◽  
Blood Clot ◽  
Chemical Activation ◽  
Healthy Controls ◽  
Activation Markers ◽  
Fold Reduction ◽  
Blood Clots ◽  
Clot Contraction

AbstractContraction (retraction) of the blood clot is a part of the clotting process driven by activated platelets attached to fibrin that can potentially modulate the obstructiveness and integrity of thrombi. The aim of this work was to reveal the pathogenic importance of contraction of clots and thrombi in venous thromboembolism (VTE). We investigated the kinetics of clot contraction in the blood of 55 patients with VTE. In addition, we studied the ultrastructure of ex vivo venous thrombi as well as the morphology and functionality of isolated platelets. Thrombi from VTE patients contained compressed polyhedral erythrocytes, a marker for clot contraction in vivo. The extent and rate of contraction were reduced by twofold in clots from the blood of VTE patients compared with healthy controls. The contraction of clots from the blood of patients with pulmonary embolism was significantly impaired compared with that of those with isolated venous thrombosis, suggesting that less compacted thrombi are prone to embolization. The reduced ability of clots to contract correlated with continuous platelet activation followed by their partial refractoriness. Morphologically, 75% of platelets from VTE patients were spontaneously activated (with filopodia) compared with only 21% from healthy controls. At the same time, platelets from VTE patients showed a 1.4-fold reduction in activation markers expressed in response to chemical activation when compared with healthy individuals. The results obtained suggest that the impaired contraction of thrombi is an underappreciated pathogenic mechanism in VTE that may regulate the obstructiveness and embologenicity of venous thrombi.

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