scholarly journals Bicyclic RGD Peptides with Exquisite Selectivity for the Integrin αvβ3 Receptor Using a “Random Design” Approach

2019 ◽  
Vol 21 (3) ◽  
pp. 198-206 ◽  
Author(s):  
Dominik Bernhagen ◽  
Vanessa Jungbluth ◽  
Nestor Gisbert Quilis ◽  
Jakub Dostalek ◽  
Paul B. White ◽  
...  
Keyword(s):  
Integrin Αvβ3 ◽  
Design Approach ◽  
Rgd Peptides ◽  
Random Design ◽  
Αvβ3 Receptor

Integrin αvβ3 Receptor Overexpressing on Tumor-Targeted Positive MRI-Guided Chemotherapy

2019 ◽  
Vol 12 (1) ◽  
pp. 163-176 ◽  
Author(s):  
Renuka Khatik ◽  
Zhengyun Wang ◽  
Debo Zhi ◽  
Sonia Kiran ◽  
Pankaj Dwivedi ◽  
...  
Keyword(s):  
Integrin Αvβ3 ◽  
Mri Guided ◽  
Αvβ3 Receptor

scholarly journals MicroPET Imaging of Integrin αvβ3 Expressing Tumors Using 89Zr-RGD Peptides

2010 ◽  
Vol 13 (6) ◽  
pp. 1224-1233 ◽  
Author(s):  
Orit Jacobson ◽  
Lei Zhu ◽  
Gang Niu ◽  
Ido D. Weiss ◽  
Lawrence P. Szajek ◽  
...  
Keyword(s):  
Integrin Αvβ3 ◽  
Rgd Peptides ◽  
Micropet Imaging

scholarly journals Non-cationic RGD-containing protein carrier for tumor-targeted siRNA delivery

2021 ◽  
Author(s):  
Xiaolin Yu ◽  
Lu Xue ◽  
Jingjing Zhao ◽  
Shuhua Zhao ◽  
Daqing Wu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Sirna Delivery ◽  
Integrin Αvβ3 ◽  
Cationic Liposome ◽  
Genetically Engineered ◽  
Endosomal Escape ◽  
Widespread Application ◽  
Rgd Peptides

Abstract Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effect, poor clearance, low serum stability, and high toxicity. In this study, we have genetically engineered a non-cationic tumor-targeted universal siRNA nanocarrier. This protein nanocarrier consists of three function domains: dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidines for endosome escape, and two RGD peptides at N-and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specific targets on integrin αvβ3 expressing cells in vitro, and homes siRNA to tumor in vivo. The delivered siRNA leads target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional, biomimetic, charge-neutral siRNA carrier is biodegradable, low toxic, suitable for mass production by fermentation, and serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.

Combined EZH2 and BCL2 Inhibitors As Precision Therapy for Genetically Defined DLBCL Subtypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 304-304 ◽  
Author(s):  
Destini Gibbs ◽  
Herman Van Besien ◽  
Stephenson Regan ◽  
Ankur Singh ◽  
Matthew Teater ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Combination Therapy ◽  
Cell Lines ◽  
Integrin Αvβ3 ◽  
Model Systems ◽  
Live Cells ◽  
Advisory Committees ◽  
Rgd Peptides ◽  
Nsg Mice ◽  
Precision Therapy

DLCBL has recently been classified into genetically defined subtypes based on groupings of particular genetic lesions (Chapuy et al, Nat Med 2018; Schmitz et al, NEJM 2018). One predominant cluster, C3 or EZB, is defined by mutations in the chromatin modifying genes EZH2, KMT2D, and CREBBP as well as alterations in BCL2 including mutations and/or translocation of BCL2 to the IgH enhancer. Since tumors in this cluster are likely dependent on both EZH2 and BCL2, and these oncogenes carry out their effects through distinct mechanisms and pathways, targeting both of these oncogenes is a rational therapeutic approach. We hypothesized that EZH2 inhibition and BCL2 inhibition would be synergistic in DLBCL with characteristics of the C3/EZB cluster. To test this, we evaluated the EZH2 inhibitor tazemetostat and the BCL2 inhibitor venetoclax in DLBCL cells, 3D lymphoma organoids, and patient derived xenografts. To assess the effect of combination therapy with tazemetostat and venetoclax, we administered each drug alone and the combination in a panel of DLBCL cell lines, including cells with and without EZH2 mutation and BCL2 translocation. In DLBCL cells with both a BCL2 translocation and EZH2 mutation, the combination resulted in increased killing compared to either drug alone (Figure 1, SUDHL6 (p<0.005), WSU-DLCL2 (p<0.005), and OCI-LY1 (p<0.005)). In contrast, in cells with WT EZH2 and no BLC2 translocation, the effect of the combination was not different than either drug alone. To evaluate for synergy, cells were exposed to increasing doses of each drug alone and the combination. The combined response was evaluated using the Chou-Talalay method. Synergy between tazemetostat and venetoclax was observed in SUDLH-6 (CI value 0.03), WSU-DLCL2 (CI 0.26) and OCI-LY1 (CI 0.06) but not in Farage and LY7 both of which have WT EZH2 and no BCL2 translocation. Since cell lines in suspension do not reflect lymph node architecture, we developed a 3D lymphoma "organoid" culture system that consists of extracellular matrix, lymphoma cells, and stromal cells (Tian et al, Biomaterials 2015; Beguelin et al, Nat Commun 2017). GCB-DLBCLs express integrin αvβ3 that may bind to RGD peptides or vitronectin in tumor extracellular matrix. Based on this, we developed matrix metalloproteinase (MMP)-degradable 3D lymphoma hydrogels functionalized with RGD peptides. To generate organoids, we homogeneously encapsulated DLBCL cells (40,000/gel) in 10 µL hydrogel droplets fabricated in individual wells of a 96-well plate. We established two organoid systems to evaluate response to tazemetostat/venetoclax combination therapy: 1) OCI-LY1 organoids; 2) patient derived xenograft (PDX) organoids. The PDX organoids were generated from a patient tumor after propagation in NSG mice. The PDX tumor harbors both a BCL2 translocation and EZH2 mutation. Organoid viability was evaluated using immunofluorescence for calcein AM (live cells) and ethidium homodimer (dead cells) as well as flow cytometry. In both OCI-Ly1 organoids and PDX organoids, tazemetostat and venetoclax had minimal activity as single agents, however the combination resulted in significant cell killing (Figure 2). To investigate potential mechanisms of synergy, we evaluated RNA-seq profiles of a panel of DLBCL cell lines (n=26) treated with vehicle vs. EZH2 inhibitor (Brach et al, Mol Cancer Ther 2017). Preliminary data suggest that EZH2 inhibition induces expression of pro-apoptotic proteins genes including BCL2L11 (Wilcoxon p=0.01), BAD (p=0.02), BMF (p<0.01), BCL2L13 (p=0.02), and BCL2L14 (p<0.01). BCL2 inhibition with venetoclax may be further enhancing pro-apoptotic signals and lymphoma cell death, especially in C3/EZB DLBCL tumors with dependence on BCL2. In summary, using novel model systems, we have demonstrated that BCL2 inhibition combined with EZH2 inhibition results in synergistic anti-tumor effect that is anticipated to be especially effective as precision therapy for the newly identified cluster 3/EZB DLBCL subtype. A clinical trial of this combination is currently in development. Disclosures Melnick: Janssen: Research Funding; Constellation: Consultancy; Epizyme: Consultancy. Roth:Janssen: Consultancy; ADC Therapuetics: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Thyroid Hormones Interaction With Immune Response, Inflammation and Non-thyroidal Illness Syndrome

2021 ◽  
Vol 8 ◽  
Author(s):  
Roberto De Luca ◽  
Paul J. Davis ◽  
Hung-Yun Lin ◽  
Fabio Gionfra ◽  
Zulema A. Percario ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Thyroid Hormones ◽  
Viral Infections ◽  
Integrin Αvβ3 ◽  
Direct Consequence ◽  
Stable Complex ◽  
Αvβ3 Receptor ◽  
Hpt Axis ◽  
Genomic Response

The interdependence between thyroid hormones (THs), namely, thyroxine and triiodothyronine, and immune system is nowadays well-recognized, although not yet fully explored. Synthesis, conversion to a bioactive form, and release of THs in the circulation are events tightly supervised by the hypothalamic–pituitary–thyroid (HPT) axis. Newly synthesized THs induce leukocyte proliferation, migration, release of cytokines, and antibody production, triggering an immune response against either sterile or microbial insults. However, chronic patho-physiological alterations of the immune system, such as infection and inflammation, affect HPT axis and, as a direct consequence, THs mechanism of action. Herein, we revise the bidirectional crosstalk between THs and immune cells, required for the proper immune system feedback response among diverse circumstances. Available circulating THs do traffic in two distinct ways depending on the metabolic condition. Mechanistically, internalized THs form a stable complex with their specific receptors, which, upon direct or indirect binding to DNA, triggers a genomic response by activating transcriptional factors, such as those belonging to the Wnt/β-catenin pathway. Alternatively, THs engage integrin αvβ3 receptor on cell membrane and trigger a non-genomic response, which can also signal to the nucleus. In addition, we highlight THs-dependent inflammasome complex modulation and describe new crucial pathways involved in microRNA regulation by THs, in physiological and patho-physiological conditions, which modify the HPT axis and THs performances. Finally, we focus on the non-thyroidal illness syndrome in which the HPT axis is altered and, in turn, affects circulating levels of active THs as reported in viral infections, particularly in immunocompromised patients infected with human immunodeficiency virus.

scholarly journals Non-Cationic RGD-Containing Protein Nanocarrier for Tumor-Targeted siRNA Delivery

Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2182
Author(s):  
Xiaolin Yu ◽  
Lu Xue ◽  
Jing Zhao ◽  
Shuhua Zhao ◽  
Daqing Wu ◽  
...  
Keyword(s):  
Targeted Delivery ◽  
Sirna Delivery ◽  
Integrin Αvβ3 ◽  
Genetically Engineered ◽  
Endosomal Escape ◽  
Widespread Application ◽  
Rgd Peptides ◽  
Low Toxicity

Despite the recent successes in siRNA therapeutics, targeted delivery beyond the liver remains the major hurdle for the widespread application of siRNA in vivo. Current cationic liposome or polymer-based delivery agents are restricted to the liver and suffer from off-target effects, poor clearance, low serum stability, and high toxicity. In this study, we genetically engineered a non-cationic non-viral tumor-targeted universal siRNA nanocarrier (MW 26 KDa). This protein nanocarrier consists of three function domains: a dsRNA binding domain (dsRBD) (from human protein kinase R) for any siRNA binding, 18-histidine for endosome escape, and two RGD peptides at the N- and C-termini for targeting tumor and tumor neovasculature. We showed that cloned dual-RGD-dsRBD-18his (dual-RGD) protein protects siRNA against RNases, induces effective siRNA endosomal escape, specifically targets integrin αvβ3 expressing cells in vitro, and homes siRNA to tumors in vivo. The delivered siRNA leads to target gene knockdown in the cell lines and tumor xenografts with low toxicity. This multifunctional and biomimetic siRNA carrier is biodegradable, has low toxicity, is suitable for mass production by fermentation, and is serum stable, holding great potential to provide a widely applicable siRNA carrier for tumor-targeted siRNA delivery.

scholarly journals Hybrid PET/optical imaging of integrin αVβ3 receptor expression using a 64Cu-labeled streptavidin/biotin-based dimeric RGD peptide

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Choong Mo Kang ◽  
Hyun-Jung Koo ◽  
Gwang Il An ◽  
Yearn Seong Choe ◽  
Joon Young Choi ◽  
...  
Keyword(s):  
Optical Imaging ◽  
Integrin Αvβ3 ◽  
Rgd Peptide ◽  
Receptor Expression ◽  
Dimeric Rgd Peptide ◽  
Αvβ3 Receptor
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