Bis(thiosemicarbazone)copper(I) Complexes as Prospective Therapeutic Agents: Interaction with DNA/BSA Molecules, and In Vitro and In Vivo Anti-Proliferative Activities

2018 ◽  
Vol 3 (25) ◽  
pp. 7100-7111 ◽  
Author(s):  
Dharmasivam Mahendiran ◽  
Narayanaperumal Pravin ◽  
Nattamai S. P. Bhuvanesh ◽  
Raju Senthil Kumar ◽  
Vijayan Viswanathan ◽  
...  
Keyword(s):  
Therapeutic Agents

scholarly journals Tumor-Targeting Peptides Search Strategy for the Delivery of Therapeutic and Diagnostic Molecules to Tumor Cells

2020 ◽  
Vol 22 (1) ◽  
pp. 314
Author(s):  
Maria D. Dmitrieva ◽  
Anna A. Voitova ◽  
Maya A. Dymova ◽  
Vladimir A. Richter ◽  
Elena V. Kuligina
Keyword(s):  
Phage Display ◽  
Cell Sorting ◽  
Targeted Delivery ◽  
Tumor Targeting ◽  
Search Strategy ◽  
Tumor Therapy ◽  
Therapeutic Agents ◽  
Phage Libraries

Background: The combination of the unique properties of cancer cells makes it possible to find specific ligands that interact directly with the tumor, and to conduct targeted tumor therapy. Phage display is one of the most common methods for searching for specific ligands. Bacteriophages display peptides, and the peptides themselves can be used as targeting molecules for the delivery of diagnostic and therapeutic agents. Phage display can be performed both in vitro and in vivo. Moreover, it is possible to carry out the phage display on cells pre-enriched for a certain tumor marker, for example, CD44 and CD133. Methods: For this work we used several methods, such as phage display, sequencing, cell sorting, immunocytochemistry, phage titration. Results: We performed phage display using different screening systems (in vitro and in vivo), different phage libraries (Ph.D-7, Ph.D-12, Ph.D-C7C) on CD44+/CD133+ and without enrichment U-87 MG cells. The binding efficiency of bacteriophages displayed tumor-targeting peptides on U-87 MG cells was compared in vitro. We also conducted a comparative analysis in vivo of the specificity of the accumulation of selected bacteriophages in the tumor and in the control organs (liver, brain, kidney and lungs). Conclusions: The screening in vivo of linear phage peptide libraries for glioblastoma was the most effective strategy for obtaining tumor-targeting peptides providing targeted delivery of diagnostic and therapeutic agents to glioblastoma.

scholarly journals Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo

2005 ◽  
Vol 201 (3) ◽  
pp. 385-396 ◽  
Author(s):  
Stefan Kraft ◽  
Tony Fleming ◽  
James M. Billingsley ◽  
Shih-Yao Lin ◽  
Marie-Hélène Jouvin ◽  
...  
Keyword(s):  
Pi3k Pathway ◽  
Therapeutic Agents ◽  
Allergic Reactions ◽  
Ecm Proteins ◽  
Broad Array ◽  
High Affinity Ige Receptor ◽  
Nonadherent Cells ◽  
Tetraspanin Cd63

High-affinity IgE receptor (FcεRI) cross-linking on mast cells (MCs) induces secretion of preformed allergy mediators (degranulation) and synthesis of lipid mediators and cytokines. Degranulation produces many symptoms of immediate-type allergic reactions and is modulated by adhesion to surfaces coated with specific extracellular matrix (ECM) proteins. The signals involved in this modulation are mostly unknown and their contribution to allergic reactions in vivo is unclear. Here we report the generation of monoclonal antibodies that potently suppress FcεRI-induced degranulation, but not leukotriene synthesis. We identified the antibody target as the tetraspanin CD63. Tetraspanins are membrane molecules that form multimolecular complexes with a broad array of molecules including ECM protein-binding β integrins. We found that anti-CD63 inhibits MC adhesion to fibronectin and vitronectin. Furthermore, anti-CD63 inhibits FcεRI-mediated degranulation in cells adherent to those ECM proteins but not in nonadherent cells. Thus the inhibition of degranulation by anti-CD63 correlates with its effect on adhesion. In support of a mechanistic linkage between the two types of inhibition, anti-CD63 had no effect on FcεRI-induced global tyrosine phosphorylation and calcium mobilization but impaired the Gab2–PI3K pathway that is known to be essential for both degranulation and adhesion. Finally, we showed that these antibodies inhibited FcεRI-mediated allergic reactions in vivo. These properties raise the possibility that anti-CD63 could be used as therapeutic agents in MC-dependent diseases.

scholarly journals Is There Potential for Repurposing Statins as Novel Antimicrobials?

2016 ◽  
Vol 60 (9) ◽  
pp. 5111-5121 ◽  
Author(s):  
Emma Hennessy ◽  
Claire Adams ◽  
F. Jerry Reen ◽  
Fergal O'Gara
Keyword(s):  
Serum Cholesterol ◽  
Bacterial Growth ◽  
Bacterial Infections ◽  
Statin Treatment ◽  
Therapeutic Agents ◽  
Pleiotropic Effects ◽  
Current Information ◽  
Potential Use

ABSTRACTStatins are members of a class of pharmaceutical widely used to reduce high levels of serum cholesterol. In addition, statins have so-called “pleiotropic effects,” which include inflammation reduction, immunomodulation, and antimicrobial effects. An increasing number of studies are emerging which detail the attenuation of bacterial growth andin vitroandin vivovirulence by statin treatment. In this review, we describe the current information available concerning the effects of statins on bacterial infections and provide insight regarding the potential use of these compounds as antimicrobial therapeutic agents.

scholarly journals TTI-281, an Orally Bioavailable Bromodomain and Extraterminal Domain (BET) Inhibitor, Is a Promising Candidate for the Treatment of Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2095-2095
Author(s):  
Zezhou Wang ◽  
Jaehyun Choi ◽  
Peter Dove ◽  
Chunlei Wang ◽  
Aaron D. Schimmer ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Therapeutic Agents ◽  
Vehicle Control ◽  
Advisory Committees ◽  
Bet Inhibitor ◽  
Low Toxicity ◽  
Orally Bioavailable

Abstract Although recent advances in the development of multiple myeloma (MM) therapies such as proteasome inhibitors and immunomodulatory agents have improved patient outcomes, MM remains incurable. Additional therapeutic agents with high efficacy, low toxicity and the convenience of oral administration are in high demand. BET inhibitors, such as JQ-1, have been considered as potential therapeutic agents for MM. In the present study, we report that TTI-281, an orally bioavailable BET inhibitor, displays anti-MM activity with a low toxicity profile in preclinical studies. First, TTI-281 was tested for binding and anti-tumor activity in vitro. BROMOscan and AlphaScreen assays demonstrated that TTI-281 bound to bromodomains of BRD2/BRD3/BRD4 with Kd values less than 10 nM. In MTS assays, TTI-281 inhibited the growth of MM cell lines (MM.1s, NCIH929, and RPMI-8826) with cell growth-inhibition (IC50) values less than 300 nM. Next, in vitro ADME screening and in vivo PK studies were conducted. Permeability assays using murine gastrointestinal epithelial cells indicated that TTI-281 had good permeability with little efflux liability (efflux ratio <1), suggesting favorable properties for oral absorption. Indeed, TTI-281 displayed excellent oral bioavailability in both mice and rats (93.1% and 91.8%, respectively). In addition, TTI-281 did not interfere with the metabolism of representative CYP isozyme substrates at concentrations up to 50 μM in pooled human liver microsomes. Data also suggested minimal potential for drug-drug interactions, allowing for the possible combination with first-line therapy to improve therapeutic and survival outcomes. Finally, TTI-281 was tested for anti-myeloma efficacy and tolerability in vivo. NOD-SCID mice (n=10/group) subcutaneously engrafted with the human myeloma cell line MM.1S were treated orally once daily for 21 days with different doses of TTI-281, vehicle control or the benchmark drug carfilzomib. TTI-281 reduced tumor growth in a dose-dependent manner in this MM xenograft model. At 30 mg/kg/day, TTI-281 led to a statistically significant decrease in tumor growth compared with the vehicle control and carfilzomib (reduced tumor volume: 67% after TTI-281 treatment vs 33% after carfilzomib treatment, p<0.0003). Furthermore, TTI-281 treatment was well tolerated, with no effect on body weight or other obvious toxicity. In summary, our preclinical data suggest that the orally available BET inhibitor TTI-281 has an excellent efficacy and safety profile, highlighting its potential as a promising drug candidate for myeloma therapy. Disclosures Wang: Trillium Therapeutics: Employment, Patents & Royalties. Choi:Trillium Therapeutics: Employment. Dove:Trillium Therapeutics: Employment, Patents & Royalties. Wang:Trillium Therapeutics: Employment. Schimmer:Novartis: Honoraria. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Slassi:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

scholarly journals 536 In vitro and in vivo efficacy of nitric oxide-releasing antiviral therapeutic agents

2016 ◽  
Vol 136 (5) ◽  
pp. S95
Author(s):  
K.A. McHale ◽  
K. Balogh ◽  
H. Wang ◽  
S. Hollenbach ◽  
N. Christensen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Therapeutic Agents ◽  
In Vivo Efficacy ◽  
Nitric Oxide Releasing

The development of ruthenium(ii) polypyridyl complexes and conjugates forin vitrocellular andin vivoapplications

2017 ◽  
Vol 46 (24) ◽  
pp. 7706-7756 ◽  
Author(s):  
Fergus E. Poynton ◽  
Sandra A. Bright ◽  
Salvador Blasco ◽  
D. Clive Williams ◽  
John M. Kelly ◽  
...  
Keyword(s):  
Therapeutic Agents ◽  
Polypyridyl Complexes

A detailed overview of the development of Ru(ii) polypyridyl complexes as diagnostic and therapeutic agentsin vitroandin vivo.

scholarly journals Development of an LDL Receptor-Targeted Peptide Susceptible to Facilitate the Brain Access of Diagnostic or Therapeutic Agents

Biology ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 161
Author(s):  
Séverine André ◽  
Lionel Larbanoix ◽  
Sébastien Verteneuil ◽  
Dimitri Stanicki ◽  
Denis Nonclercq ◽  
...  
Keyword(s):  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Therapeutic Agents ◽  
In Vivo Studies ◽  
Phage Display Technology ◽  
Brain Penetration ◽  
Wide Range ◽  
The Brain

Blood-brain barrier (BBB) crossing and brain penetration are really challenging for the delivery of therapeutic agents and imaging probes. The development of new crossing strategies is needed, and a wide range of approaches (invasive or not) have been proposed so far. The receptor-mediated transcytosis is an attractive mechanism, allowing the non-invasive penetration of the BBB. Among available targets, the low-density lipoprotein (LDL) receptor (LDLR) shows favorable characteristics mainly because of the lysosome-bypassed pathway of LDL delivery to the brain, allowing an intact discharge of the carried ligand to the brain targets. The phage display technology was employed to identify a dodecapeptide targeted to the extracellular domain of LDLR (ED-LDLR). This peptide was able to bind the ED-LDLR in the presence of natural ligands and dissociated at acidic pH and in the absence of calcium, in a similar manner as the LDL. In vitro, our peptide was endocytosed by endothelial cells through the caveolae-dependent pathway, proper to the LDLR route in BBB, suggesting the prevention of its lysosomal degradation. The in vivo studies performed by magnetic resonance imaging and fluorescent lifetime imaging suggested the brain penetration of this ED-LDLR-targeted peptide.

scholarly journals Pharmaceutical Applications of Molecular Tweezers, Clefts and Clips

Molecules ◽  
2019 ◽  
Vol 24 (9) ◽  
pp. 1803 ◽  
Author(s):  
Amira Mbarek ◽  
Ghina Moussa ◽  
Jeanne Leblond Chain
Keyword(s):  
Cardiovascular Disease ◽  
Neurodegenerative Disorders ◽  
Therapeutic Agents ◽  
Mechanistic Studies ◽  
Molecular Tweezers ◽  
The Past ◽  
Pharmaceutical Applications ◽  
Controlled Motion

Synthetic acyclic receptors, composed of two arms connected with a spacer enabling molecular recognition, have been intensively explored in host-guest chemistry in the past decades. They fall into the categories of molecular tweezers, clefts and clips, depending on the geometry allowing the recognition of various guests. The advances in synthesis and mechanistic studies have pushed them forward to pharmaceutical applications, such as neurodegenerative disorders, infectious diseases, cancer, cardiovascular disease, diabetes, etc. In this review, we provide a summary of the synthetic molecular tweezers, clefts and clips that have been reported for pharmaceutical applications. Their structures, mechanism of action as well as in vitro and in vivo results are described. Such receptors were found to selectively bind biological guests, namely, nucleic acids, sugars, amino acids and proteins enabling their use as biosensors or therapeutics. Particularly interesting are dynamic molecular tweezers which are capable of controlled motion in response to an external stimulus. They proved their utility as imaging agents or in the design of controlled release systems. Despite some issues, such as stability, cytotoxicity or biocompatibility that still need to be addressed, it is obvious that molecular tweezers, clefts and clips are promising candidates for several incurable diseases as therapeutic agents, diagnostic or delivery tools.

scholarly journals Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer

Medicines ◽  
2019 ◽  
Vol 6 (1) ◽  
pp. 17 ◽  
Author(s):  
Maryam Nakhjavani ◽  
Jennifer E Hardingham ◽  
Helen M Palethorpe ◽  
Yoko Tomita ◽  
Eric Smith ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Metastatic Breast ◽  
Therapeutic Agents ◽  
Ginsenoside Rg3 ◽  
Cancer Models ◽  
Anti Cancer ◽  
Ginseng Plant

Breast cancer is still one of the most prevalent cancers and a leading cause of cancer death worldwide. The key challenge with cancer treatment is the choice of the best therapeutic agents with the least possible toxicities on the patient. Recently, attention has been drawn to herbal compounds, in particular ginsenosides, extracted from the root of the Ginseng plant. In various studies, significant anti-cancer properties of ginsenosides have been reported in different cancers. The mode of action of ginsenoside Rg3 (Rg3) in in vitro and in vivo breast cancer models and its value as an anti-cancer treatment for breast cancer will be reviewed.

scholarly journals Tiny Actors in the Big Cellular World: Extracellular Vesicles Playing Critical Roles in Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7688 ◽  
Author(s):  
Ancuta Jurj ◽  
Cecilia Pop-Bica ◽  
Ondrej Slaby ◽  
Cristina D. Ştefan ◽  
William C. Cho ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Molecular Mechanisms ◽  
Recipient Cell ◽  
Cell Communication ◽  
Therapeutic Agents ◽  
Bioactive Molecules ◽  
Cellular Functions ◽  
Membrane Bound

Communications among cells can be achieved either via direct interactions or via secretion of soluble factors. The emergence of extracellular vesicles (EVs) as entities that play key roles in cell-to-cell communication offer opportunities in exploring their features for use in therapeutics; i.e., management and treatment of various pathologies, such as those used for cancer. The potential use of EVs as therapeutic agents is attributed not only for their cell membrane-bound components, but also for their cargos, mostly bioactive molecules, wherein the former regulate interactions with a recipient cell while the latter trigger cellular functions/molecular mechanisms of a recipient cell. In this article, we highlight the involvement of EVs in hallmarks of a cancer cell, particularly focusing on those molecular processes that are influenced by EV cargos. Moreover, we explored the roles of RNA species and proteins carried by EVs in eliciting drug resistance phenotypes. Interestingly, engineered EVs have been investigated and proposed as therapeutic agents in various in vivo and in vitro studies, as well as in several clinical trials.

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