Integrins have been extensively investigated as therapeutic targets over the last decades, which has been inspired by their multiple functions in cancer progression, metastasis, and angiogenesis as well as a continuously expanding number of other diseases, e.g., sepsis, fibrosis, and viral infections, possibly also Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2). Although integrin-targeted (cancer) therapy trials did not meet the high expectations yet, integrins are still valid and promising targets due to their elevated expression and surface accessibility on diseased cells. Thus, for the future successful clinical translation of integrin-targeted compounds, revisited and innovative treatment strategies have to be explored based on accumulated knowledge of integrin biology. For this, refined approaches are demanded aiming at alternative and improved preclinical models, optimized selectivity and pharmacological properties of integrin ligands, as well as more sophisticated treatment protocols considering dose fine-tuning of compounds. Moreover, integrin ligands exert high accuracy in disease monitoring as diagnostic molecular imaging tools, enabling patient selection for individualized integrin-targeted therapy. The present review comprehensively analyzes the state-of-the-art knowledge on the roles of RGD-binding integrin subtypes in cancer and non-cancerous diseases and outlines the latest achievements in the design and development of synthetic ligands and their application in biomedical, translational, and molecular imaging approaches. Indeed, substantial progress has already been made, including advanced ligand designs, numerous elaborated pre-clinical and first-in-human studies, while the discovery of novel applications for integrin ligands remains to be explored.

Cisplatin occupies a crucial role in the treatment of various malignant tumours. However, its efficacy and applicability are heavily restricted by severe systemic toxicities and drug resistance. Our study exploits the active targeting of supramolecular metallacages to enhance the activity of cisplatin in cancer cells while reducing its toxicity. Thus, Pd2L4 cages (L = ligand) have been conjugated to four integrin ligands with different binding affinity and selectivity. Cage formation and encapsulation of cisplatin was proven by NMR spectroscopy. Upon encapsulation, cisplatin showed increased cytotoxicity in vitro, in melanoma A375 cells overexpressing αvβ3 integrins. Moreover, ex vivo studies in tissue slices indicated reduced toxicity towards healthy liver and kidney tissues for cage-encapsulated cisplatin. Analysis of metal content by ICP-MS demonstrated that encapsulated drug is less accumulated in these organs compared to the 'free' one.

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Human brain cells generated by in vitro cell programming provide exciting prospects for disease modeling, drug discovery and cell therapy. These applications frequently require efficient and clinically compliant tools for genetic modification of the cells. Recombinant adeno-associated viruses (AAVs) fulfill these prerequisites for a number of reasons, including the availability of a myriad of AAV capsid variants with distinct cell type specificity (also called tropism). Here, we harnessed a customizable parallel screening approach to assess a panel of natural or synthetic AAV capsid variants for their efficacy in lineage-related human neural cell types. We identified common lead candidates suited for the transduction of directly converted, early-stage induced neural stem cells (iNSCs), induced pluripotent stem cell (iPSC)-derived later-stage, radial glia-like neural progenitors, as well as differentiated astrocytic and mixed neuroglial cultures. We then selected a subset of these candidates for functional validation in iNSCs and iPSC-derived astrocytes, using shRNA-induced downregulation of the citrate transporter SLC25A1 and overexpression of the transcription factor NGN2 for proofs-of-concept. Our study provides a comparative overview of the susceptibility of different human cell programming-derived brain cell types to AAV transduction and a critical discussion of the assets and limitations of this specific AAV capsid screening approach.

Functional selectivity is the ligand-specific activation of certain signal transduction pathways at a receptor and has been described for G protein-coupled receptors. However, it has not yet been described for ligands interacting with integrins without αI domain. Here, we show by molecular dynamics simulations that four side chain-modified derivatives of tauroursodeoxycholic acid (TUDC), an agonist of α 5 β 1 integrin, differentially shift the conformational equilibrium of α 5 β 1 integrin towards the active state, in line with the extent of β 1 integrin activation from immunostaining. Unlike TUDC, 24-norursodeoxycholic acid (norUDCA)-induced β 1 integrin activation triggered only transient activation of extracellular signal-regulated kinases and p38 mitogen-activated protein kinase and, consequently, only transient insertion of the bile acid transporter Bsep into the canalicular membrane, and did not involve activation of epidermal growth factor receptor. these results provide evidence that tUDc and norUDCA exert a functional selectivity at α 5 β 1 integrin and may provide a rationale for differential therapeutic use of UDcA and norUDcA.

Background: neoatherosclerosis represents an accelerated manifestation of atherosclerosis in nascent neointima after stenting, associated with adverse events. We investigated whether improved reendothelialization using RGD-coated stents results in diminished vascular permeability and reduced foam cell formation compared to standard DeS in atherosclerotic rabbits. Methods and Results: neointimal foam cell formation was induced in rabbits (n = 7). Enhanced endothelial integrity in RGDcoated stents resulted in decreased vascular permeability relative to DES, which was further confirmed by SEM and TEM. Cell culture experiments examined the effect of everolimus on endothelial integrity. increasing concentrations of everolimus resulted in a dose-dependent decrease of endothelial cell junctions and foam cell transformation of monocytes, confirming the relevance of endothelial integrity in preventing permeability of LDL. Conclusion: Incomplete endothelial integrity was confirmed as a key factor of neointimal foam cell formation following stent implantation. pro-healing stent coatings may facilitate reendothelialization and reduce the risk of neoatherosclerosis.