Alternative Strategies for Delivering Immunotherapeutics Targeting the PD-1/PD-L1 Immune Checkpoint in Cancer.

The programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) immune checkpoint constitutes an inhibitory pathway best known for its regulation of cluster of differentiation 8 (CD8) T cell-mediated immune responses. Engagement of PD-L1 with PD-1 expressed on CD8 T cells activates downstream signaling pathways that culminate in T cell exhaustion and/or apoptosis. Physiologically, these immunosuppressive effects exist to prevent autoimmunity, but cancer cells exploit this pathway by overexpressing PD-L1 to facilitate immune escape.

Blood vessel wall shear stress determines regions of liposome accumulation in angiogenic vasculature.

Nanoparticles used for drug delivery often require intravenous administration exposing them to fluid forces within the vasculature, yet the impact of blood flow on nanoparticle delivery remains incompletely understood. Here, we utilized transgenic zebrafish embryos to investigate the relationship between the accumulation of fluorescently labeled PEGylated liposomes and various hemodynamic factors (such as flow velocity, wall shear stress (WSS), and flow pattern) across a wide range of angiogenic blood vessels. We reconstructed 3D models of vascular structures from confocal images and used computational fluid dynamics to calculate local WSS, velocities, and define flow patterns.

Omics approaches for the assessment of biological responses to nanoparticles.

Nanotechnology has enabled the development of innovative therapeutics, diagnostics, and drug delivery systems. Nanoparticles (NPs) can influence gene expression, protein synthesis, cell cycle, metabolism, and other subcellular processes. While conventional methods have limitations in characterizing responses to NPs, omics approaches can analyze complete sets of molecular entities that change upon exposure to NPs.

Critical design parameters to develop biomimetic organ-on-a-chip models for the evaluation of the safety and efficacy of nanoparticles.

Introduction: Organ-on-a-chip (OOC) models are based on microfluidics and can recapitulate the healthy and diseased microstructure of organs and tissues and the dynamic microenvironment inside the human body. However, the use of OOC models to evaluate the safety and efficacy of nanoparticles (NPs) is still in the early stages.

Areas Covered: The different design parameters of the microfluidic chip and the mechanical forces generated by fluid flow play a pivotal role in simulating the human environment.

Placental Nanoparticle Uptake-On-a-Chip: The Impact of Trophoblast Syncytialization and Shear Stress.

The placenta is a dynamic and complex organ that plays an essential role in the health and development of the fetus. Placental disorders can affect the health of both the mother and the fetus. There is currently an unmet clinical need to develop nanoparticle-based therapies to target and treat placental disorders.

The maternal-fetal transfer of passive immunity as a mechanism of transplacental nanoparticle drug delivery for prenatal therapies.

Nanoparticles administered into the maternal circulation and across the placenta are a potential clinical therapy to treat congenital diseases. The mechanism by which nanoparticles can safely cross the placenta for targeted drug delivery to the fetus remains poorly understood. We demonstrate that the maternal-fetal transfer of passive immunity through the neonatal Fc Receptor (FcRn) can induce the transplacental transfer of chitosan nanoparticles modifed with IgG antibodies (414 ± 27 nm).

Extracellular Vesicles as Predictors of Individual Response to Exercise Training in Youth Living with Obesity.

Background: Exercise is associated with health benefits, including the prevention and management of obesity. However, heterogeneity in the adaptive response to exercise training exists. Our objective was to evaluate if changes in extracellular vesicles (EVs) after acute aerobic exercise were associated with the responder phenotype following 6-weeks of resistance training (RT).

Characterizing Extracellular Vesicles and Particles Derived from Skeletal Muscle Myoblasts and Myotubes and the Effect of Acute Contractile Activity.

Extracellular vesicles (EVs), released from all cells, are essential to cellular communication and contain biomolecular cargo that can affect recipient cell function. Studies on the effects of contractile activity (exercise) on EVs usually rely on plasma/serum-based assessments, which contain EVs from many different cells. To specifically characterize skeletal muscle−derived vesicles and the effect of acute contractile activity, we used an in vitro model where C2C12 mouse myoblasts were differentiated to form myotubes.

Role of drug delivery technologies in the success of COVID-19 vaccines: a perspective.

The triumphant success of mRNA vaccines is a testimony to the important role drug delivery technologies have played in protecting billions of people against SARS-CoV-2 (or the Corona Virus Disease 2019; COVID-19). Several lipid nanoparticle (LNP) mRNA vaccines were developed and have been instrumental in preventing the disease by boosting the immune system against the pathogen, SARS-CoV-2. These vaccines have been built on decades of scientific research in drug delivery of mRNA, vaccines, and other biologicals.

Collagen - a newly discovered major player in protein corona formation on nanoparticles.

Tracking protein corona (PC) formation on the surface of nanoparticles (NPs) is a prerequisite for successful design of next generation nanocarriers with predictable fate and behavior. However, PC formation has mostly been investigated for plasma proteins without considering potential competition with the extravascular proteins either when the NPs exit the blood circulation or when they are injected extravascularly. This study investigates the deposition of collagen, an extravascular protein that is the most abundant in the body, and albumin, the most abundant vascular protein, on the surface of gold (Au) NPs using UV-Vis and fluorescence spectroscopy with the support of mathematical modeling.

Microfluidics for Development of Lipid Nanoparticles: Paving the Way for Nucleic Acids to the Clinic.

Nucleic acid therapeutics hold an unprecedented promise toward treating many challenging diseases; however, their use is hampered by delivery issues. Microfluidics, dealing with fluids in the microscale dimensions, have provided a robust means to screening raw materials for development of nano delivery vectors, in addition to controlling their size and minimizing their polydispersity. In this mini-review, we are briefly highlighting the different types of nucleic acid therapies with emphasis on the delivery requirement for each type.

Dynamic placenta-on-a-chip model for fetal risk assessment of nanoparticles intended to treat pregnancy-associated diseases.

Pregnant women often have to take medication either for pregnancy-related diseases or for previously existing medical conditions. Current maternal medications pose fetal risks due to off target accumulation in the fetus. Nanoparticles, engineered particles in the nanometer scale, have been used for targeted drug delivery to the site of action without off-target effects.

Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now.

Localized Plasmonic Photothermal Therapy as a Life-saving Treatment Paradigm for Hospitalized COVID-19 Patients.

Lung failure is the main reason for mortality in COVID-19 patients, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To date, no drug has been clinically approved for treatment of COVID-19. Nanotechnology has a great potential in contributing significantly to the fight against COVID-19 by developing effective therapies that can selectively eradicate the respiratory virus load.

Autophagy and SARS-CoV-2 infection: Apossible smart targeting of the autophagy pathway.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak resulted in 5,993,317 confirmed cases worldwide with 365,394 confirmed deaths (as of May 29, 2020, WHO). The molecular mechanism of virus infection and spread in the body is not yet disclosed, but studies on other betacoronaviruses show that, upon cell infection, these viruses inhibit macroautophagy/autophagy flux and cause the accumulation of autophagosomes. No drug has yet been approved for the treatment of SARS-CoV-2 infection; however, preclinical investigations suggested repurposing of several FDA-approved drugs for clinical trials.

Meta-Analysis of Nanoparticle Cytotoxicity via Data-Mining the Literature.

Developing predictive modeling frameworks of potential cytotoxicity of engineered nanoparticles is critical for environmental and health risk analysis. The complexity and the heterogeneity of available data on potential risks of nanoparticles, in addition to interdependency of relevant influential attributes, makes it challenging to develop a generalization of nanoparticle toxicity behavior. Lack of systematic approaches to investigate these risks further adds uncertainties and variability to the body of literature and limits generalizability of existing studies.

Nanoparticle localization in blood vessels: dependence on fluid shear stress, flow disturbances, and flow-induced changes in endothelial physiology.

Nanoparticles in the bloodstream are subjected to complex fluid forces as they move through the curves and branches of healthy or tumor vasculature. While nanoparticles are known to preferentially accumulate in angiogenic vessels, little is known about the flow conditions in these vessels and how these conditions may influence localization. Here, we report a methodology which combines confocal imaging of nanoparticle-injected transgenic zebrafish embryos, 3D modeling of the vasculature, particle mapping, and computational fluid dynamics, to quantitatively assess the effects of fluid forces on nanoparticle distribution in vivo.

Understanding and improving assays for cytotoxicity of nanoparticles: what really matters?

Despite years of excellent individual studies, the impact of nanoparticle (NP) cytotoxicity studies remains limited by inconsistent data collection and analysis. It is often unclear how exposure conditions can be used to determine cytotoxicity quantitatively. Discrepancies due to using different measurement conditions, readouts and controls to characterize NP interactions with cells lead to further challenges.

Surface-grafted polyethylene glycol conformation impacts the transport of PEG-functionalized liposomes through a tumour extracellular matrix model.

The effect of surface PEGylation on nanoparticle transport through an extracellular matrix (ECM) is an important determinant for tumor targeting success. Fluorescent stealth liposomes (base lipid DOPC) were prepared incorporating different proportions of PEG-grafted lipids (2.5, 5 and 10% of the total lipid content) for a series of PEG molecular weights (1000, 2000 and 5000 Da).

Calcifediol-loaded liposomes for local treatment of pulmonary bacterial infections.

The influence of vitamin D3 and its metabolites calcifediol (25(OH)D) and calcitriol on immune regulation and inflammation is well described, and raises the question of potential benefit against bacterial infections. In the current study, 25(OH)D was encapsulated in liposomes to enable aerosolisation, and tested for the ability to prevent pulmonary infection by Pseudomonas aeruginosa. Prepared 25(OH)D-loaded liposomes were nanosized and monodisperse, with a negative surface charge and a 25(OH)D entrapment efficiency of approximately 23%.

Bacteriomimetic invasin-functionalized nanocarriers for intracellular delivery.

Intracellular bacteria invade mammalian cells to establish an infectious niche. The current work models adhesion and subsequent internalization strategy of pathogenic bacteria into mammalian cells to design a bacteriomimetic bioinvasive delivery system. We report on the surface functionalization of liposomes with a C-terminal fragment of invasin (InvA497), an invasion factor in the outer membrane of Yersinia pseudotuberculosis.

Laser scanning microscopy approach for semiquantitation of in vitro dermal particle penetration.

Skin penetration of nanoparticles is a recent research area in focus for the aim of development of topical nanoparticulate delivery systems as well as for health risk analysis. So far, monitoring skin penetration of nanoparticles is mostly based on qualitative microscopical examination. Here, we describe an experimental approach for extracting semiquantitative data from multiphoton images of skin specimens treated with gold nanoparticles.

Setup for investigating gold nanoparticle penetration through reconstructed skin and comparison to published human skin data.

Owing to the limited source of human skin (HS) and the ethical restrictions of using animals in experiments, in vitro skin equivalents are a possible alternative for conducting particle penetration experiments. The conditions for conducting penetration experiments with model particles, 15-nm gold nanoparticles (AuNP), through nonsealed skin equivalents are described for the first time. These conditions include experimental setup, sterility conditions, effective applied dose determination, skin sectioning, and skin integrity check.

Interaction of inorganic nanoparticles with the skin barrier: current status and critical review.

Unlabelled: Integration of nanotechnology with biology leads to various advantages in applied pharmaceutical and medical sciences. In that regard, the behavior of nanoparticles (NPs) in relation to the skin, an important biological barrier, has been the target of several recent studies. Yet the potential ability of NPs to penetrate into the underlying viable tissue lies at the center of debate.