Preparation Method and In Vitro Characterization of Nanoparticles Sensitive to Tumor Microenvironment.

Immunotherapy is considered a powerful clinical strategy aiming to boost the immune system to fight cancer. In this context, nanomaterials (NMs) are uniquely suited to improve the development and the broad implementation of cancer immunotherapies by overcoming several challenges. In fact, NMs can be rationally designed to navigate complex physical barriers, respond to tumor microenvironments, and enhance/modulate immune system activation.

Intracellular Localization during Blood-Brain Barrier Crossing Influences Extracellular Release and Uptake of Fluorescent Nanoprobes.

To improve the efficacy of nanoparticles (NPs) and boost their theragnostic potential for brain diseases, it is key to understand the mechanisms controlling blood-brain barrier (BBB) crossing. Here, the capability of 100 nm carboxylated polystyrene NPs, used as a nanoprobe model, to cross the human brain endothelial hCMEC/D3 cell layer, as well as to be consequently internalized by human brain tumor U87 cells, is investigated as a function of NPs' different intracellular localization. We compared NPs confined in the endo-lysosomal compartment, delivered to the cells through endocytosis, with free NPs in the cytoplasm, delivered by the gene gun method.

Sol-Gel Dipping Devices for HS Visualization.

In this contribution we report the synthesis and full characterization, via a combination of different spectroscopies (e.g., H NMR, UV-vis, fluorescence, MALDI), of a new family of fluorescent zinc complexes with extended π-conjugated systems, with the final aim of setting up higher performance HS sensing devices.

Inter-Organelle Contact Sites Mediate the Intracellular Antioxidant Activity of Platinum Nanozymes: A New Perspective on Cell-Nanoparticle Interaction and Signaling.

The catalytic and antioxidant properties of platinum nanoparticles (PtNPs) make them promising candidates for several applications in nanomedicine. However, an open issue, still shared among most nanomaterials, is the understanding on how internalized PtNPs, which are confined within endo-lysosomal compartments, can exert their activities. To address this problem, here we study the protective effect of 5 nm PtNPs on a human hepatic (HepG2) cell line exposed to dichlorodiphenylethylene (DDE) as a model of oxidative stress.

Cocoa Extract Provides Protection against 6-OHDA Toxicity in SH-SY5Y Dopaminergic Neurons by Targeting PERK.

Parkinson's disease (PD) represents one of the most common neurodegenerative disorders, characterized by a dopamine (DA) deficiency in striatal synapses and misfolded toxic α-synuclein aggregates with concomitant cytotoxicity. In this regard, the misfolded proteins accumulation in neurodegenerative disorders induces a remarkable perturbations of endoplasmic reticulum (ER) homeostasis leading to persistent ER stress, which in turn, effects protein synthesis, modification, and folding quality control. A large body of evidence suggests that natural products target the ER stress signaling pathway, exerting a potential action in cancers, diabetes, cardiovascular and neurodegenerative diseases.

Paper-Strip-Based Sensors for HS Detection: A Proof-of-Principle Study.

In this work, the authors explored the interaction of a suite of fluorescent zinc complexes with HS. The authors provide evidence that HS binds the zinc center of all the complexes under investigation, allowing them to possibly function as sensors by a 'coordinative-based' approach. Naked-eye color changes occur when treating the systems with HS, so the fluorescence responses are modulated by the presence of HS, which has been related to a change in the energy level and coupling of excited states through a computational study.

Imidazo-pyridine-based zinc(II) complexes as fluorescent hydrogen sulfide probes.

In this work we explore the interaction of HS with a family of fluorescent zinc complexes. In particular we selected a family of complexes with N,O-bidentate ligands aiming at assessing whether the zinc-chelating ligand plays a role in influencing the reactivity of HS with the complexes under investigation. Different experiments, performed by diverse spectroscopic techniques, provide evidence that HS binds the zinc center of all the complexes included in this study.

Biotransformation of Silver Nanoparticles into Oro-Gastrointestinal Tract by Integrated In Vitro Testing Assay: Generation of Exposure-Dependent Physical Descriptors for Nanomaterial Grouping.

Grouping approaches of nanomaterials have the potential to facilitate high throughput and cost effective nanomaterial screening. However, an effective grouping of nanomaterials hinges on the application of suitable physicochemical descriptors to identify similarities. To address the problem, we developed an integrated testing approach coupling acellular and cellular phases, to study the full life cycle of ingested silver nanoparticles (NPs) and silver salts in the oro-gastrointestinal (OGI) tract including their impact on cellular uptake and integrity.

Association Mechanism of Peptide-Coated Metal Nanoparticles with Model Membranes: A Coarse-Grained Study.

Functionalized metal nanoparticles (NPs) hold great promise as innovative tools in nanomedicine. However, one of the main challenges is how to optimize their association with the cell membrane, which is critical for their effective delivery. Recent findings show high cellular uptake rates for NPs coated with the polycationic cell-penetrating peptide gH625-644 (gH), although the underlying internalization mechanism is poorly understood.

Mechanical behavior of bioactive poly(ethylene glycol) diacrylate matrices for biomedical application.

The biomedical applications of physically entangled polymeric hydrogels are generally limited due to their weak mechanical properties, rapid swelling and dissolution in physiologically relevant environment. Chemical crosslinking helps stabilizing hydrogel structure and enhancing mechanical properties, thereby allowing a higher stability in phisiological environment. In this context, it is known that the mechanical properties of the hydrogel are affected by both the molecular weight (MW) of the starting polymer and the concentration of the crosslinker.

Antiangiogenic Effect of Graphene Oxide in Primary Human Endothelial Cells.

In this work, we exploited an integrated approach combining systematic analysis of cytotoxicity, angiogenic potential, and metabolomics to shed light on the effects of graphene oxide (GO) on primary human endothelial Huvec cells. Contrary to the outcomes observed in immortalized cell lines able to internalize a similar amount of GO, significant toxicity was found in Huvec cells at high GO concentrations (25 and 50 μg/mL). In particular, we found that the steric hindrance of GO intracellular aggregates perturbed the correct assembly of cytoskeleton and distribution of mitochondria.

In Vitro Blood-Brain Barrier Models for Nanomedicine: Particle-Specific Effects and Methodological Drawbacks.

Predicting the therapeutic efficacy of a nanocarrier, in a rapid and cost-effective way, is pivotal for the drug delivery to the central nervous system (CNS). In this context, in vitro testing platforms, like the transwell systems, offer numerous advantages to study the passage through the blood-brain barrier (BBB), such as overcoming ethical and methodological issues of in vivo models. However, the use of different transwell filters and nanocarriers with various physical-chemical features makes it difficult to assess the nanocarrier efficacy and achieve data reproducibility.

Enhancement of Tumor Homing by Chemotherapy-Loaded Nanoparticles.

Targeted delivery of anticancer drugs with nanocarriers can reduce side effects and ameliorate therapeutic efficacy. However, poorly perfused and dysfunctional tumor vessels limit the transport of the payload into solid tumors. The use of tumor-penetrating nanocarriers might enhance tumor uptake and antitumor effects.

Design, Synthesis and Characterization of Novel Co-Polymers Decorated with Peptides for the Selective Nanoparticle Transport across the Cerebral Endothelium.

The development of new strategies for enhancing drug delivery to the brain represents a major challenge in treating cerebral diseases. In this paper, we report on the synthesis and structural characterization of a biocompatible nanoparticle (NP) made up of poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) co-polymer (namely PELGA) functionalized with the membranotropic peptide gH625 (gH) and the iron-mimicking peptide CRTIGPSVC (CRT) for transport across the blood-brain barrier (BBB). gH possesses a high translocation potency of the cell membrane.

Laser Ablation as a Versatile Tool To Mimic Polyethylene Terephthalate Nanoplastic Pollutants: Characterization and Toxicology Assessment.

The presence of micro- and nanoplastics in the marine environment is raising strong concerns since they can possibly have a negative impact on human health. In particular, the lack of appropriate methodologies to collect the nanoplastics from water systems imposes the use of engineered model nanoparticles to explore their interactions with biological systems, with results not easily correlated with the real case conditions. In this work, we propose a reliable top-down approach based on laser ablation of polymers to form polyethylene terephthalate (PET) nanoplastics, which mimic real environmental nanopollutants, unlike synthetic samples obtained by colloidal chemistry.

3D breast cancer microtissue reveals the role of tumor microenvironment on the transport and efficacy of free-doxorubicin in vitro.

Unlabelled: The use of 3D cancer models will have both ethical and economic impact in drug screening and development, to promote the reduction of the animals employed in preclinical studies. Nevertheless, to be effective, such cancer surrogates must preserve the physiological relevance of the in vivo models in order to provide realistic information on drugs' efficacy. To figure out the role of the architecture and composition of 3D cancer models on their tumor-mimicking capability, here we studied the efficacy of doxorubicin (DOX), a well-known anticancer molecule in two different 3D cancer models: our 3D breast cancer microtissue (3D-μTP) versus the golden standard represented by spheroid model (sph).

Biotransformation and Biological Interaction of Graphene and Graphene Oxide during Simulated Oral Ingestion.

The biotransformation and biological impact of few layer graphene (FLG) and graphene oxide (GO) are studied, following ingestion as exposure route. An in vitro digestion assay based on a standardized operating procedure (SOP) is exploited. The assay simulates the human ingestion of nanomaterials during their dynamic passage through the different environments of the gastrointestinal tract (salivary, gastric, intestinal).

PMA-Induced THP-1 Macrophage Differentiation is Not Impaired by Citrate-Coated Platinum Nanoparticles.

The innate immune system consists of several complex cellular and molecular mechanisms. During inflammatory responses, blood-circulating monocytes are driven to the sites of inflammation, where they differentiate into tissue macrophages. The research of novel nanomaterials applied to biomedical sciences is often limited by their toxicity or dangerous interactions with the immune cell functions.

Enhanced Drug Delivery into Cell Cytosol via Glycoprotein H-Derived Peptide Conjugated Nanoemulsions.

The key role of nanocarriers in improving the pharmacological properties of commonly used drugs is recognized worldwide. It is also known that in the development of new effective nanocarriers the use of targeting moieties integrated on their surface is essential. Herein, we propose a nanocarrier based on an oil in water nanoemulsion coated with a membranotropic peptide derived from the glycoprotein H of Herpes simplex virus 1, known as gH625, in order to reduce endolysosomal accumulation and to enhance cytosolic localization.

ECM Mechano-Sensing Regulates Cytoskeleton Assembly and Receptor-Mediated Endocytosis of Nanoparticles.

It is possible to create sophisticated and target-specific devices for nanomedicine thanks to technological advances in the engineering of nanomaterials. When on target, these nanocarriers often have to be internalized by cells in order to accomplish their diagnostic or therapeutic function. Therefore, the control of such uptake mechanism by active targeting strategy has today become the new challenge in nanoparticle designing.

Particle size affects the cytosolic delivery of membranotropic peptide-functionalized platinum nanozymes.

Delivery of therapeutic agents inside the cytosol, avoiding the confinement in endo-lysosomal compartments and their degradative environment, is one of the key targets of nanomedicine to gain the maximum remedial effects. Current approaches based on cell penetrating peptides (CPPs), despite improving the cellular uptake efficiency of nanocarriers, have shown controversial results in terms of intracellular localization. To elucidate the delivery potential of CPPs, in this work we analyzed the role of the particle size in influencing the ability of a membranotropic peptide, namely gH625, to escape the endo-lysosomal pathway and deliver the particles in the cytosol.

Down-regulation of miRNAs in the brain and development of diet-induced obesity.

Novel therapeutic interventions for obesity and comorbid conditions require knowledge of the molecular elements playing a role in the development of obesity. Chronic low-grade inflammation has been consistently reported in obese individuals. In this study, we first determined whether key molecular modulators of inflammation, microRNA-155 (miR-155) and microRNA-146a (miR-146a), are regulated by an obesogenic diet within brain regions associated with reward, metabolism and energy balance.

3D tumor microtissues as an in vitro testing platform for microenvironmentally-triggered drug delivery systems.

Unlabelled: Therapeutic approaches based on nanomedicine have garnered great attention in cancer research. In vitro biological models that better mimic in vivo conditions are crucial tools to more accurately predict their therapeutic efficacy in vivo. In this work, a new 3D breast cancer microtissue has been developed to recapitulate the complexity of the tumor microenvironment and to test its efficacy as screening platform for drug delivery systems.

Boosting the therapeutic efficiency of nanovectors: exocytosis engineering.

In this work, we developed a new general strategy, which we named "exocytosis engineering", to strongly increase the intracellular persistence of nanocarriers and thus the effective dose of transported drugs. The strategy is based on the co-loading of a drug and an exocytosis inhibitor in the nanocarrier, to hinder the high tendency of cells to remove internalized nanocarriers, limiting the pharmacological efficiency of the nanoformulation. In particular, by using a well-known chemotherapeutic drug (doxorubicin) and an efficient exocytosis inhibitor (dimethilamyloride) co-loaded in mesoporous silica nanocarriers, we demonstrated a >6-fold increase in the intracellular dose of the drug (for the same administered dose), achieving a great improvement in its therapeutic action.