Insulin Activation Mediated by Uptake Mechanisms: A Comparison of the Behavior between Polymer Nanoparticles and Extracellular Vesicles in 3D Liver Tissues.

In this work, we compare the role of two different uptake mechanisms in the effectiveness of a nanoformulated drug, specifically insulin. Insulin is activated by interacting with insulin receptors exposed on the liver cell membrane that triggers the uptake and storage of glucose. To prove that the uptake mechanism of a delivery system can interfere directly with the effectiveness of the delivered drug, two extremely different delivery systems are tested. In detail, hydrogel-based NPs (cHANPs) and natural lipid vesicles (EVs) encapsulating insulin are used to trigger the activation of this hormone in 3D liver microtissues (µTs) based on their different uptake mechanisms. Results demonstrated that the fusion mechanism of Ins-EVs mediates faster and more pronounced insulin activation with respect to the endocytic mechanism of Ins-cHANPs. Indeed, the fusion causes an increased reduction in glucose concentration in the culture medium EV-treated l-µTs with respect to free insulin-treated tissues. The same effect is not observed for Ins-cHANPs that, taken up by endocytosis, can only equal the reduction in glucose concentration produced by free insulin in 48 h. Overall, these results demonstrate that the effectiveness of nanoformulated drugs depends on the identity they acquire in the biological context (biological identity). Indeed, the nanoparticle (NP) biological identity, such as the uptake mechanism, triggers a unique set of nano-bio-interactions that is ultimately responsible for their fate both in the extracellular and intracellular compartments.

Revealing Angiopep-2/LRP1 Molecular Interaction for Optimal Delivery to Glioblastoma (GBM).

BACKGROUND: The family of synthetic peptide angiopeps, and particularly angiopep-2 (ANG-2) demonstrated the ability preclinically and clinically to shuttle active molecules across the blood-brain barrier (BBB) and selectively toward brain tumor cells. The literature has also proved that the transport occurs through a specific receptor-mediated transcytosis of the peptide by LRP-1 receptors present both on BBB and tumor cell membranes. However, contradictory results about exploiting this promising mechanism to engineer complex delivery systems, such as nanoparticles, are being obtained. METHODOLOGY: For this reason, we applied a molecular docking (MD)-based strategy to investigate the molecular interaction of ANG-2 and the LRP-1 ligand-binding moieties (CR56 and CR17), clarifying the impact of peptide conjugation on its transport mechanism. RESULTS: MD results proved that ANG-2/LRP-1 binding involves the majority of ANG-2 residues, is characterized by high binding energies, and that it is site-specific for CR56 where the binding to 929ASP recalls a transcytosis mechanism, resembling the binding of the receptor to the receptor-associated protein. On the other hand, ANG-2 binding to CR17 is less site-specific but, as proved for apolipoprotein internalization in physiological conditions, it involves the ANG-2 lysin residue. CONCLUSIONS: Overall, our results proved that ANG-2 energetic interaction with the LRP-1 receptor is not hindered if specific residues of the peptide are chemically crosslinked to simple or complex engineered delivery systems.

A High Throughput Approach Based on Dynamic High Pressure for the Encapsulation of Active Compounds in Exosomes for Precision Medicine.

In recent decades, endogenous nanocarrier-exosomes have received considerable scientific interest as drug delivery systems. The unique proteo-lipid architecture allows the crossing of various natural barriers and protects exosomes cargo from degradation in the bloodstream. However, the presence of this bilayer membrane as well as their endogenous content make loading of exogenous molecules challenging. In the present work, we will investigate how to promote the manipulation of vesicles curvature by a high-pressure microfluidic system as a ground-breaking method for exosomes encapsulation. Exosomes isolated from Uppsala 87 Malignant Glioma (U87-MG) cell culture media were characterized before and after the treatment with high-pressure homogenization. Once their structural and biological stability were validated, we applied this novel method for the encapsulation in the lipidic exosomal bilayer of the chemotherapeutic Irinotecan HCl Trihydrate-CPT 11. Finally, we performed in vitro preliminary test to validate the nanobiointeraction of exosomes, uptake mechanisms, and cytotoxic effect in cell culture model.

Biocompatible superparamagnetic core-shell nanoparticles for potential use in hyperthermia-enabled drug release and as an enhanced contrast agent.

Superparamagnetic iron oxide nanoparticles (SPIONs) and core-shell type nanoparticles, consisting of SPIONs coated with mesoporous silica and/or lipid, were synthesised and tested for their potential theranostic applications in drug delivery, magnetic hyperthermia and as a contrast agent. Transmission Electron Microscopy (TEM) confirmed the size of bare and coated SPIONs was in the range of 5-20 nm and 100-200 nm respectively. The superparamagnetic nature of all the prepared nanomaterials as indicated by Vibrating Sample Magnetometry (VSM) and their heating properties under an AC field confirm their potential for hyperthermia applications. Scanning Column Magnetometry (SCM) data showed that extrusion of bare-SPION (b-SPION) dispersions through a 100 nm polycarbonate membrane significantly improved the dispersion stability of the sample. No sedimentation was apparent after 18 h compared to a pre-extrusion estimate of 43% settled at the bottom of the tube over the same time. Lipid coating also enhanced dispersion stability. Transversal relaxation time (T2) measurements for the nanoparticles, using a bench-top relaxometer, displayed a significantly lower value of 46 ms, with a narrow relaxation time distribution, for lipid silica coated SPIONs (Lip-SiSPIONs) as compared to that of 1316 ms for the b-SPIONs. Entrapment efficiency of the anticancer drug, Doxorubicin (DOX) for Lip-SPIONs was observed to be 35% which increased to 58% for Lip-SiSPIONs. Moreover, initial in-vitro cytotoxicity studies against human breast adenocarcinoma, MCF-7 cells showed that % cell viability increased from 57% for bSPIONs to 82% for Lip-SPIONs and to 87% for Lip-SiSPIONs. This suggests that silica and lipid coatings improve the biocompatibility of bSPIONs significantly and enhance the suitability of these particles as drug carriers. Hence, the magnetic nanomaterials prepared in this work have potential theranostic properties as a drug carrier for hyperthermia cancer therapy and also offer enhancement of contrast agent efficacy and a route to a significant increase in dispersion stability.

Multimodal imaging for a theranostic approach in a murine model of B-cell lymphoma with engineered nanoparticles.

Nanoparticles (NPs) are a promising tool for in vivo multimodality imaging and theranostic applications. Hyaluronic acid (HA)-based NPs have numerous active groups that make them ideal as tumor-targeted carriers. The B-lymphoma neoplastic cells express on their surfaces a clone-specific immunoglobulin receptor (Ig-BCR). The peptide A20-36 (pA20-36) selectively binds to the Ig-BCR of A20 lymphoma cells. In this work, we demonstrated the ability of core-shell chitosan-HA-NPs decorated with pA20-36 to specifically target A20 cells and reduce the tumor burden in a murine xenograft model. We monitored tumor growth using high-frequency ultrasonography and demonstrated targeting specificity and kinetics of the NPs via in vivo fluorescent reflectance imaging. This result was also confirmed by ex vivo magnetic resonance imaging and confocal microscopy. In conclusion, we demonstrated the ability of NPs loaded with fluorescent and paramagnetic tracers to act as multimodal imaging contrast agents and hence as a non-toxic, highly specific theranostic system.

Commentary on "A Microfluidic Platform to Design Crosslinked Hyaluronic Acid Nanoparticles (cHANPs) for Enhanced MRI".

Strategies to enhance the relaxometric properties of gadolinium (Gd)-based contrast agents (CAs) for magnetic resonance imaging (MRI), without the chemical modification of chelates, have recently had a strong impact on the diagnostic field. We have taken advantage of the interaction between Gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA) and the hydrogel structure of hyaluronic acid to design cross-linked hyaluronic acid nanoparticles down to 35 nm for use in MRI applications. The proposed bioformulations enable the control of the relaxometric properties of CAs, thus boosting the relaxation rate of T1. Our results led us to identify this approach as an adjustable scenario to design intravascularly injectable hydrogel nanoparticles entrapping Gd-DTPA. This approach overcomes the general drawbacks of clinically approved CAs having poor relaxivity and toxic effects.

Experimental Investigation and Thermodynamic Assessment of Phase Equilibria in the PLLA/Dioxane/Water Ternary System for Applications in the Biomedical Field.

Fundamental understanding of thermodynamic of phase separation plays a key role in tuning the desired features of biomedical devices. In particular, phase separation of ternary solution is of remarkable interest in processes to obtain biodegradable and biocompatible architectures applied as artificial devices to repair, replace, or support damaged tissues or organs. In these perspectives, thermally induced phase separation (TIPS) is the most widely used technique to obtained porous morphologies and, in addition, among different ternary systems, polylactic acid (PLLA)/dioxane/water has given promising results and has been largely studied. However, to increase the control of TIPS-based processes and architectures, an investigation of the basic energetic phenomena occurring during phase separation is still required. Here we propose an experimental investigation of the selected ternary system by using isothermal titration calorimetric approach at different solvent/antisolvent ratio and a thermodynamic explanation related to the polymer-solvents interactions in terms of energetic contribution to the phase separation process. Furthermore, relevant information about the phase diagrams and interaction parameters of the studied systems are furnished in terms of liquid-liquid miscibility gap. Indeed, polymer-solvents interactions are responsible for the mechanism of the phase separation process and, therefore, of the final features of the morphologies; the knowledge of such data is fundamental to control processes for the production of membranes, scaffolds and several nanostructures. The behavior of the polymer at different solvent/nonsolvent ratios is discussed in terms of solvation mechanism and a preliminary contribution to the understanding of the role of the hydrogen bonding in the interface phenomena is also reported. It is the first time that thermodynamic data of a ternary system are collected by mean of nano-isothermal titration calorimetry (nano-ITC). Supporting Information is available.

Spatio-Temporal Positron Emission Tomography Reconstruction with Attenuation and Motion Correction.

The detection of cancer lesions of a comparable size to that of the typical system resolution of modern scanners is a long-standing problem in Positron Emission Tomography. In this paper, the effect of composing an image-registering convolutional neural network with the modeling of the static data acquisition (i.e., the forward model) is investigated. Two algorithms for Positron Emission Tomography reconstruction with motion and attenuation correction are proposed and their performance is evaluated in the detectability of small pulmonary lesions. The evaluation is performed on synthetic data with respect to chosen figures of merit, visual inspection, and an ideal observer. The commonly used figures of merit-Peak Signal-to-Noise Ratio, Recovery Coefficient, and Signal Difference-to-Noise Ration-give inconclusive responses, whereas visual inspection and the Channelised Hotelling Observer suggest that the proposed algorithms outperform current clinical practice.

Artificial neural network modelling hydrodenticity for optimal design by microfluidics of polymer nanoparticles to apply in magnetic resonance imaging.

The engineering of nanoparticles impacts the control of their nano-bio interactions at each level of the delivery pathway. Therefore, optimal nanoparticle physicochemical properties should be identified to favour on-target interactions and deliver efficiently active compounds to a specific target. To date, traditional batch processes do not guarantee the reproducibility of results and low polydispersity index of the nanostructures, while microfluidics has emerged as cost effectiveness, short-production time approach to control the nanoparticle size and size distribution. Several thermodynamic processes have been implemented in microfluidics, such as nanoprecipitation, ionotropic gelation, self-assembly, etc., to produce nanoparticles in a continuous mode and high throughput way.   In this work, we show how the Artificial Neural Network (ANN) can be adopted to model the impact of microfluidic parameters (namely, flow rates and polymer concentrations) on the size of the nanoparticles. Promising results have been obtained, with the highest model accuracy reaching 98.9 %, thus confirming the proposed approach's potential applicability for an ANN-guided biopolymer nanoparticle design for biomedical applications. Nanostructures with different degrees of complexity are analysed, and a proof-of-concept machine learning approach is proposed to evaluate Hydrodenticity in biopolymer matrices. STATEMENT OF SIGNIFICANCE: Size, shape and surface charge determine nano-bio interactions of nanoparticles and their ability to target diseases. The ideal nanoparticle design avoids off-target interactions and favours on-target interactions. So, tools enabling the identification of the optimal nanoparticle physicochemical properties for delivery to a specific target are required. In this work, we evaluate the use of Artificial Neural Network (ANN) to analyse the role of microfluidic parameters in predicting the optimal size of the different hydrogel nanoparticles and their ability to trigger Hydrodenticity.

coupled Hydrodynamic Flow Focusing (cHFF) to Engineer Lipid-Polymer Nanoparticles (LiPoNs) for Multimodal Imaging and Theranostic Applications.

An optimal design of nanocarriers is required to overcome the gap between synthetic and biological identity, improving the clinical translation of nanomedicine. A new generation of hybrid vehicles based on lipid-polymer coupling, obtained by Microfluidics, is proposed and validated for theranostics and multimodal imaging applications. A coupled Hydrodynamic Flow Focusing (cHFF) is exploited to control the time scales of solvent exchange and the coupling of the polymer nanoprecipitation with the lipid self-assembly simultaneously, guiding the formation of Lipid-Polymer NPs (LiPoNs). This hybrid lipid-polymeric tool is made up of core-shell structure, where a polymeric chitosan core is enveloped in a lipid bilayer, capable of co-encapsulating simultaneously Gd-DTPA and Irinotecan/Atto 633 compounds. As a result, a monodisperse population of hybrid NPs with an average size of 77 nm, with preserved structural integrity in different environmental conditions and high biocompatibility, can be used for MRI and Optical applications. Furthermore, preliminary results show the enhanced delivery and therapeutic efficacy of Irinotecan-loaded hybrid formulation against U87 MG cancers cells.

Update on the Use of PET/MRI Contrast Agents and Tracers in Brain Oncology: A Systematic Review.

The recent advancements in hybrid positron emission tomography-magnetic resonance imaging systems (PET/MRI) have brought massive value in the investigation of disease processes, in the development of novel treatments, in the monitoring of both therapy response and disease progression, and, not least, in the introduction of new multidisciplinary molecular imaging approaches. While offering potential advantages over PET/CT, the hybrid PET/MRI proved to improve both the image quality and lesion detectability. In particular, it showed to be an effective tool for the study of metabolic information about lesions and pathological conditions affecting the brain, from a better tumor characterization to the analysis of metabolic brain networks. Based on the PRISMA guidelines, this work presents a systematic review on PET/MRI in basic research and clinical differential diagnosis on brain oncology and neurodegenerative disorders. The analysis includes literature works and clinical case studies, with a specific focus on the use of PET tracers and MRI contrast agents, which are usually employed to perform hybrid PET/MRI studies of brain tumors. A systematic literature search for original diagnostic studies is performed using PubMed/MEDLINE, Scopus and Web of Science. Patients, study, and imaging characteristics were extracted from the selected articles. The analysis included acquired data pooling, heterogeneity testing, sensitivity analyses, used tracers, and reported patient outcomes. Our analysis shows that, while PET/MRI for the brain is a promising diagnostic method for early diagnosis, staging and recurrence in patients with brain diseases, a better definition of the role of tracers and imaging agents in both clinical and preclinical hybrid PET/MRI applications is needed and further efforts should be devoted to the standardization of the contrast imaging protocols, also considering the emerging agents and multimodal probes.

Tuning of Hydrogel Architectures by Ionotropic Gelation in Microfluidics: Beyond Batch Processing to Multimodal Diagnostics.

Microfluidics is emerging as a promising tool to control physicochemical properties of nanoparticles and to accelerate clinical translation. Indeed, microfluidic-based techniques offer more advantages in nanomedicine over batch processes, allowing fine-tuning of process parameters. In particular, the use of microfluidics to produce nanoparticles has paved the way for the development of nano-scaled structures for improved detection and treatment of several diseases. Here, ionotropic gelation is implemented in a custom-designed microfluidic chip to produce different nanoarchitectures based on chitosan-hyaluronic acid polymers. The selected biomaterials provide biocompatibility, biodegradability and non-toxic properties to the formulation, making it promising for nanomedicine applications. Furthermore, results show that morphological structures can be tuned through microfluidics by controlling the flow rates. Aside from the nanostructures, the ability to encapsulate gadolinium contrast agent for magnetic resonance imaging and a dye for optical imaging is demonstrated. In conclusion, the polymer nanoparticles here designed revealed the dual capability of enhancing the relaxometric properties of gadolinium by attaining Hydrodenticity and serving as a promising nanocarrier for multimodal imaging applications.

Antifouling Strategies of Nanoparticles for Diagnostic and Therapeutic Application: A Systematic Review of the Literature.

Nanoparticles (NPs) are promising platforms for the development of diagnostic and therapeutic tools. One of the main hurdle to their medical application and translation into the clinic is the fact that they accumulate in the spleen and liver due to opsonization and scavenging by the mononuclear phagocyte system. The "protein corona" controls the fate of NPs in vivo and becomes the interface with cells, influencing their physiological response like cellular uptake and targeting efficiency. For these reasons, the surface properties play a pivotal role in fouling and antifouling behavior of particles. Therefore, surface engineering of the nanocarriers is an extremely important issue for the design of useful diagnostic and therapeutic systems. In recent decades, a huge number of studies have proposed and developed different strategies to improve antifouling features and produce NPs as safe and performing as possible. However, it is not always easy to compare the various approaches and understand their advantages and disadvantages in terms of interaction with biological systems. Here, we propose a systematic study of literature with the aim of summarizing current knowledge on promising antifouling coatings to render NPs more biocompatible and performing for diagnostic and therapeutic purposes. Thirty-nine studies from 2009 were included and investigated. Our findings have shown that two main classes of non-fouling materials (i.e., pegylated and zwitterionic) are associated with NPs and their applications are discussed here highlighting pitfalls and challenges to develop biocompatible tools for diagnostic and therapeutic uses. In conclusion, although the complexity of biofouling strategies and the field is still young, the collective data selected in this review indicate that a careful tuning of surface moieties is a pivotal step to lead NPs through their future clinical applications.

Theranostic Design of Angiopep-2 Conjugated Hyaluronic Acid Nanoparticles (Thera-ANG-cHANPs) for Dual Targeting and Boosted Imaging of Glioma Cells.

Glioblastoma multiforme (GBM) has a mean survival of only 15 months. Tumour heterogeneity and blood-brain barrier (BBB) mainly hinder the transport of active agents, leading to late diagnosis, ineffective therapy and inaccurate follow-up. The use of hydrogel nanoparticles, particularly hyaluronic acid as naturally occurring polymer of the extracellular matrix (ECM), has great potential in improving the transport of drug molecules and, furthermore, in facilitatating the early diagnosis by the effect of hydrodenticity enabling the T1 boosting of Gadolinium chelates for MRI. Here, crosslinked hyaluronic acid nanoparticles encapsulating gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA) and the chemotherapeutic agent irinotecan (Thera-cHANPs) are proposed as theranostic nanovectors, with improved MRI capacities. Irinotecan was selected since currently repurposed as an alternative compound to the poorly effective temozolomide (TMZ), generally approved as the gold standard in GBM clinical care. Also, active crossing and targeting are achieved by theranostic cHANPs decorated with angiopep-2 (Thera-ANG-cHANPs), a dual-targeting peptide interacting with low density lipoprotein receptor related protein-1(LRP-1) receptors overexpressed by both endothelial cells of the BBB and glioma cells. Results showed preserving the hydrodenticity effect in the advanced formulation and internalization by the active peptide-mediated uptake of Thera-cHANPs in U87 and GS-102 cells. Moreover, Thera-ANG-cHANPs proved to reduce ironotecan time response, showing a significant cytotoxic effect in 24 h instead of 48 h.

Targeting Nanostrategies for Imaging of Atherosclerosis.

Despite the progress in cardiovascular research, atherosclerosis still represents the main cause of death worldwide. Clinically, the diagnosis of Atherosclerotic Cardiovascular Disease (ASCVD) relies on imaging methodologies including X-ray angiography and computed tomography (CT), which however still fails in the identification of patients at high risk of plaque rupture, the main cause of severe clinical events as stroke and heart attack. Magnetic resonance imaging, which is characterized by very high spatial resolution, could provide a better characterization of atherosclerotic plaque (AP) anatomy and composition, aiding in the identification of "vulnerable" plaques. In this context, hydrogel matrices, which have been demonstrated able to boost relaxometric properties of Gd-based contrast agents (CAs) by the effect of Hydrodenticity, represent a valuable tool towards the precision imaging of ASCVD improving the performance of this class of CAs while reducing systemic toxicity. In particular, hydrogel nanoparticles encapsulating Gd-DTPA can further contribute to providing CA-specific accumulation in the AP by nanoparticle surface decoration triggering an active targeting of the AP with the overall effect of allowing an earlier and more accurate diagnosis. In this work, we tested crosslinked Hyaluronic Acid Nanoparticles (cHANPs) in the complex environment of human atherosclerotic plaque. In addition, the surface of cHANPs was decorated with the antibody anti-CD36 (Ab36-cHANPs) for the active targeting of AP-associated macrophages. Results demonstrate that the Hydrodenticity of cHANPs and Ab36-cHANPs is preserved in this complex system and, preliminarily, that interaction of these probes with the AP is present.

Morphology and stability of CO2-in-water foams with nonionic hydrocarbon surfactants.

The morphologies, stabilities, and viscosities of high-pressure carbon dioxide-in-water (C/W) foams (emulsions) formed with branched nonionic hydrocarbon surfactants were investigated by in situ optical microscopy and capillary rheology. Over two dozen hydrocarbon surfactants were shown to stabilize C/W foams with Sauter mean bubble diameters as low as 1 to 2 microm. Coalescence of the C/W foam bubbles was rare for bubbles larger than about 0.5 microm over a 60 h time frame, and Ostwald ripening became very slow. By better blocking of the CO(2) and water phases with branched and double-tailed surfactants, the interfacial tension decreases, the surface pressure increases, and the C/W foams become very stable. For branched surfactants with propylene oxide middle groups, the stabilities were markedly lower for air/water foams and decane-water emulsions. The greater stability of the C/W foams to coalescence may be attributed to a smaller capillary pressure, lower drainage rates, and a sufficient surface pressure and thus limiting surface elasticity, plus small film sizes, to hinder spatial and surface density fluctuations that lead to coalescence. Unexpectedly, the foams were stable even when the surfactant favored the CO(2) phase over the water phase, in violation of Bancroft's rule. This unusual behavior is influenced by the low drainage rate, which makes Marangoni stabilization of less consequence and the strong tendency of emerging holes in the lamella to close as a result of surfactant tail flocculation in CO(2). The high distribution coefficient toward CO(2) versus water is of significant practical interest for mobility control in CO(2) sequestration and enhanced oil recovery by foam formation.

New Strategies in the Design of Paramagnetic CAs.

Nowadays, magnetic resonance imaging (MRI) is the first diagnostic imaging modality for numerous indications able to provide anatomical information with high spatial resolution through the use of magnetic fields and gradients. Indeed, thanks to the characteristic relaxation time of each tissue, it is possible to distinguish between healthy and pathological ones. However, the need to have brighter images to increase differences and catch important diagnostic details has led to the use of contrast agents (CAs). Among them, Gadolinium-based CAs (Gd-CAs) are routinely used in clinical MRI practice. During these last years, FDA highlighted many risks related to the use of Gd-CAs such as nephrotoxicity, heavy allergic effects, and, recently, about the deposition within the brain. These alerts opened a debate about the opportunity to formulate Gd-CAs in a different way but also to the use of alternative and safer compounds to be administered, such as manganese- (Mn-) based agents. In this review, the physical principle behind the role of relaxivity and the T 1 boosting will be described in terms of characteristic correlation times and inner and outer spheres. Then, the recent advances in the entrapment of Gd-CAs within nanostructures will be analyzed in terms of relaxivity boosting obtained without the chemical modification of CAs as approved in the chemical practice. Finally, a critical evaluation of the use of manganese-based CAs will be illustrated as an alternative ion to Gd due to its excellent properties and endogenous elimination pathway.

Glycosaminoglycans and Contrast Agents: The Role of Hyaluronic Acid as MRI Contrast Enhancer.

A comprehensive understanding of the behaviour of Glycosaminoglycans (GAGs) combined with imaging or therapeutic agents can be a key factor for the rational design of drug delivery and diagnostic systems. In this work, physical and thermodynamic phenomena arising from the complex interplay between GAGs and contrast agents for Magnetic Resonance Imaging (MRI) have been explored. Being an excellent candidate for drug delivery and diagnostic systems, Hyaluronic acid (HA) (0.1 to 0.7%w/v) has been chosen as a GAG model, and Gd-DTPA (0.01 to 0.2 mM) as a relevant MRI contrast agent. HA samples crosslinked with divinyl sulfone (DVS) have also been investigated. Water Diffusion and Isothermal Titration Calorimetry studies demonstrated that the interaction between HA and Gd-DTPA can form hydrogen bonds and coordinate water molecules, which plays a leading role in determining both the polymer conformation and the relaxometric properties of the contrast agent. This interaction can be modulated by changing the GAG/contrast agent molar ratio and by acting on the organization of the polymer network. The fine control over the combination of GAGs and imaging agents could represent an enormous advantage in formulating novel multifunctional diagnostic probes paving the way for precision nanomedicine tools.

Exosomes in Gliomas: Biogenesis, Isolation, and Preliminary Applications in Nanomedicine.

Exosomes are phospholipid-based particles endogenously produced by both normal and tumor cells. Initially identified as a pathway for shuttling cellular waste, for a long time they were thought to act as "garbage bags", and only in the past few years have they emerged as a promising drug delivery system. In this review, we provide an overview of the knowledge about exosome architecture and biogenesis and the recent progress in isolation methods. Furthermore, we describe the mechanisms involved in both extra- and intracellular communication with a focus on glioma brain tumors. Glioma is considered a rare disease and is the most prominent aggressive brain malignancy. How exosomes target glial tumoral cells in vivo remains largely unknown. However, they are able to influence numerous physio-pathological aspects. Here, we discuss the role they play in this heterogeneous and complex microenvironment and their potential applications.

A Microfluidic Platform to design Multimodal PEG - crosslinked Hyaluronic Acid Nanoparticles (PEG-cHANPs) for diagnostic applications.

The combination of different imaging modalities can allow obtaining simultaneously morphological and functional information providing a more accurate diagnosis. This advancement can be reached through the use of multimodal tracers, and nanotechnology-based solutions allow the simultaneous delivery of different diagnostic compounds moving a step towards their safe administration for multimodal imaging acquisition. Among different processes, nanoprecipitation is a consolidate method for the production of nanoparticles and its implementation in microfluidics can further improve the control over final product features accelerating its potential clinical translation. A Hydrodynamic Flow Focusing (HFF) approach is proposed to produce through a ONE-STEP process Multimodal Pegylated crosslinked Hyaluronic Acid NanoParticles (PEG-cHANPs). A monodisperse population of NPs with an average size of 140 nm is produced and Gd-DTPA and ATTO488 compounds are co-encapsulated, simultaneously. The results showed that the obtained multimodal nanoparticle could work as MRI/Optical imaging probe. Furthermore, under the Hydrodenticity effect, a boosting of the T1 values with respect to free Gd-DTPA is preserved.