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Staff member

Giuseppe Battaglia
Group Leader / ICREA Research Professor
+34 934034664/33745
gbattagliaibecbarcelona.eu
Staff member publications

Cao, HZ, Zhong, SQ, Shen, Y, Lv, MQ, Zhu, YH, Tian, YP, Luo, K, Huang, W, Battaglia, G, Gong, QY, Tian, XH, (2022). MtDNA specific fluorescent probe uncovering mitochondrial nucleoids dynamics during programmed cell death under super-resolution nanoscopy Chemical Engineering Journal 449, 137763

Mitochondrial nucleoids or mitochondrial DNA (mtDNA) encodes for a variety of enzymes and proteins that are essential for oxidative phosphorylation, mitochondrial fussion/fission and apoptotic processes. However, visulization of mtDNA dynamics in response to external stumili has not yet been achieved. Herein, we developed a fluorescent probe, named BDP, that is capable of specifically bind to mtDNA in vitro and in living cells, without interfering mitochondrial functions. Its large Stokes-Shift and red-emission tail render its suitability for stimulated emission depletion (STED) visulization of mtDNA dynamics in living cells. We sucessfully demonstrated for the first time how apoptotic induced anti-cancer drug could impact on mitochondrial nucleoids, and the morphology evolution of mtDNA from segmentation to dispersion was recorded, in a single mitochondria at nanoscale.

JTD Keywords: Dna, Mitochondrial dna (mtdna), Pyridine salt derivatives, Stimulated emission depletion (sted), Tumor


Acosta-Gutiérrez, Silvia, Matias, Diana, Avila-Olias, Milagros, Gouveia, Virginia M., Scarpa, Edoardo, Forth, Joe, Contini, Claudia, Duro-Castano, Aroa, Rizzello, Loris, Battaglia, Giuseppe, (2022). A Multiscale Study of Phosphorylcholine Driven Cellular Phenotypic Targeting Acs Central Science 8, 891-904

Gouveia, Virgínia M., Rizzello, Loris, Vidal, Bruno, Nunes, Claudia, Poma, Alessandro, Lopez?Vasquez, Ciro, Scarpa, Edoardo, Brandner, Sebastian, Oliveira, António, Fonseca, João E., Reis, Salette, Battaglia, Giuseppe, (2022). Targeting Macrophages and Synoviocytes Intracellular Milieu to Augment Anti-Inflammatory Drug Potency Advanced Therapeutics 5, 2100167

Leite, DM, Seifi, M, Ruiz-Perez, L, Nguemo, F, Plomann, M, Swinny, JD, Battaglia, G, (2022). Syndapin-2 mediated transcytosis of amyloid-beta across the blood brain barrier Brain Commun 4, fcac093

A deficient transport of amyloid-beta across the blood-brain barrier, and its diminished clearance from the brain, contribute to neurodegenerative and vascular pathologies, such as Alzheimer's disease and cerebral amyloid angiopathy, respectively. At the blood-brain barrier, amyloid-beta efflux transport is associated with the low-density lipoprotein receptor-related protein 1. However, the precise mechanisms governing amyloid-beta transport across the blood-brain barrier, in health and disease, remain to be fully understood. Recent evidence indicates that the low-density lipoprotein receptor-related protein 1 transcytosis occurs through a tuhulation-mediated mechanism stabilized by syndapin-2. Here, we show that syndapin-2 is associated with amyloid-beta clearance via low-density lipoprotein receptor-related protein 1 across the blood-brain barrier. We further demonstrate that risk factors for Alzheimer's disease, amyloid-beta expression and ageing, are associated with a decline in the native expression of syndapin-2 within the brain endothelium. Our data reveals that syndapin-2-mediated pathway, and its balance with the endosomal sorting, are important for amyloid-beta clearance proposing a measure to evaluate Alzheimer's disease and ageing, as well as a target for counteracting amyloid-beta build-up. Moreover, we provide evidence for the impact of the avidity of amyloid-beta assemblies in their trafficking across the brain endothelium and in low-density lipoprotein receptor-related protein 1 expression levels, which may affect the overall clearance of amyloid-beta across the blood-brain barrier.

JTD Keywords: Alzheimer's disease, Alzheimers-disease, Amyloid-beta, Apolipoprotein-j, Blood-brain barrier, Clearance, Expression, Membrane invagination, Peptide, Protein, Rab gtpases, Receptor, Syndapin-2, Transport, Tubular transcytosis


Duro-Castano, Aroa, Rodríguez-Arco, Laura, Ruiz-Pérez, Lorena, De Pace, Cesare, Marchello, Gabriele, Noble-Jesus, Carlos, Battaglia, Giuseppe, (2021). One-Pot Synthesis of Oxidation-Sensitive Supramolecular Gels and Vesicles Biomacromolecules 22, 5052-5064

Polypeptide-based nanoparticles offer unique advantages from a nanomedicine perspective such as biocompatibility, biodegradability, and stimuli-responsive properties to (patho)physiological conditions. Conventionally, self-assembled polypeptide nanostructures are prepared by first synthesizing their constituent amphiphilic polypeptides followed by postpolymerization self-assembly. Herein, we describe the one-pot synthesis of oxidation-sensitive supramolecular micelles and vesicles. This was achieved by polymerization-induced self-assembly (PISA) of the N-carboxyanhydride (NCA) precursor of methionine using poly(ethylene oxide) as a stabilizing and hydrophilic block in dimethyl sulfoxide (DMSO). By adjusting the hydrophobic block length and concentration, we obtained a range of morphologies from spherical to wormlike micelles, to vesicles. Remarkably, the secondary structure of polypeptides greatly influenced the final morphology of the assemblies. Surprisingly, wormlike micellar morphologies were obtained for a wide range of methionine block lengths and solid contents, with spherical micelles restricted to very short hydrophobic lengths. Wormlike micelles further assembled into oxidation-sensitive, self-standing gels in the reaction pot. Both vesicles and wormlike micelles obtained using this method demonstrated to degrade under controlled oxidant conditions, which would expand their biomedical applications such as in sustained drug release or as cellular scaffolds in tissue engineering.

JTD Keywords: alpha-amino-acid, hydrogels, leuchs anhydrides, platform, polypeptides, transformation, triggered cargo release, Amino acids, Amphiphilics, Biocompatibility, Biodegradability, Block lengths, Controlled drug delivery, Dimethyl sulfoxide, Ethylene, Gels, Hydrophobicity, Medical nanotechnology, Methionine, Micelles, Morphology, One-pot synthesis, Organic solvents, Oxidation, Physiological condition, Polyethylene oxides, Post-polymerization, Ring-opening polymerization, Scaffolds (biology), Self assembly, Stimuli-responsive properties, Supramolecular chemistry, Supramolecular gels, Supramolecular micelles, Wormlike micelle


Pepe, G, Sfogliarini, C, Rizzello, L, Battaglia, G, Pinna, C, Rovati, G, Ciana, P, Brunialti, E, Mornata, F, Maggi, A, Locati, M, Vegeto, E, (2021). ER alpha-independent NRF2-mediated immunoregulatory activity of tamoxifen Biomedicine & Pharmacotherapy 144, 112274

Sex differences in immune-mediated diseases are linked to the activity of estrogens on innate immunity cells, including macrophages. Tamoxifen (TAM) is a selective estrogen receptor modulator (SERM) used in estrogen receptor-alpha (ER alpha)-dependent breast cancers and off-target indications such as infections, although the immune activity of TAM and its active metabolite, 4-OH tamoxifen (4HT), is poorly characterized. Here, we aimed at investigating the endocrine and immune activity of these SERMs in macrophages. Using primary cultures of female mouse macrophages, we analyzed the expression of immune mediators and activation of effector functions in competition experiments with SERMs and 17 beta-estradiol (E2) or the bacterial endotoxin LPS. We observed that 4HT and TAM induce estrogen antagonist effects when used at nanomolar concentrations, while pharmacological concentrations that are reached by TAM in clinical settings regulate the expression of VEGF alpha and other immune activation genes by ER alpha- and G protein-coupled receptor 1 (GPER1)-independent mechanisms that involve NRF2 through PI3K/Akt-dependent mechanisms. Importantly, we observed that SERMs potentiate cell phagocytosis and modify the effects of LPS on the expression of inflammatory cytokines, such as TNF alpha and IL1 beta, with an overall increase in cell inflammatory phenotype, further sustained by potentiation of IL1 beta secretion through caspase-1 activation.

JTD Keywords: drug repurposing, inflammation, macrophage, nrf2, Apoptosis, Breast-cancer, Drug repurposing, Expression, Inflammation, Macrophage, Nrf2, Resistance, Sex-differences, Tamoxifen, Tumor-associated macrophages


Noble Jesus C, Evans R, Forth J, Estarellas C, Gervasio FL, Battaglia G, (2021). Amphiphilic Histidine-Based Oligopeptides Exhibit pH-Reversible Fibril Formation Acs Macro Letters 10, 984-989

We report the design, simulation, synthesis, and reversible self-assembly of nanofibrils using polyhistidine-based oligopeptides. The inclusion of aromatic amino acids in the histidine block produces distinct antiparallel β-strands that lead to the formation of amyloid-like fibrils. The structures undergo self-assembly in response to a change in pH. This creates the potential to produce well-defined fibrils for biotechnological and biomedical applications that are pH-responsive in a physiologically relevant range.

JTD Keywords: peptide, recognition, Amyloid fibrils


Liu, M., Apriceno, A., Sipin, M., Scarpa, E., Rodriguez-Arco, L., Poma, A., Marchello, G., Battaglia, G., Angioletti-Uberti, S., (2020). Combinatorial entropy behaviour leads to range selective binding in ligand-receptor interactions Nature Communications 11, (1), 4836

From viruses to nanoparticles, constructs functionalized with multiple ligands display peculiar binding properties that only arise from multivalent effects. Using statistical mechanical modelling, we describe here how multivalency can be exploited to achieve what we dub range selectivity, that is, binding only to targets bearing a number of receptors within a specified range. We use our model to characterise the region in parameter space where one can expect range selective targeting to occur, and provide experimental support for this phenomenon. Overall, range selectivity represents a potential path to increase the targeting selectivity of multivalent constructs.

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Sola-Barrado, B., M. Leite, D., Scarpa, E., Duro-Castano, A., Battaglia, G., (2020). Combinatorial intracellular delivery screening of anticancer drugs Molecular Pharmaceutics 17, (12), 4709-4714

Conventional drug solubilization strategies limit the understanding of the full potential of poorly water-soluble drugs during drug screening. Here, we propose a screening approach in which poorly water-soluble drugs are entrapped in poly(2-(methacryloyloxyethyl phosphorylcholine)-poly(2-(diisopropylaminoethyl methacryate) (PMPC-PDPA) polymersomes (POs) to enhance drug solubility and facilitate intracellular delivery. By using a human pediatric glioma cell model, we demonstrated that PMPC-PDPA POs mediated intracellular delivery of cytotoxic and epigenetic drugs by receptor-mediated endocytosis. Additionally, when delivered in combination, drug-loaded PMPC-PDPA POs triggered both an enhanced drug efficacy and synergy compared to that of a conventional combinatorial screening. Hence, our comprehensive synergy analysis illustrates that our screening methodology, in which PMPC-PDPA POs are used for intracellular codelivery of drugs, allows us to identify potent synergistic profiles of anticancer drugs.

JTD Keywords: Combination therapy, Drug screening, Drug solubilization, Intracellular drug delivery, Polymeric nanoparticles, Synergy analysis


Tian, X., De Pace, C., Ruiz-Perez, L., Chen, B., Su, R., Zhang, M., Zhang, R., Zhang, Q., Wang, Q., Zhou, H., Wu, J., Zhang, Z., Tian, Y., Battaglia, G., (2020). A Cyclometalated iridium (III) complex as a microtubule probe for correlative super-resolution fluorescence and electron microscopy Advanced Materials 32, (39), 2003901

The visualization of microtubules by combining optical and electron microscopy techniques provides valuable information to understand correlated intracellular activities. However, the lack of appropriate probes to bridge both microscopic resolutions restricts the areas and structures that can be comprehended within such highly assembled structures. Here, a versatile cyclometalated iridium (III) complex is designed that achieves synchronous fluorescence–electron microscopy correlation. The selective insertion of the probe into a microtubule triggers remarkable fluorescence enhancement and promising electron contrast. The long-life, highly photostable probe allows live-cell super-resolution imaging of tubulin localization and motion with a resolution of ≈30 nm. Furthermore, correlative light–electron microscopy and energy-filtered transmission electron microscopy reveal the well-associated optical and electron signal at a high specificity, with an interspace of ≈41 Å of microtubule monomer in cells.

JTD Keywords: Correlation light–electron microscopy, Microtubules, Organometallic probes, Super-resolution microscopy


Duro-Castano, A., Moreira Leite, D., Forth, J., Deng, Y., Matias, D., Noble Jesus, C., Battaglia, G., (2020). Designing peptide nanoparticles for efficient brain delivery Advanced Drug Delivery Reviews 160, 52-77

The targeted delivery of therapeutic compounds to the brain is arguably the most significant open problem in drug delivery today. Nanoparticles (NPs) based on peptides and designed using the emerging principles of molecular engineering show enormous promise in overcoming many of the barriers to brain delivery faced by NPs made of more traditional materials. However, shortcomings in our understanding of peptide self-assembly and blood–brain barrier (BBB) transport mechanisms pose significant obstacles to progress in this area. In this review, we discuss recent work in engineering peptide nanocarriers for the delivery of therapeutic compounds to the brain: from synthesis, to self-assembly, to in vivo studies, as well as discussing in detail the biological hurdles that a nanoparticle must overcome to reach the brain.

JTD Keywords: Alzheimer's disease, Blood-brain barrier, Drug delivery, Glioma, Parkinson's disease, Peptides, Self-assembly, Transcytosis


Williams, I., Lee, S., Apriceno, A., Sear, R. P., Battaglia, G., (2020). Diffusioosmotic and convective flows induced by a nonelectrolyte concentration gradient Proceedings of the National Academy of Sciences of the United States of America 117, (41), 25263-25271

Glucose is an important energy source in our bodies, and its consumption results in gradients over length scales ranging from the subcellular to entire organs. Concentration gradients can drive material transport through both diffusioosmosis and convection. Convection arises because concentration gradients are mass density gradients. Diffusioosmosis is fluid flow induced by the interaction between a solute and a solid surface. A concentration gradient parallel to a surface creates an osmotic pressure gradient near the surface, resulting in flow. Diffusioosmosis is well understood for electrolyte solutes, but is more poorly characterized for nonelectrolytes such as glucose. We measure fluid flow in glucose gradients formed in a millimeter-long thin channel and find that increasing the gradient causes a crossover from diffusioosmosis-dominated to convection-dominated flow. We cannot explain this with established theories of these phenomena which predict that both scale linearly. In our system, the convection speed is linear in the gradient, but the diffusioosmotic speed has a much weaker concentration dependence and is large even for dilute solutions. We develop existing models and show that a strong surface-solute interaction, a heterogeneous surface, and accounting for a concentration-dependent solution viscosity can explain our data. This demonstrates how sensitive nonelectrolyte diffusioosmosis is to surface and solution properties and to surface-solute interactions. A comprehensive understanding of this sensitivity is required to understand transport in biological systems on length scales from micrometers to millimeters where surfaces are invariably complex and heterogeneous.

JTD Keywords: Convection, Diffusioosmosis, Microfluidics


Donnelly, Joanna L., Offenbartl-Stiegert, Daniel, Marín-Beloqui, José M., Rizzello, Loris, Battaglia, Guiseppe, Clarke, Tracey M., Howorka, Stefan, Wilden, Jonathan D., (2020). Exploring the relationship between BODIPY structure and spectroscopic properties to design fluorophores for bioimaging Chemistry - A European Journal 26, (4), 863-872

Designing chromophores for biological applications requires a fundamental understanding of how the chemical structure of a chromophore influences its photophysical properties. We here describe the synthesis of a library of BODIPY dyes, exploring diversity at various positions around the BODIPY core. The results show that the nature and position of substituents have a dramatic effect on the spectroscopic properties. Substituting in a heavy atom or adjusting the size and orientation of a conjugated system provides a means of altering the spectroscopic profiles with high precision. The insight from the structure–activity relationship was applied to devise a new BODIPY dye with rationally designed photochemical properties including absorption towards the near-infrared region. The dye also exhibited switch-on fluorescence to enable visualisation of cells with high signal-to-noise ratio without washing-out of unbound dye. The BODIPY-based probe is non-cytotoxic and compatible with staining procedures including cell fixation and immunofluorescence microscopy.

JTD


Bueno, C. Z., Apolinário, A. C., Duro-Castano, A., Poma, A., Pessoa, A., Jr., Rangel-Yagui, C. O., Battaglia, G., (2020). L-Asparaginase encapsulation into asymmetric permeable polymersomes ACS Macro Letters 9, (10), 1471-1477

This work reports, for the encapsulation of l-asparaginase, an anticancer enzyme into hybrid PMPC25-PDPA70/PEO16-PBO22 asymmetric polymersomes previously developed by our group, with loading capacities with over 800 molecules per vesicle. Enzyme-loaded polymersomes show permeability and capacity to hydrolyze l-asparagine, which is essential to cancer cells. The nanoreactors proposed in this work can be potentially used in further studies to develop novel therapeutic alternatives based on l-asparaginase.

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Tian, Xiaohe, Angioletti-Uberti, Stefano, Battaglia, Giuseppe, (2020). On the design of precision nanomedicines Science Advances 6, (4), eaat0919

The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across.

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Tian, Xiaohe, Leite, Diana M., Scarpa, Edoardo, Nyberg, Sophie, Fullstone, Gavin, Forth, Joe, Matias, Diana, Apriceno, Azzurra, Poma, Alessandro, Duro-Castano, Aroa, Vuyyuru, Manish, Harker-Kirschneck, Lena, Šarić, Zhang, Zhongping, Xiang, Pan, Fang, Bin, Tian, Yupeng, Luo, Lei, Rizzello, Loris, Battaglia, Giuseppe, (2020). On the shuttling across the blood-brain barrier via tubule formation: Mechanism and cargo avidity bias Science Advances 6, (48), eabc4397

The blood-brain barrier is made of polarized brain endothelial cells (BECs) phenotypically conditioned by the central nervous system (CNS). Although transport across BECs is of paramount importance for nutrient uptake as well as ridding the brain of waste products, the intracellular sorting mechanisms that regulate successful receptor-mediated transcytosis in BECs remain to be elucidated. Here, we used a synthetic multivalent system with tunable avidity to the low-density lipoprotein receptor–related protein 1 (LRP1) to investigate the mechanisms of transport across BECs. We used a combination of conventional and super-resolution microscopy, both in vivo and in vitro, accompanied with biophysical modeling of transport kinetics and membrane-bound interactions to elucidate the role of membrane-sculpting protein syndapin-2 on fast transport via tubule formation. We show that high-avidity cargo biases the LRP1 toward internalization associated with fast degradation, while mid-avidity augments the formation of syndapin-2 tubular carriers promoting a fast shuttling across.

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Fenaroli, Federico, Robertson, James D., Scarpa, Edoardo, Gouveia, Virginia M., Di Guglielmo, Claudia, De Pace, Cesare, Elks, Philip M., Poma, Alessandro, Evangelopoulos, Dimitrios, Ortiz, Julio, Prajsnar, Tomasz K., Marriott, Helen M., Dockrell, David H., Foster, Simon J., McHugh, Timothy D., Renshaw, Stephen A., Samitier, Josep, Battaglia, Giuseppe, Rizzello, Loris, (2020). Polymersomes eradicating intracellular bacteria ACS Nano 14, (7), 8287-8298

Mononuclear phagocytes such as monocytes, tissue-specific macrophages, and dendritic cells are primary actors in both innate and adaptive immunity. These professional phagocytes can be parasitized by intracellular bacteria, turning them from housekeepers to hiding places and favoring chronic and/or disseminated infection. One of the most infamous is the bacteria that cause tuberculosis (TB), which is the most pandemic and one of the deadliest diseases, with one-third of the world’s population infected and an average of 1.8 million deaths/year worldwide. Here we demonstrate the effective targeting and intracellular delivery of antibiotics to infected macrophages both in vitro and in vivo, using pH-sensitive nanoscopic polymersomes made of PMPC–PDPA block copolymer. Polymersomes showed the ability to significantly enhance the efficacy of the antibiotics killing Mycobacterium bovis, Mycobacterium tuberculosis, and another established intracellular pathogen, Staphylococcus aureus. Moreover, they demonstrated to easily access TB-like granuloma tissues—one of the harshest environments to penetrate—in zebrafish models. We thus successfully exploited this targeting for the effective eradication of several intracellular bacteria, including M. tuberculosis, the etiological agent of human TB.

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Kocere, A., Resseguier, J., Wohlmann, J., Skjeldal, F. M., Khan, S., Speth, M., Dal, N. J. K., Ng, M. Y. W., Alonso-Rodriguez, N., Scarpa, E., Rizzello, L., Battaglia, G., Griffiths, G., Fenaroli, F., (2020). Real-time imaging of polymersome nanoparticles in zebrafish embryos engrafted with melanoma cancer cells: Localization, toxicity and treatment analysis EBioMedicine 58, 102902

Background: The developing zebrafish is an emerging tool in nanomedicine, allowing non-invasive live imaging of the whole animal at higher resolution than is possible in the more commonly used mouse models. In addition, several transgenic fish lines are available endowed with selected cell types expressing fluorescent proteins; this allows nanoparticles to be visualized together with host cells. Methods: Here, we introduce the zebrafish neural tube as a robust injection site for cancer cells, excellently suited for high resolution imaging. We use light and electron microscopy to evaluate cancer growth and to follow the fate of intravenously injected nanoparticles. Findings: Fluorescently labelled mouse melanoma B16 cells, when injected into this structure proliferated rapidly and stimulated angiogenesis of new vessels. In addition, macrophages, but not neutrophils, selectively accumulated in the tumour region. When injected intravenously, nanoparticles made of Cy5-labelled poly(ethylene glycol)-block-poly(2-(diisopropyl amino) ethyl methacrylate) (PEG-PDPA) selectively accumulated in the neural tube cancer region and were seen in individual cancer cells and tumour associated macrophages. Moreover, when doxorubicin was released from PEG-PDPA, in a pH dependant manner, these nanoparticles could strongly reduce toxicity and improve the treatment outcome compared to the free drug in zebrafish xenotransplanted with mouse melanoma B16 or human derived melanoma cells. Interpretation: The zebrafish has the potential of becoming an important intermediate step, before the mouse model, for testing nanomedicines against patient-derived cancer cells.

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M Leite, D., Matias, D., Battaglia, G., (2020). The role of BAR proteins and the glycocalyx in brain endothelium transcytosis Cells 9, (12), 2685

Within the brain, endothelial cells lining the blood vessels meticulously coordinate the transport of nutrients, energy metabolites and other macromolecules essential in maintaining an appropriate activity of the brain. While small molecules are pumped across specialised molecular transporters, large macromolecular cargos are shuttled from one side to the other through membrane-bound carriers formed by endocytosis on one side, trafficked to the other side and released by exocytosis. Such a process is collectively known as transcytosis. The brain endothelium is recognised to possess an intricate vesicular endosomal network that mediates the transcellular transport of cargos from blood-to-brain and brain-to-blood. However, mounting evidence suggests that brain endothelial cells (BECs) employ a more direct route via tubular carriers for a fast and efficient transport from the blood to the brain. Here, we compile the mechanism of transcytosis in BECs, in which we highlight intracellular trafficking mediated by tubulation, and emphasise the possible role in transcytosis of the Bin/Amphiphysin/Rvs (BAR) proteins and glycocalyx (GC)-a layer of sugars covering BECs, in transcytosis. Both BAR proteins and the GC are intrinsically associated with cell membranes and involved in the modulation and shaping of these membranes. Hence, we aim to summarise the machinery involved in transcytosis in BECs and highlight an uncovered role of BAR proteins and the GC at the brain endothelium.

JTD Keywords: BAR proteins, Blood-brain barrier, Endothelium, Glycocalyx, Transcytosis, Tubulation


Scarpa, E., de Pace, C., Joseph, A. S., de Souza, S. C., Poma, A., Liatsi-Douvitsa, E., Contini, C., de Matteis, V., Samitier, J., Battaglia, G., Rizzello, L., (2020). Tuning cell behavior with nanoparticle shape PLoS ONE 15, (11), e0240197

We investigated how the shape of polymeric vesicles, made by the exact same material, impacts the replication activity and metabolic state of both cancer and non-cancer cell types. First, we isolated discrete geometrical structures (spheres and tubes) from a heterogeneous sample using density-gradient centrifugation. Then, we characterized the cellular internalization and the kinetics of uptake of both types of polymersomes in different cell types (either cancer or non-cancer cells). We also investigated the cellular metabolic response as a function of the shape of the structures internalized and discovered that tubular vesicles induce a significant decrease in the replication activity of cancer cells compared to spherical vesicles. We related this effect to the significant up-regulation of the tumor suppressor genes p21 and p53 with a concomitant activation of caspase 3/7. Finally, we demonstrated that combining the intrinsic shape-dependent effects of tubes with the delivery of doxorubicin significantly increases the cytotoxicity of the system. Our results illustrate how the geometrical conformation of nanoparticles could impact cell behavior and how this could be tuned to create novel drug delivery systems tailored to specific biomedical application.

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De Pace, Cesare, Marchello, Gabriele, Perez, Lorena Ruiz, Battaglia, Giuseppe, (2020). Brownian tomography of biomolecules and soft polymer assemblies Microscopy and Microanalysis Microscopy and Microanalysis 2020 , Cambridge University Press (Virtual) 26, (S2), 1024-1025

One of the most powerful techniques for structural determination is electron microscopy (EM), which is able to achieve imaging at atomic resolution. However, EM requires keeping the beam under high vacuum to avoid undesired scattering in the electron path. This drawback leads to solidification techniques (such as controlled drying cryogenic techniques), which may alter the microstructure and chemical nature of the sample. The mesoscopic structure of biological and soft specimens is controlled by the presence of their media. Fast vitrification overcame these drawbacks; yet, cryogenic TEM works on static snapshots and does not allow the observation of dynamic events.

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Zhu, Yunqing, Poma, Alessandro, Rizzello, Loris, Gouveia, Virginia, Ruiz Perez, Lorena, Battaglia, Guiseppe, Williams, Charlotte Katherine, (2019). Metabolic-active fully hydrolysable polymersomes Angewandte Chemie International Edition 58, (14), 4581-4586

The synthesis and aqueous self-assembly of a new class of amphiphilic aliphatic polyesters are presented. These AB block polyesters comprise polycaprolactone (hydrophobe) and an alternating polyester from succinic acid and an ether substituted epoxide (hydrophile). They self-assemble into biodegradable polymersomes capable of entering cells. Their degradation products are bioactive giving rise to differentiated cellular responses inducing stromal cell proliferation and macrophage apoptosis. Both effects emerge only when the copolymers enter cells as polymersomes and their magnitudes are size dependent.

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Gouveia, Virgínia M., Rizzello, Loris, Nunes, Claudia, Poma, Alessandro, Ruiz-Perez, Lorena, Oliveira, António, Reis, Salette, Battaglia, Giuseppe, (2019). Macrophage targeting pH responsive polymersomes for glucocorticoid therapy Pharmaceutics 11, (11), 614

Glucocorticoid (GC) drugs are the cornerstone therapy used in the treatment of inflammatory diseases. Here, we report pH responsive poly(2-methacryloyloxyethyl phosphorylcholine)–poly(2-(diisopropylamino)ethyl methacrylate) (PMPC–PDPA) polymersomes as a suitable nanoscopic carrier to precisely and controllably deliver GCs within inflamed target cells. The in vitro cellular studies revealed that polymersomes ensure the stability, selectivity and bioavailability of the loaded drug within macrophages. At molecular level, we tested key inflammation-related markers, such as the nuclear factor-κB, tumour necrosis factor-α, interleukin-1β, and interleukin-6. With this, we demonstrated that pH responsive polymersomes are able to enhance the anti-inflammatory effect of loaded GC drug. Overall, we prove the potential of PMPC–PDPA polymersomes to efficiently promote the inflammation shutdown, while reducing the well-known therapeutic limitations in GC-based therapy.

JTD Keywords: Inflammation, Macrophages, Glucocorticoid, Polymersomes