Publications by authors named "Simo Schwartz"

96 Publications

Hyaluronic acid (HA)-coated naproxen-nanoparticles selectively target breast cancer stem cells through COX-independent pathways.

Mater Sci Eng C Mater Biol Appl 2021 May 10;124:112024. Epub 2021 Mar 10.

Biomaterials Group, Institute of Polymer Science and Technology (ICTP-CSIC), 28006 Madrid, Spain; Networking Biomedical Research Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029 Madrid, Spain. Electronic address:

Cytotoxic chemotherapy continues to be the main therapeutic option for patients with metastatic breast cancer. Several studies have reported a significant association between chronic inflammation, carcinogenesis and the presence of cancer stem cells (CSC). We hypothesized that the use of non-steroidal anti-inflammatory drugs targeted to the CSC population could help reducing tumor progression and dissemination in otherwise hard to treat metastatic breast cancer. Within this study cationic naproxen (NAP)-bearing polymeric nanoparticles (NPs) were obtained by self-assembly and they were coated with hyaluronic acid (HA) via electrostatic interaction. HA-coated and uncoated NAP-bearing NPs with different sizes were produced by changing the ionic strength of the aqueous preparation solutions (i.e. 300 and 350 nm or 100 and 130 nm in diameter, respectively). HA-NPs were fully characterized in terms of physicochemical parameters and biological response in cancer cells, macrophages and endothelial cells. Our results revealed that HA-coating of NPs provided a better control in NAP release and improved their hemocompatibility, while ensuring a strong CSC-targeting in MCF-7 breast cancer cells. Furthermore, the best polymeric NPs formulation significantly (p < 0.001) reduced MCF-7 cells viability when compared to free drug (i.e. 45 ± 6% for S-HA-NPs and 87 ± 10% for free NAP) by p53-dependent induction of apoptosis; and the migration of these cell line was also significantly (p < 0.01) reduced by the nano-formulated NAP (i.e. 76.4% of open wound for S-HA-NPs and 61.6% of open wound for NAP). This increased anti-cancer activity of HA-NAP-NPs might be related to the induction of apoptosis through alterations of the GSK-3β-related COX-independent pathway. Overall, these findings suggest that the HA-NAP-NPs have the potential to improve the treatment of advanced breast cancer by increasing the anti-proliferative effect of NAP within the CSC subpopulation.
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http://dx.doi.org/10.1016/j.msec.2021.112024DOI Listing
May 2021

Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis.

Clin Epigenetics 2021 Apr 23;13(1):88. Epub 2021 Apr 23.

Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035, Barcelona, Spain.

Background: Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation.

Results: Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer.

Conclusions: We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.
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http://dx.doi.org/10.1186/s13148-021-01070-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063439PMC
April 2021

Stimuli-Responsive Hydrogels for Cancer Treatment: The Role of pH, Light, Ionic Strength and Magnetic Field.

Cancers (Basel) 2021 Mar 9;13(5). Epub 2021 Mar 9.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Cancer remains as the second leading cause of death, worldwide. Despite the enormous important advances observed in the last decades, advanced stages of the disease remain incurable. The severe side effects associated to systemic high doses of chemotherapy and the development of drug resistance impairs a safe and efficiency anticancer therapy. Therefore, new formulations are continuously under research and development to improve anticancer drugs therapeutic index through localized delivery at tumor sites. Among a wide range of possibilities, hydrogels have recently gained special attention due to their potential to allow in situ sustained and controlled anticancer drug release. In particular, stimuli-responsive hydrogels which are able to change their physical state from liquid to gel accordingly to external factors such as temperature, pH, light, ionic strength, and magnetic field, among others. Some of these formulations presented promising results for the localized control and treatment of cancer. The present work aims to discuss the main properties and application of stimuli-responsive hydrogels in cancer treatment and summarize the most important advances observed in the last decades focusing on the use of pH-, light-, ionic strength-, and magnetic-responsive hydrogels.
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http://dx.doi.org/10.3390/cancers13051164DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7963181PMC
March 2021

Extracellular vesicles from recombinant cell factories improve the activity and efficacy of enzymes defective in lysosomal storage disorders.

J Extracell Vesicles 2021 Mar 12;10(5):e12058. Epub 2021 Mar 12.

Drug Delivery & Targeting CIBBIM-Nanomedicine Vall d'Hebron Institute of Research Universitat Autònoma de Barcelona Barcelona Spain.

In the present study the use of extracellular vesicles (EVs) as vehicles for therapeutic enzymes in lysosomal storage disorders was explored. EVs were isolated from mammalian cells overexpressing alpha-galactosidase A (GLA) or N-sulfoglucosamine sulfohydrolase (SGSH) enzymes, defective in Fabry and Sanfilippo A diseases, respectively. Direct purification of EVs from cell supernatants was found to be a simple and efficient method to obtain highly active GLA and SGSH proteins, even after EV lyophilization. Likewise, EVs carrying GLA (EV-GLA) were rapidly uptaken and reached the lysosomes in cellular models of Fabry disease, restoring lysosomal functionality much more efficiently than the recombinant enzyme in clinical use. In vivo, EVs were well tolerated and distributed among all main organs, including the brain. DiR-labelled EVs were localized in brain parenchyma 1 h after intra-arterial (internal carotid artery) or intravenous (tail vein) administrations. Moreover, a single intravenous administration of EV-GLA was able to reduce globotriaosylceramide (Gb3) substrate levels in clinically relevant tissues, such kidneys and brain. Overall, our results demonstrate that EVs from cells overexpressing lysosomal enzymes act as natural protein delivery systems, improving the activity and the efficacy of the recombinant proteins and facilitating their access to organs neglected by conventional enzyme replacement therapies.
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http://dx.doi.org/10.1002/jev2.12058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7953474PMC
March 2021

Impact of Chemical Composition on the Nanostructure and Biological Activity of α-Galactosidase-Loaded Nanovesicles for Fabry Disease Treatment.

ACS Appl Mater Interfaces 2021 Feb 14;13(7):7825-7838. Epub 2021 Feb 14.

Institut de Ciència de Materials de Barcelona, ICMAB-CSIC, Campus UAB, 08193 Bellaterra, Spain.

Fabry disease is a rare lysosomal storage disorder characterized by a deficiency of α-galactosidase A (GLA), a lysosomal hydrolase. The enzyme replacement therapy administering naked GLA shows several drawbacks including poor biodistribution, limited efficacy, and relatively high immunogenicity in Fabry patients. An attractive strategy to overcome these problems is the use of nanocarriers for encapsulating the enzyme. Nanoliposomes functionalized with RGD peptide have already emerged as a good platform to protect and deliver GLA to endothelial cells. However, low colloidal stability and limited enzyme entrapment efficiency could hinder the further pharmaceutical development and the clinical translation of these nanoformulations. Herein, the incorporation of the cationic miristalkonium chloride (MKC) surfactant to RGD nanovesicles is explored, comparing two different nanosystems-quatsomes and hybrid liposomes. In both systems, the positive surface charge introduced by MKC promotes electrostatic interactions between the enzyme and the nanovesicles, improving the loading capacity and colloidal stability. The presence of high MKC content in quatsomes practically abolishes GLA enzymatic activity, while low concentrations of the surfactant in hybrid liposomes stabilize the enzyme without compromising its activity. Moreover, hybrid liposomes show improved efficacy in cell cultures and a good in vitro/in vivo safety profile, ensuring their future preclinical and clinical development.
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http://dx.doi.org/10.1021/acsami.0c16871DOI Listing
February 2021

Polymeric micelles targeted against CD44v6 receptor increase niclosamide efficacy against colorectal cancer stem cells and reduce circulating tumor cells in vivo.

J Control Release 2021 Mar 20;331:198-212. Epub 2021 Jan 20.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain. Electronic address:

Colorectal cancer (CRC) is a highly prevalent disease worldwide. Patient survival is hampered by tumor relapse and the appearance of drug-resistant metastases, which are sustained by the presence of cancer stem cells (CSC). Specific delivery of anti-CSC chemotherapeutic drugs to tumors by using targeted drug delivery systems that can also target CSC sub-population might substantially improve current clinical outcomes. CD44v6 is a robust biomarker for advanced CRC and CSC, due to its functional role in tumorigenesis and cancer initiation process. Here, we show that CD44v6-targeted polymeric micelles (PM) loaded with niclosamide (NCS), a drug against CSC, is a good therapeutic strategy against colorectal CSC and circulating tumor cells (CTC) in vivo. HCT116 cells were sorted according to their CD44v6 receptor expression into CD44v6+ (high) and CDv44v6- (low) subpopulations. Accordingly, CD44v6+ cells presented stemness properties, such as overexpression of defined stemness markers (ALDH1A1, CD44v3 and CXCR4) and high capacity to form colonspheres in low attachment conditions. NCS-loaded PM functionalized with an antibody fragment against CD44v6 (Fab-CD44v6) presented adequate size, charge, and encapsulation efficiency. In addition, Fab-CD44v6 significantly increased PM internalization in CD44v6+ cells. Further, encapsulation of NCS improved its effectiveness in vitro, particularly against colonspheres, and allowed to increase its intravenous dosage in vivo by increasing the amount of NCS able to be administered without causing toxicity. Remarkably, functionalized PM accumulate in tumors and significantly reduce CTC in vivo. In conclusion, CD44v6 targeted PM meet the essential conditions to become an efficient anti-CSC therapy.
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http://dx.doi.org/10.1016/j.jconrel.2021.01.022DOI Listing
March 2021

Nanotechnology-based approaches for treating lysosomal storage disorders, a focus on Fabry disease.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2021 May 13;13(3):e1684. Epub 2020 Dec 13.

Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.

Lysosomal storage disorders (LSDs) are a group of rare diseases in which the defect of a lysosomal protein results in a pathogenic accumulation of nonmetabolized products within the cells. The main treatment for LSDs is enzyme replacement therapy (ERT), consisting in the exogenous administration a recombinant protein to replace the defective one. Although several diseases such as Gaucher, Fabry, and Pompe are treated following this approach, ERT is limited to LSDs without severe neuronal affectation because recombinant enzymes do not cross the blood-brain barrier. Moreover, ERT shows additional drawbacks, including enzyme low half-life, poor bioavailability, and immunogenic responses. In this scenario, nanotechnology-based drug delivery systems (DDS) have been proposed as solution to overcome these limitations and improve the efficacy of ERT. The present review summarizes distinct approaches followed by our group and collaborators on the use of DDS for restoring lysosomal enzymes in disease-affected cells. During the last decade, we have been exploring different synthetic nanoparticles, from electrolytic complexes, to liposomes and aggresomes, for the delivery of α-galactosidase A (GLA) enzyme. Studies were mainly conducted on Fabry disease models, but results can be also extrapolated to other LSDs, as well as to other diseases treated with alternative therapeutic proteins. The advantages and disadvantages of different DDS, the difficulties from working with very labile and highly glycosylated enzymes and the relevance of using appropriate targeting moieties is thoroughly discussed. Finally, the use of natural DDS, namely extracellular vesicles (EVs) is also introduced. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Cardiovascular Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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http://dx.doi.org/10.1002/wnan.1684DOI Listing
May 2021

Increased risk of late-onset, immune-mediated, adverse reactions related to dermal fillers in patients bearing HLA-B*08 and DRB1*03 haplotypes.

Dermatol Ther 2021 01 19;34(1):e14644. Epub 2020 Dec 19.

Aging Basic Research Unit, Molecular Biology and Biochemistry Research Centerfor Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron University Research Institute (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain.

Even though manufacturers claim that the dermal fillers are nontoxic and nonimmunogenic, adverse events may occur. Clinically and histologically, most of the late onset adverse events present as an inflammatory response. To assess whether HLA polymorphisms are associated with late-onset inflammatory adverse events related to dermal fillers. A total of 211 patients were included, of whom 129 experienced late-onset inflammatory adverse events to different fillers (Inflammation group) and 82 who did not (Reference group). Patients completed a standardized questionnaire and provided a blood sample or oral swap for HLA testing. The study population consisted of 188 (89%) women and 23 (11%) men. The two study groups were similar in the distributions of filler type, location of injecting, allergy, autoimmune disease, gender, age, ethnicity, and smoking status. Of the 211 patients in the sample, 25 had the combination of HLA subtype-B*08 and HLA subtype-DRB1*03. This was 16.3% of the inflammatory group and 4.9% of the reference group. This combination of HLA subtypes was associated with an almost 4-fold increase in the odds of developing immune mediated adverse events (odds ratio = 3.79, 95% CI 1.25-11.48). Genetic polymorphisms such as HLA combinations may identify patients at risk of developing late onset immune mediated adverse events to dermal fillers.
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http://dx.doi.org/10.1111/dth.14644DOI Listing
January 2021

Extracellular Vesicles as Drug Delivery Systems in Cancer.

Pharmaceutics 2020 Nov 26;12(12). Epub 2020 Nov 26.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Within tumors, Cancer Stem Cell (CSC) subpopulation has an important role in maintaining growth and dissemination while preserving high resistance against current treatments. It has been shown that, when CSCs are eliminated, the surrounding Differentiated Cancer Cells (DCCs) may reverse their phenotype and gain CSC-like features to preserve tumor progression and ensure tumor survival. This strongly suggests the existence of paracrine communication within tumor cells. It is evidenced that the molecular crosstalk is at least partly mediated by Extracellular Vesicles (EVs), which are cell-derived membranous nanoparticles that contain and transport complex molecules that can affect and modify the biological behavior of distal cells and their molecular background. This ability of directional transport of small molecules prospects EVs as natural Drug Delivery Systems (DDS). EVs present inherent homing abilities and are less immunogenic than synthetic nanoparticles, in general. Currently, strong efforts are focused into the development and improvement of EV-based DDS. Even though EV-DDS have already reached early phases in clinical trials, their clinical application is still far from commercialization since protocols for EVs loading, modification and isolation need to be standardized for large-scale production. Here, we summarized recent knowledge regarding the use of EVs as natural DDS against CSCs and cancer resistance.
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http://dx.doi.org/10.3390/pharmaceutics12121146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761384PMC
November 2020

The potential of nanomedicine to alter cancer stem cell dynamics: the impact of extracellular vesicles.

Nanomedicine (Lond) 2020 12 16;15(28):2785-2800. Epub 2020 Nov 16.

Drug Delivery & Targeting Group, Molecular Biology & Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

The presence of highly resistant cancer stem cells (CSCs) within tumors as drivers of metastatic spread has been commonly accepted. Nonetheless, the likelihood of its dynamic phenotype has been strongly discussed. Importantly, intratumoral cell-to-cell communication seems to act as the main regulatory mechanism of CSC reversion. Today, new strategies for cancer treatment focusing into modulating tumor cell intercommunication and the possibility to modulate the composition of the tumor microenvironment are being explored. In this review, we summarize the literature describing the phenomenon of CSC reversion and the factors known to influence this phenotypic switch. Furthermore, we will discuss the possible role of nanomedicine toward altering this reversion, and to influence the tumor microenvironment composition and the metastatic spread of the disease.
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http://dx.doi.org/10.2217/nnm-2020-0099DOI Listing
December 2020

Simvastatin-loaded polymeric micelles are more effective and less toxic than conventional statins in a pre-clinical model of advanced chronic liver disease.

Nanomedicine 2020 10 15;29:102267. Epub 2020 Jul 15.

Liver Unit, Department of Medicine, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institut Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain. Electronic address:

Chronic liver disease (CLD) has no effective treatments apart from reducing its complications. Simvastatin has been tested as vasoprotective drug in experimental models of CLD showing promising results, but also limiting adverse effects. Two types of Pluronic® carriers loading simvastatin (PM108-simv and PM127-simv) as a drug delivery system were developed to avoid these toxicities while increasing the therapeutic window of simvastatin. PM127-simv showed the highest rates of cell internalization in rat liver sinusoidal endothelial cells (LSECs) and significantly lower toxicity than free simvastatin, improving cell phenotype. The in vivo biodistribution was mainly hepatic with 50% of the injected PM found in the liver. Remarkably, after one week of administration in a model of CLD, PM127-simv demonstrated superior effect than free simvastatin in reducing portal hypertension. Moreover, no signs of toxicity of PM127-simv were detected. Our results indicate that simvastatin targeted delivery to LSEC is a promising therapeutic approach for CLD.
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http://dx.doi.org/10.1016/j.nano.2020.102267DOI Listing
October 2020

Novel amphiphilic chitosan micelles as carriers for hydrophobic anticancer drugs.

Mater Sci Eng C Mater Biol Appl 2020 Jul 3;112:110920. Epub 2020 Apr 3.

i3S - Institute for Research and Innovation in Health/INEB -Institute of Biomedical Engineering (INEB), University of Porto, Portugal; CESPU, IINFACTS - Institute for Research and Advanced Training in Health Sciences and Technologies, Rua Central de Gandra 1317, 4585-116 Gandra, Portugal. Electronic address:

Chitosan was grafted with O-methyl-O'-succinylpolyethylene glycol and oleic acid after a two-step carbodiimide coupling. The structural and physicochemical characterization of the compounds confirmed the successful conjugation of the hydrophilic and hydrophobic moieties to the chitosan backbone. The amphiphilic chitosan derivative obtained allowed the formation of polymeric micelles with an average size of 140 nm, a polydispersity index <0.234, and a positive superficial charge. Camptothecin, used as a model hydrophobic drug, was successfully carried into the polymeric micelles with an encapsulation efficiency of 78%. The in vitro drug release was evaluated in simulated gastrointestinal fluids, exhibiting a low release of camptothecin in gastric media and a controlled release in intestinal fluids. Furthermore, it was demonstrated that chitosan micelles were able to stabilize camptothecin, protecting up to 75% of the drug from hydrolysis, preserving its active lactone form. This new chitosan amphiphilic system exhibits great potential to load hydrophobic drugs, acting as a promising delivery system.
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http://dx.doi.org/10.1016/j.msec.2020.110920DOI Listing
July 2020

Intracellular Delivery of Anti-SMC2 Antibodies against Cancer Stem Cells.

Pharmaceutics 2020 Feb 21;12(2). Epub 2020 Feb 21.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Structural maintenance of chromosomes protein 2 (SMC2) is a central component of the condensin complex involved in DNA supercoiling, an essential process for embryonic stem cell survival. SMC2 over-expression has been related with tumorigenesis and cancer malignancy and its inhibition is regarded as a potential therapeutic strategy even though no drugs are currently available. Here, we propose to inhibit SMC2 by intracellular delivery of specific antibodies against the SMC2 protein. This strategy aims to reduce cancer malignancy by targeting cancer stem cells (CSC), the tumoral subpopulation responsible of tumor recurrence and metastasis. In order to prevent degradation and improve cellular internalization, anti-SMC2 antibodies (Ab-SMC2) were delivered by polymeric micelles (PM) based on Pluronic F127 amphiphilic polymers. Importantly, scaffolding the Ab-SMC2 onto nanoparticles allowed its cellular internalization and highly increased its efficacy in terms of cytotoxicity and inhibition of tumorsphere formation in MDA-MB-231 and HCT116 breast and colon cancer cell lines, respectively. Moreover, in the case of the HCT116 cell line G1, cell-cycle arrest was also observed. In contrast, no effects from free Ab-SMC2 were detected in any case. Further, combination therapy of anti-SMC2 micelles with paclitaxel (PTX) and 5-Fluorouracil (5-FU) was also explored. For this, PTX and 5-FU were respectively loaded into an anti-SMC2 decorated PM. The efficacy of both encapsulated drugs was higher than their free forms in both the HCT116 and MDA-MB-231 cell lines. Remarkably, micelles loaded with Ab-SMC2 and PTX showed the highest efficacy in terms of inhibition of tumorsphere formation in HCT116 cells. Accordingly, our data clearly suggest an effective intracellular release of antibodies targeting SMC2 in these cell models and, further, strong cytotoxicity against CSC, alone and in combined treatments with Standard-of-Care drugs.
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http://dx.doi.org/10.3390/pharmaceutics12020185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076674PMC
February 2020

The Biological Potential Hidden in Inclusion Bodies.

Pharmaceutics 2020 Feb 15;12(2). Epub 2020 Feb 15.

Department of Ruminant Production, Institut de Recerca i Tecnologia Agroalimentàries (IRTA), 08140 Caldes de Montbui, Spain.

Inclusion bodies (IBs) are protein nanoclusters obtained during recombinant protein production processes, and several studies have demonstrated their potential as biomaterials for therapeutic protein delivery. Nevertheless, IBs have been, so far, exclusively sifted by their biological activity in vitro to be considered in further protein-based treatments in vivo. Matrix metalloproteinase-9 (MMP-9) protein, which has an important role facilitating the migration of immune cells, was used as model protein. The MMP-9 IBs were compared with their soluble counterpart and with MMP-9 encapsulated in polymeric-based micelles (PM) through ionic and covalent binding. The soluble MMP-9 and the MMP-9-ionic PM showed the highest activity values in vitro. IBs showed the lowest activity values in vitro, but the specific activity evolution in 50% bovine serum at room temperature proved that they were the most stable format. The data obtained with the use of an air-pouch mouse model showed that MMP-9 IBs presented the highest in vivo activity compared to the soluble MMP-9, which was associated only to a low and a transitory peak of activity. These results demonstrated that the in vivo performance is the addition of many parameters that did not always correlate with the in vitro behavior of the protein of interest, becoming especially relevant at evaluating the potential of IBs as a protein-based nanomaterial for therapeutic purposes.
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http://dx.doi.org/10.3390/pharmaceutics12020157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7076398PMC
February 2020

Engineering a Nanostructured Nucleolin-Binding Peptide for Intracellular Drug Delivery in Triple-Negative Breast Cancer Stem Cells.

ACS Appl Mater Interfaces 2020 Feb 21;12(5):5381-5388. Epub 2020 Jan 21.

CIBER de Bioingeniería , Biomateriales y Nanomedicina (CIBER-BBN) , C/ Monforte de Lemos 3-5 , 28029 Madrid , Spain.

Five peptide ligands of four different cell surface receptors (nucleolin, CXCR1, CMKLR1, and CD44v6) have been evaluated as targeting moieties for triple-negative human breast cancers. Among them, the peptide F3, derived from phage display, promotes the fast and efficient internalization of a genetically fused green fluorescent protein (GFP) inside MDA-MB-231 cancer stem cells in a specific receptor-dependent fashion. The further engineering of this protein into the modular construct F3-RK-GFP-H6 and the subsequent construct F3-RK-PE24-H6 resulted in self-assembling polypeptides that organize as discrete and regular nanoparticles. These materials, 15-20 nm in size, show enhanced nucleolin-dependent cell penetrability. We show that the F3-RK-PE24-H6, based on the exotoxin A (PE24) as a core functional domain, is highly cytotoxic over target cells. The combination of F3, the cationic peptide (RK), and the toxin domain PE24 in such unusual presentation appears as a promising approach to cell-targeted drug carriers in breast cancers and addresses selective drug delivery in otherwise difficult-to-treat triple-negative breast cancers.
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http://dx.doi.org/10.1021/acsami.9b15803DOI Listing
February 2020

Zileuton™ loaded in polymer micelles effectively reduce breast cancer circulating tumor cells and intratumoral cancer stem cells.

Nanomedicine 2020 02 27;24:102106. Epub 2019 Oct 27.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Barcelona, Spain; Networking Research Centre for Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III, Zaragoza, Spain. Electronic address:

Tumor recurrence, metastatic spread and progressive gain of chemo-resistance of advanced cancers are sustained by the presence of cancer stem cells (CSCs) within the tumor. Targeted therapies with the aim to eradicate these cells are thus highly regarded. However, often the use of new anti-cancer therapies is hampered by pharmacokinetic demands. Drug delivery through nanoparticles has great potential to increase efficacy and reduce toxicity and adverse effects. However, its production has to be based on intelligent design. Likewise, we developed polymeric nanoparticles loaded with Zileuton™, a potent inhibitor of cancer stem cells (CSCs), which was chosen based on high throughput screening. Its great potential for CSCs treatment was subsequently demonstrated in in vitro and in in vivo CSC fluorescent models. Encapsulated Zileuton™ reduces amount of CSCs within the tumor and effectively blocks the circulating tumor cells (CTCs) in the blood stream and metastatic spread.
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http://dx.doi.org/10.1016/j.nano.2019.102106DOI Listing
February 2020

Targeting Antitumoral Proteins to Breast Cancer by Local Administration of Functional Inclusion Bodies.

Adv Sci (Weinh) 2019 Sep 24;6(18):1900849. Epub 2019 Jul 24.

Institut de Biotecnologia i de Biomedicina Universitat Autònoma de Barcelona Bellaterra 08193 Barcelona Spain.

Two structurally and functionally unrelated proteins, namely Omomyc and p31, are engineered as CD44-targeted inclusion bodies produced in recombinant bacteria. In this unusual particulate form, both types of protein materials selectively penetrate and kill CD44 tumor cells in culture, and upon local administration, promote destruction of tumoral tissue in orthotropic mouse models of human breast cancer. These findings support the concept of bacterial inclusion bodies as versatile protein materials suitable for application in chronic diseases that, like cancer, can benefit from a local slow release of therapeutic proteins.
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http://dx.doi.org/10.1002/advs.201900849DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6755514PMC
September 2019

Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells.

Cancers (Basel) 2019 Jul 26;11(8). Epub 2019 Jul 26.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, 08035 Barcelona, Spain.

Therapeutic resistance seen in aggressive forms of breast cancer remains challenging for current treatments. More than half of the patients suffer from a disease relapse, most of them with distant metastases. Cancer maintenance, resistance to therapy, and metastatic disease seem to be sustained by the presence of cancer stem cells (CSC) within a tumor. The difficulty in targeting this subpopulation derives from their dynamic interconversion process, where CSC can differentiate to non-CSC, which in turn de-differentiate into cells with CSC properties. Using fluorescent CSC models driven by the expression of (aldehyde dehydrogenase 1A1), we confirmed this dynamic phenotypic change in MDA-MB-231 breast cancer cells and to identify Serine/Threonine Kinase 2 (AKT2) as an important player in the process. To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines. Our results revealed that AKT2 inhibition effectively prevents non-CSC reversion through mesenchymal to epithelial transition, reducing invasion and colony formation ability of both, non-CSC and CSC. Further, AKT2 inhibition reduced CSC survival in low attachment conditions. Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential.
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http://dx.doi.org/10.3390/cancers11081058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721305PMC
July 2019

Sterilization Procedure for Temperature-Sensitive Hydrogels Loaded with Silver Nanoparticles for Clinical Applications.

Nanomaterials (Basel) 2019 Mar 6;9(3). Epub 2019 Mar 6.

Drug Delivery and Targeting Group, Molecular Biology and Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain.

Hydrogels (HG) have recognized benefits as drug delivery platforms for biomedical applications. Their high sensitivity to sterilization processes is however one of the greatest challenges regarding their clinical translation. Concerning infection diseases, prevention of post-operatory related infections is crucial to ensure appropriate patient recovery and good clinical outcomes. Silver nanoparticles (AgNPs) have shown good antimicrobial properties but sustained release at the right place is required. Thus, we produced and characterized thermo-sensitive HG based on Pluronic F127 loaded with AgNPs (HG-AgNPs) and their integrity and functionality after sterilization by dry-heat and autoclave methods were carefully assessed. The quality attributes of HG-AgNPs were seriously affected by dry-heat methods but not by autoclaving methods, which allowed to ensure the required sterility. Also, direct sterilization of the final HG-AgNPs product proved more effective than of the raw material, allowing simpler production procedures in non-sterile conditions. The mechanical properties were assessed in rat models and the HG-AgNPs were tested for its antimicrobial properties in vitro using extremely drug-resistant (XDR) clinical strains. The produced HG-AgNPs prove to be versatile, easy produced and cost-effective products, with activity against XDR strains and an adequate gelation time and spreadability features and optimal for in situ biomedical applications.
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http://dx.doi.org/10.3390/nano9030380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474025PMC
March 2019

Dynamism, Sensitivity, and Consequences of Mesenchymal and Stem-Like Phenotype of Cancer Cells.

Stem Cells Int 2018 10;2018:4516454. Epub 2018 Oct 10.

Drug Delivery and Targeting Group, CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain.

There are remarkable similarities in the description of cancer stem cells (CSCs) and cancer cells with mesenchymal phenotype. Both cell types are highly tumorigenic, resistant against common anticancer treatment, and thought to cause metastatic growth. Moreover, cancer cells are able to switch between CSC and non-CSC phenotypes and vice versa, to ensure the necessary balance within the tumor. Likewise, cancer cells can switch between epithelial and mesenchymal phenotypes via well-described transition (EMT/MET) that is thought to be crucial for tumor propagation. In this review, we discuss whether, and to which extend, the CSCs and mesenchymal cancer cells are overlapping phenomena in terms of mechanisms, origin, and implication for cancer treatment. As well, we describe the dynamism of both phenotypes and involvement of the tumor microenvironment in CSC reversion and in EMT.
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http://dx.doi.org/10.1155/2018/4516454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199882PMC
October 2018

Extracellular HMGA1 Promotes Tumor Invasion and Metastasis in Triple-Negative Breast Cancer.

Clin Cancer Res 2018 12 22;24(24):6367-6382. Epub 2018 Aug 22.

Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.

Purpose: The study of the cancer secretome suggests that a fraction of the intracellular proteome could play unanticipated roles in the extracellular space during tumorigenesis. A project aimed at investigating the invasive secretome led us to study the alternative extracellular function of the nuclear protein high mobility group A1 (HMGA1) in breast cancer invasion and metastasis.

Experimental Design: Antibodies against HMGA1 were tested in signaling, adhesion, migration, invasion, and metastasis assays using breast cancer cell lines and xenograft models. Fluorescence microscopy was used to determine the subcellular localization of HMGA1 in cell lines, xenograft, and patient-derived xenograft models. A cohort of triple-negative breast cancer (TNBC) patients was used to study the correlation between subcellular localization of HMGA1 and the incidence of metastasis.

Results: Our data show that treatment of invasive cells with HMGA1-blocking antibodies in the extracellular space impairs their migration and invasion abilities. We also prove that extracellular HMGA1 (eHMGA1) becomes a ligand for the Advanced glycosylation end product-specific receptor (RAGE), inducing pERK signaling and increasing migration and invasion. Using the cytoplasmic localization of HMGA1 as a surrogate marker of secretion, we showed that eHMGA1 correlates with the incidence of metastasis in a cohort of TNBC patients. Furthermore, we show that HMGA1 is enriched in the cytoplasm of tumor cells at the invasive front of primary tumors and in metastatic lesions in xenograft models.

Conclusions: Our results strongly suggest that eHMGA1 could become a novel drug target in metastatic TNBC and a biomarker predicting the onset of distant metastasis.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0517DOI Listing
December 2018

AKT2 siRNA delivery with amphiphilic-based polymeric micelles show efficacy against cancer stem cells.

Drug Deliv 2018 Nov;25(1):961-972

a Research Institute for Medicines and Pharmaceutical Sciences, Faculdade de Farmácia , Universidade de Lisboa (iMed.ULisboa) , Lisbon , Portugal.

Development of RNA interference-based therapies with appropriate therapeutic window remains a challenge for advanced cancers. Because cancer stem cells (CSC) are responsible of sustaining the metastatic spread of the disease to distal organs and the progressive gain of resistance of advanced cancers, new anticancer therapies should be validated specifically for this subpopulation of cells. A new amphihilic-based gene delivery system that combines Pluronic F127 micelles with polyplexes spontaneously formed by electrostatic interaction between anionic siRNA and cationic polyethylenimine (PEI) 10K, was designed (PM). Resultant PM gather the requirements for an efficient and safe transport of siRNA in terms of its physicochemical characteristics, internalization capacity, toxicity profile and silencing efficacy. PM were loaded with a siRNA against AKT2, an important oncogene involved in breast cancer tumorigenesis, with a special role in CSC malignancy. Efficacy of siAKT2-PM was validated in CSC isolated from two breast cancer cell lines: MCF-7 and Triple Negative MDA-MB-231 corresponding to an aggressive subtype of breast cancer. In both cases, we observed significant reduction on cell invasion capacity and strong inhibition of mammosphere formation after treatment. These results prompt AKT2 inhibition as a powerful therapeutic target against CSC and pave the way to the appearance of more effective nanomedicine-based gene therapies aimed to prevent CSC-related tumor recurrence.
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http://dx.doi.org/10.1080/10717544.2018.1461276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060707PMC
November 2018

Mechanisms of inactivation of the tumour suppressor gene RHOA in colorectal cancer.

Br J Cancer 2018 01 5;118(1):106-116. Epub 2017 Dec 5.

Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona 08035, Spain.

Background: Reduced RHOA signalling has been shown to increase the growth/metastatic potential of colorectal tumours. However, the mechanisms of inactivation of RHOA signalling in colon cancer have not been characterised.

Methods: A panel of colorectal cancer cell lines and large cohorts of primary tumours were used to investigate the expression and activity of RHOA, as well as the presence of RHOA mutations/deletions and promoter methylation affecting RHOA. Changes in RHOA expression were assessed by western blotting and qPCR after modulation of microRNAs, SMAD4 and c-MYC.

Results: We show here that RHOA point mutations and promoter hypermethylation do not significantly contribute to the large variability of RHOA expression observed among colorectal tumours. However, RHOA copy number loss was observed in 16% of colorectal tumours and this was associated with reduced RHOA expression. Moreover, we show that miR-200a/b/429 downregulates RHOA in colorectal cancer cells. In addition, we found that TGF-β/SMAD4 upregulates the RHOA promoter. Conversely, RHOA expression is transcriptionally downregulated by canonical Wnt signalling through the Wnt target gene c-MYC that interferes with the binding of SP1 to the RHOA promoter in colon cancer cells.

Conclusions: We demonstrate a complex pattern of inactivation of the tumour suppressor gene RHOA in colon cancer cells through genetic, transcriptional and post-transcriptional mechanisms.
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http://dx.doi.org/10.1038/bjc.2017.420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5765235PMC
January 2018

TNFα-senescence initiates a STAT-dependent positive feedback loop, leading to a sustained interferon signature, DNA damage, and cytokine secretion.

Aging (Albany NY) 2017 11;9(11):2411-2435

Aging Basic Research Group, Molecular Biology and Biochemistry Research Center for Nanomedicine, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Barcelona, Spain.

Cellular senescence is a cell fate program that entails essentially irreversible proliferative arrest in response to damage signals. Tumor necrosis factor-alpha (TNFα), an important pro-inflammatory cytokine secreted by some types of senescent cells, can induce senescence in mouse and human cells. However, downstream signaling pathways linking TNFα-related inflammation to senescence are not fully characterized. Using human umbilical vein endothelial cells (HUVECs) as a model, we show that TNFα induces permanent growth arrest and increases p21CIP1, p16INK4A, and SA-β-gal, accompanied by persistent DNA damage and ROS production. By gene expression profiling, we identified the crucial involvement of inflammatory and JAK/STAT pathways in TNFα-mediated senescence. We found that TNFα activates a STAT-dependent autocrine loop that sustains cytokine secretion and an interferon signature to lock cells into senescence. Furthermore, we show STAT1/3 activation is necessary for cytokine and ROS production during TNFα-induced senescence. However, inhibition of STAT1/3 did not rescue cells from proliferative arrest, but rather suppressed cell cycle regulatory genes and altered TNFα-induced senescence. Our findings suggest a positive feedback mechanism via the STAT pathway that sustains cytokine production and reveal a reciprocal regulatory role of JAK/STAT in TNFα-mediated senescence.
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http://dx.doi.org/10.18632/aging.101328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723694PMC
November 2017

Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανβ3-targeted polyurethane-polyurea nanoparticles.

Nanomedicine 2018 02 7;14(2):257-267. Epub 2017 Nov 7.

Functional Validation & Preclinical Research (FVPR), Drug Delivery and Targeting Group, CIBBIM-Nanomedicine, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), Barcelona, Spain; Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain. Electronic address:

Glutathione degradable polyurethane-polyurea nanoparticles (PUUa NP) with a disulfide-rich multiwalled structure and a cyclic RGD peptide as a targeting moiety were synthesized, incorporating a very lipophilic chemotherapeutic drug named Plitidepsin. In vitro studies indicated that encapsulated drug maintained and even improved its cytotoxic activity while in vivo toxicity studies revealed that the maximum tolerated dose (MTD) of Plitidepsin could be increased three-fold after encapsulation. We also found that pharmacokinetic parameters such as maximum concentration (Cmax), area under the curve (AUC) and plasma half-life were significantly improved for Plitidepsin loaded in PUUa NP. Moreover, biodistribution assays in mice showed that RGD-decorated PUUa NP accumulate less in spleen and liver than non-targeted conjugates, suggesting that RGD-decorated nanoparticles avoid sequestration by macrophages from the reticuloendothelial system. Overall, our results indicate that polyurethane-polyurea nanoparticles represent a very valuable nanoplatform for the delivery of lipophilic drugs by improving their toxicological, pharmacokinetic and whole-body biodistribution profiles.
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http://dx.doi.org/10.1016/j.nano.2017.10.009DOI Listing
February 2018

Effect of Specific Mutations in Cd300 Complexes Formation; Potential Implication of Cd300f in Multiple Sclerosis.

Sci Rep 2017 10 19;7(1):13544. Epub 2017 Oct 19.

CIBBIM-Nanomedicine-Immune Regulation and Immunotherapy Group. Institut de Recerca Vall Hebrón (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Herein, we have used bioinformatics tools to predict five clusters defining ligand-binding sites on the extracellular domain of human CD300b receptor, presumably involved in the formation of both homodimers and heterodimers with other CD300 family members. Site-directed mutagenesis revealed residues glutamic acid 28 and glutamine 29 in cluster 5 to be necessary for the formation of CD300b complexes. Surprisingly, the disruption of cluster 2 and 4 reconstituted the binding capability lost by the mutation of residues glutamic acid 28 to alanine, glutamine 29 to alanine (E28A-Q29G). We identified a missense mutation arginine 33 to glutamine (R33Q) in CD300f by direct sequencing of exon 2 in peripheral blood samples from 50 patients with multiple sclerosis (MS). Levels of expression of CD300f were almost undetectable on monocytes from the patient bearing the R33Q mutation compared with healthy individuals. Whereas R33Q mutation had no effect in the formation of CD300f complexes, the inhibition of protein synthesis with cycloheximide indicated that CD300f R33Q is less stable than native CD300f. Finally, we report that the levels of expression of CD300f on the surface of classical and intermediate monocytes from MS patients are significantly lower when compared to the same cell populations in healthy individuals.
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http://dx.doi.org/10.1038/s41598-017-12881-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5648872PMC
October 2017

Loss of the EPH receptor B6 contributes to colorectal cancer metastasis.

Sci Rep 2017 03 6;7:43702. Epub 2017 Mar 6.

Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Although deregulation of EPHB signaling has been shown to be an important step in colorectal tumorigenesis, the role of EPHB6 in this process has not been investigated. We found here that manipulation of EPHB6 levels in colon cancer cell lines has no effect on their motility and growth on a solid substrate, soft agar or in a xenograft mouse model. We then used an EphB6 knockout mouse model to show that EphB6 inactivation does not efficiently initiate tumorigenesis in the intestinal tract. In addition, when intestinal tumors are initiated genetically or pharmacologically in EphB6 and EphB6 mice, no differences were observed in animal survival, tumor multiplicity, size or histology, and proliferation of intestinal epithelial cells or tumor cells. However, reintroduction of EPHB6 into colon cancer cells significantly reduced the number of lung metastasis after tail-vein injection in immunodeficient mice, while EPHB6 knockdown in EPHB6-expressing cells increased their metastatic spread. Consistently, although EPHB6 protein expression in a series of 130 primary colorectal tumors was not associated with patient survival, EPHB6 expression was significantly lower in lymph node metastases compared to primary tumors. Our results indicate that the loss of EPHB6 contributes to the metastatic process of colorectal cancer.
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http://dx.doi.org/10.1038/srep43702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5337985PMC
March 2017

Investigation of the role of tyrosine kinase receptor EPHA3 in colorectal cancer.

Sci Rep 2017 02 7;7:41576. Epub 2017 Feb 7.

Group of Biomedical Research in Digestive Tract Tumors, CIBBIM-Nanomedicine, Vall d'Hebron University Hospital, Research Institute (VHIR), Universitat Autònoma de Barcelona, Passeig Vall d'Hebron, 119-129, 08035 Barcelona, Spain.

EPH signaling deregulation has been shown to be important for colorectal carcinogenesis and genome-wide sequencing efforts have identified EPHA3 as one of the most frequently mutated genes in these tumors. However, the role of EPHA3 in colorectal cancer has not been thoroughly investigated. We show here that ectopic expression of wild type EPHA3 in colon cancer cells did not affect their growth, motility/invasion or metastatic potential in vivo. Moreover, overexpression of mutant EPHA3 or deletion of the endogenous mutant EPHA3 in colon cancer cells did not affect their growth or motility. EPHA3 inactivation in mice did not initiate the tumorigenic process in their intestine, and had no effects on tumor size/multiplicity after tumor initiation either genetically or pharmacologically. In addition, immunohistochemical analysis of EPHA3 tumor levels did not reveal associations with survival or clinicopathological features of colorectal cancer patients. In conclusion, we show that EPHA3 does not play a major role in colorectal tumorigenesis. These results significantly contribute to our understanding of the role of EPH signaling during colorectal carcinogenesis, and highlighting the need for detailed functional studies to confirm the relevance of putative cancer driver genes identified in sequencing efforts of the cancer genome.
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http://dx.doi.org/10.1038/srep41576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294649PMC
February 2017

Unmet needs in developing nanoparticles for precision medicine.

Authors:
Simo Schwartz

Nanomedicine (Lond) 2017 02 17;12(4):271-274. Epub 2017 Jan 17.

Molecular Biology & Biochemistry Research Centre for Nanomedicine (CIBBIM-Nanomedicine), Vall d'Hebron Institut de Recerca, Barcelona, Spain.

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http://dx.doi.org/10.2217/nnm-2016-0390DOI Listing
February 2017

Design of chalcogen-containing norepinephrines: efficient GPx mimics and strong cytotoxic agents against HeLa cells.

Future Med Chem 2016 12 15;8(18):2185-2195. Epub 2016 Nov 15.

Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, 41071, Seville, Spain.

Aim: Numerous chronic diseases exhibit multifactorial etiologies, so focusing on a single therapeutic target is usually an inadequate treatment; instead, multi-target drugs are preferred. Herein, a panel of phenolic thioureas and selenoureas were designed as new prototypes against multifactorial diseases concerning antioxidation and cytotoxicity, as a pro-oxidant environment is usually found in such diseases.

Results: Selenoureas were excellent antiradical agents and biomimetic catalysts of glutathione peroxidase for the scavenging of HO. They were also potent and selective cytotoxic agents against cancer cells, in particular HeLa (IC 2.77-6.13 μM), apoptosis being involved. Selenoureas also reduced oxidative stress in HeLa cells (IC= 3.76 μM).

Conclusion: Phenolic selenoureas are promising lead structures for the development of drugs targeting multifactorial diseases like cancer.
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http://dx.doi.org/10.4155/fmc-2016-0139DOI Listing
December 2016