Publications by authors named "Marcelo J Kogan"

86 Publications

Plasmonic Nanoparticles as Optical Sensing Probes for the Detection of Alzheimer's Disease.

Sensors (Basel) 2021 Mar 16;21(6). Epub 2021 Mar 16.

Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Dr. Carlos Lorca Tobar 964, Independencia, 8380000 Santiago, Chile.

Alzheimer's disease (AD), considered a common type of dementia, is mainly characterized by a progressive loss of memory and cognitive functions. Although its cause is multifactorial, it has been associated with the accumulation of toxic aggregates of the amyloid-β peptide (Aβ) and neurofibrillary tangles (NFTs) of tau protein. At present, the development of highly sensitive, high cost-effective, and non-invasive diagnostic tools for AD remains a challenge. In the last decades, nanomaterials have emerged as an interesting and useful tool in nanomedicine for diagnostics and therapy. In particular, plasmonic nanoparticles are well-known to display unique optical properties derived from their localized surface plasmon resonance (LSPR), allowing their use as transducers in various sensing configurations and enhancing detection sensitivity. Herein, this review focuses on current advances in in vitro sensing techniques such as Surface-enhanced Raman scattering (SERS), Surface-enhanced fluorescence (SEF), colorimetric, and LSPR using plasmonic nanoparticles for improving the sensitivity in the detection of main biomarkers related to AD in body fluids. Additionally, we refer to the use of plasmonic nanoparticles for in vivo imaging studies in AD.
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http://dx.doi.org/10.3390/s21062067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998661PMC
March 2021

The Influence of Size and Chemical Composition of Silver and Gold Nanoparticles on in vivo Toxicity with Potential Applications to Central Nervous System Diseases.

Int J Nanomedicine 2021 15;16:2187-2201. Epub 2021 Mar 15.

Department of Pharmacological and Toxicological Chemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.

The physicochemical and optical properties of silver nanoparticles (SNPs) and gold nanoparticles (GNPs) have allowed them to be employed for various biomedical applications, including delivery, therapy, imaging, and as theranostic agents. However, since they are foreign body systems, they are usually redistributed and accumulated in some vital organs, which can produce toxic effects; therefore, this a crucial issue that should be considered for potential clinical trials. This review aimed to summarize the reports from the past ten years that have used SNPs and GNPs for in vivo studies on the diagnosis and treatment of brain diseases and those related to the central nervous system, emphasizing their toxicity as a crucial topic address. The article focuses on the effect of the nanoparticle´s size and chemical composition as relevant parameters for in vivo toxicity. At the beginning of this review, the general toxicity and distribution studies are discussed separately for SNPs and GNPs. Subsequently, this manuscript analyzes the principal applications of both kinds of nanoparticles for glioma, neurodegenerative, and other brain diseases, and discusses the advances in clinical trials. Finally, we analyze research prospects towards clinical applications for both types of metallic nanoparticles.
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http://dx.doi.org/10.2147/IJN.S260375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979359PMC
April 2021

Functionalization of Gold Nanostars with Cationic β-Cyclodextrin-Based Polymer for Drug Co-Loading and SERS Monitoring.

Pharmaceutics 2021 Feb 15;13(2). Epub 2021 Feb 15.

Laboratorio de Nanoquímica y Química Supramolecular, Departamento de Química, Facultad de Ciencias, Universidad de Chile, Las Palmeras 3425, Ñuñoa, Santiago 7800003, Chile.

Gold nanostars (AuNSs) exhibit modulated plasmon resonance and have a high SERS enhancement factor. However, their low colloidal stability limits their biomedical application as a nanomaterial. Cationic β-cyclodextrin-based polymer (CCD/P) has low cytotoxicity, can load and transport drugs more efficiently than the corresponding monomeric form, and has an appropriate cationic group to stabilize gold nanoparticles. In this work, we functionalized AuNSs with CCD/P to load phenylethylamine (PhEA) and piperine (PIP) and evaluated SERS-based applications of the products. PhEA and PIP were included in the polymer and used to functionalize AuNSs, forming a new AuNS-CCD/P-PhEA-PIP nanosystem. The system was characterized by UV-VIS, IR, and NMR spectroscopy, TGA, SPR, DLS, zeta potential analysis, FE-SEM, and TEM. Additionally, Raman optical activity, SERS analysis and complementary theoretical studies were used for characterization. Minor adjustments increased the colloidal stability of AuNSs. The loading capacity of the CCD/P with PhEA-PIP was 95 ± 7%. The physicochemical parameters of the AuNS-CCD/P-PhEA-PIP system, such as size and Z potential, are suitable for potential biomedical applications Raman and SERS studies were used to monitor PhEA and PIP loading and their preferential orientation upon interaction with the surface of AuNSs. This unique nanomaterial could be used for simultaneous drug loading and SERS-based detection.
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http://dx.doi.org/10.3390/pharmaceutics13020261DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919026PMC
February 2021

Microfluidics-assisted conjugation of chitosan-coated polymeric nanoparticles with antibodies: Significance in drug release, uptake, and cytotoxicity in breast cancer cells.

J Colloid Interface Sci 2021 Jun 13;591:440-450. Epub 2021 Feb 13.

Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Mexico. Electronic address:

Nanoparticle-based drug delivery systems, in combination with high-affinity disease-specific targeting ligands, provide a sophisticated landscape in cancer theranostics. Due to their high diversity and specificity to target cells, antibodies are extensively used to provide bioactivity to a plethora of nanoparticulate systems. However, controlled and reproducible assembly of nanoparticles (NPs) with these targeting ligands remains a challenge. In this context, determinants such as ligand density and orientation, play a significant role in antibody bioactivity; nevertheless, these factors are complicated to control in traditional bulk labeling methods. Here, we propose a microfluidic-assisted methodology using a polydimethylsiloxane (PDMS) Y-shaped microreactor for the covalent conjugation of Trastuzumab (TZB), a recombinant antibody targeting HER2 (human epidermal growth factor receptor 2), to doxorubicin-loaded PLGA/Chitosan NPs (PLGA/DOX/Ch NPs) using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and N-hydroxysulfosuccinimide (sNHS) mediated bioconjugation reactions. Our labeling approach led to smaller and less disperse nanoparticle-antibody conjugates providing differential performance when compared to bulk-labeled NPs in terms of drug release kinetics (fitted and analyzed with DDSolver), cell uptake/labeling, and cytotoxic activity on HER2 + breast cancer cells in vitro. By controlling NP-antibody interactions in a laminar regime, we managed to optimize NP labeling with antibodies resulting in ordered coronas with optimal orientation and density for bioactivity, providing a cheap and reproducible, one-step method for labeling NPs with globular targeting moieties.
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http://dx.doi.org/10.1016/j.jcis.2021.02.031DOI Listing
June 2021

Functionalization with PEG/Angiopep-2 peptide to improve the delivery of gold nanoprisms to central nervous system: in vitro and in vivo studies.

Mater Sci Eng C Mater Biol Appl 2021 Feb 10;121:111785. Epub 2020 Dec 10.

Laboratorio de Nanobiotecnología y Nanotoxicología, Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile; Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile. Electronic address:

One of main drawbacks for the treatment of neurodegenerative pathologies is ensuring the delivery of therapeutic agents into the central nervous system (CNS). Nowadays, gold nanoprisms (GNPr) have become an emerging nanomaterial with a localized surface plasmon resonance in the biological window, showing applications in both detection and treatment of diseases. In this work, GNPr were functionalized with polyethylene glycol (PEG) and Angiopep-2 (Ang2) peptide to obtain a new highly stable nanomaterial and evaluate its toxicity and ability to cross the blood-brain barrier (BBB) in a zebrafish larvae model. The success in the functionalization was confirmed by a full characterization that showed the physicochemical changes at each step. In turn, the colloidal stability of GNPr-PEG-Ang2 in biologically relevant media also was demonstrated. The toxicity assays of GNPr-PEG-Ang2 performed on SH-SY5Y neuroblastoma cell line and on zebrafish larvae showed no effects both in vitro and in vivo. GNPr delivery to the CNS was studied in zebrafish larvae by immersion. We confirmed that functionalization with PEG-Ang2 improved the crossing through the BBB in this model compared with GNPr functionalized only with PEG. Notably, our nanomaterial was not detected in the CNS of zebrafish larvae 24 h after exposure that correlates with an adequate clearance of GNPr-PEG-Ang2 from the brain. This report is the first study of GNPr in the in vivo model of zebrafish larvae demonstrating that its functionalization with Ang2 allows the crossing of the BBB. Moreover, considering the stability achieved of the GNPr-PEG-Ang2 and the results of in vitro and in vivo studies, this work becomes a high contribution to the design of new nanomaterials with potential biomedical applications for CNS-related diseases.
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http://dx.doi.org/10.1016/j.msec.2020.111785DOI Listing
February 2021

The Combined Use of Gold Nanoparticles and Infrared Radiation Enables Cytosolic Protein Delivery.

Chemistry 2021 Mar 15;27(14):4670-4675. Epub 2021 Feb 15.

Institute for Research in Biomedicine, Barcelona Institute of, Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.

Cytosolic protein delivery remains elusive. The inability of most proteins to cross the cellular membrane is a huge hurdle. Here we explore the unique photothermal properties of gold nanorods (AuNRs) to trigger cytosolic delivery of proteins. Both partners, protein and AuNRs, are modified with a protease-resistant cell-penetrating peptide with nuclear targeting properties to induce internalization. Once internalized, spatiotemporal control of protein release is achieved by near-infrared laser irradiation in the safe second biological window. Importantly, catalytic amounts of AuNRs are sufficient to trigger cytosolic protein delivery. To the best of our knowledge, this is the first time that AuNRs with their maximum of absorption in the second biological window are used to deliver proteins into the intracellular space. This strategy represents a powerful tool for the cytosolic delivery of virtually any class of protein.
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http://dx.doi.org/10.1002/chem.202005000DOI Listing
March 2021

Poly-ε-caprolactone Nanoparticles Loaded with 4-Nerolidylcatechol (4-NC) for Growth Inhibition of .

Antibiotics (Basel) 2020 Dec 11;9(12). Epub 2020 Dec 11.

Department of Drugs and Medicines, School of Pharmaceutical Sciences, School of Pharmaceutical Sciences of São Paulo State University (UNESP), Rodovia Araraquara-Jaú, Km 1, Araraquara, SP 14800-903, Brazil.

Dermatophyte fungal infections are difficult to treat because they need long-term treatments. 4-Nerolidylcatechol (4-NC) is a compound found in that has been reported to demonstrate significant antifungal activity, but is easily oxidizable. Due to this characteristic, the incorporation in nanostructured systems represents a strategy to guarantee the compound's stability compared to the isolated form and the possibility of improving antifungal activity. The objective of this study was to incorporate 4-NC into polymeric nanoparticles to evaluate, in vitro and in vivo, the growth inhibition of . 4-NC was isolated from fresh leaves of and polymer nanoparticles of polycaprolactone were developed by nanoprecipitation using a 1:5 weight ratio (drug:polymer). Nanoparticles exhibited excellent encapsulation efficiency, and the antifungal activity was observed in nanoparticles with 4-NC incorporated. Polymeric nanoparticles can be a strategy employed for decreased cytotoxicity, increasing the stability and solubility of substances, as well as improving the efficacy of 4-NC.
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http://dx.doi.org/10.3390/antibiotics9120894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763452PMC
December 2020

Light-induced release of the cardioprotective peptide angiotensin-(1-9) from thermosensitive liposomes with gold nanoclusters.

J Control Release 2020 12 4;328:859-872. Epub 2020 Nov 4.

Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceúticas & Facultad Medicina, Universidad de Chile, Santiago 8380492, Chile; Departamento de Química Farmacológica y Toxicológica, Facultad Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380492, Chile; Corporación Centro de Estudios Científicos de las Enfermedades Crónicas (CECEC), Santiago 7680201, Chile. Electronic address:

Angiotensin-(1-9), a component of the non-canonical renin-angiotensin system, has a short half-life in blood. This peptide has shown to prevent and/or attenuate hypertension and cardiovascular remodeling. A controlled release of angiotensin-(1-9) is needed for its delivery to the heart. Our aim was to develop a drug delivery system for angiotensin-(1-9). Thermosensitive liposomes (LipoTherm) were prepared with gold nanoclusters (LipoTherm-AuNC) to increase the stability and reach a temporal and spatial control of angiotensin-(1-9) release. Encapsulation efficiencies of nearly 50% were achieved in LipoTherm, reaching a total angiotensin-(1-9) loading of around 180 μM. This angiotensin-(1-9)-loaded LipoTherm sized around 100 nm and exhibited a phase transition temperature of 43 °C. AuNC were grown on LipoTherm and the new hybrid nanosystem showed energy absorption in the near-infrared (NIR) wavelength range. By NIR laser irradiation, a controlled release of angiotensin-(1-9) was achieved from the LipoTherm-AuNC nanosystem. These nanosystems did not show any cytotoxic effect on cultured cardiomyocytes. Biological activity of angiotensin-(1-9) released from the LipoTherm-AuNC-based nanosystem was confirmed using an ex vivo Langendorff heart model.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.002DOI Listing
December 2020

Label-Free Oligonucleotide-Based SPR Biosensor for the Detection of the Gene Mutation Causing Prothrombin-Related Thrombophilia.

Sensors (Basel) 2020 Oct 31;20(21). Epub 2020 Oct 31.

Laboratorio de Biosensores, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile; Santos Dumont N° 964, Independencia, Santiago 8380492, Chile.

Prothrombin-related thrombophilia is a genetic disorder produced by a substitution of a single DNA base pair, replacing guanine with adenine, and is detected mainly by polymerase chain reaction (PCR). A suitable alternative that could detect the single point mutation without requiring sample amplification is the surface plasmon resonance (SPR) technique. SPR biosensors are of great interest: they offer a platform to monitor biomolecular interactions, are highly selective, and enable rapid analysis in real time. Oligonucleotide-based SPR biosensors can be used to differentiate complementary sequences from partially complementary or noncomplementary strands. In this work, a glass chip covered with an ultrathin (50 nm) gold film was modified with oligonucleotide strands complementary to the mutated or normal (nonmutated) DNA responsible for prothrombin-related thrombophilia, forming two detection platforms called mutated thrombophilia (MT) biosensor and normal thrombophilia (NT) biosensor. The results show that the hybridization response is obtained in 30 min, label free and with high reproducibility. The sensitivity obtained in both systems was approximately 4 ΔμRIU/nM. The dissociation constant and limits of detection calculated were 12.2 nM and 20 pM (3 fmol), respectively, for the MT biosensor, and 8.5 nM and 30 pM (4.5 fmol) for the NT biosensor. The two biosensors selectively recognize their complementary strand (mutated or normal) in buffer solution. In addition, each platform can be reused up to 24 times when the surface is regenerated with HCl. This work contributes to the design of the first SPR biosensor for the detection of prothrombin-related thrombophilia based on oligonucleotides with single point mutations, label-free and without the need to apply an amplification method.
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http://dx.doi.org/10.3390/s20216240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7663036PMC
October 2020

Exploiting the Natural Properties of Extracellular Vesicles in Targeted Delivery towards Specific Cells and Tissues.

Pharmaceutics 2020 Oct 26;12(11). Epub 2020 Oct 26.

Advanced Center for Chronic Diseases (ACCDiS), University of Chile, Santos Dumont 964 Independencia, 8380000 Santiago, Chile.

Extracellular vesicles (EVs) are important mediators of intercellular communication that participate in many physiological/pathological processes. As such, EVs have unique properties related to their origin, which can be exploited for drug delivery applications in cell regeneration, immunosuppression, inflammation, cancer treatment or cardioprotection. Moreover, their cell-like membrane organization facilitates uptake and accumulation in specific tissues and organs, which can be exploited to improve selectivity of cargo delivery. The combination of these properties with the inclusion of drugs or imaging agents can significantly improve therapeutic efficacy and selectivity, reduce the undesirable side effects of drugs or permit earlier diagnosis of diseases. In this review, we will describe the natural properties of EVs isolated from different cell sources and discuss strategies that can be applied to increase the efficacy of targeting drugs or other contents to specific locations. The potential risks associated with the use of EVs will also be addressed.
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http://dx.doi.org/10.3390/pharmaceutics12111022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692617PMC
October 2020

Intranasal administration of gold nanoparticles designed to target the central nervous system: Fabrication and comparison between nanospheres and nanoprisms.

Int J Pharm 2020 Nov 6;590:119957. Epub 2020 Oct 6.

Laboratory for Biopharmaceutics, Department of Biomedical Engineering, Ben Gurion University of the Negev, E.D. Bergmann Campus, Be'er Sheva 84105, Israel. Electronic address:

The presence of the blood-brain barrier (BBB) limit gold nanoparticles (GNP) accumulation in central nervous system (CNS) after intravenous (IV) administration. The intranasal (IN) route has been suggested as a good strategy for circumventing the BBB. In this report, we used gold nanoprisms (78 nm) and nanospheres (47 nm), of comparable surface areas (8000 vs 7235 nm) functionalized with a polyethylene glycol (PEG) and D1 peptide (GNPr-D1 and GNS-D1, respectively) to evaluate their delivery to the CNS after IN administration. Cell viability assay showed that GNPr-D1 and GNS-D1 were not cytotoxic at concentrations ranged between 0.05 and 0.5 nM. IN administration of GNPr-D1 and GNS-D1 demonstrated a significant difference between the two types of GNP, in which the latter reached the CNS in higher levels. Pharmacokinetic study showed that the peak brain level of gold was 0.75 h after IN administration of GNS-D1. After IN and IV administrations of GNS-D1, gold concentrations found in brain were 55 times higher via the IN route compared to IV administration. Data revealed that the IN route is more effective for targeting gold to the brain than IV administration. Finally, no significant difference was observed between the IN and IV routes in the distribution of GNS-D1 in the various brain areas.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119957DOI Listing
November 2020

Adsorption of bovine serum albumin on gold nanoprisms: interaction and effect of NIR irradiation on protein corona.

J Mater Chem B 2020 09;8(37):8644-8657

Advanced Center for Chronic Diseases (ACCDiS), Santos Dumont 964, Independencia, Santiago, Chile and Departamento de Ciencias Químicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Av. Republica 275, Santiago, Chile.

Because of their photothermal properties, gold nanoparticles (AuNPs) have gained attention regarding their use in drug delivery and therapeutic applications. In this sense, it is interesting to consider their interactions with biologically available proteins, such as serum albumin, as well as the effects of irradiation and photothermal conversion on the protein structure that can lead to a loss of function or generate an immune response. Gold nanoprisms (AuNPrs) have gained interest due to their low toxicity, ease of synthesis, and excellent stability, promoting their use in bioapplications such as surface-enhanced Raman spectroscopy (SERS), drug delivery, and photothermal therapy. The interaction between AuNPrs, with plasmon bands centred in the near-infrared region (NIR), and bovine serum albumin (BSA) has not been explored yet. UV-Vis spectroscopy, dynamic light scattering (DLS) and fluorescence spectroscopy were used to study the interaction between AuNPrs and BSA in addition to estimation of the adsorption rate and kinetic and thermodynamic parameters (K, ΔH°, ΔG°, ΔS°, and Ea) using adsorption isotherms and Langmuir and Freundlich models. The results suggest spontaneous cooperative binding in multilayer adsorption, achieved by the chemisorption of BSA on the AuNPr surface through the S-Au interaction, as confirmed by Raman spectroscopy. On the other hand, the photothermal conversion efficiency (PE) of the coated nanoparticles after NIR irradiation was assessed, resulting in a slight decrease in the PE of BSA coated on AuNPrs in comparison with that of noncapped nanoparticles. The effect of the irradiation on the protein conformation of capped nanoparticles was also assessed; circular dichroism showed BSA unfolding upon interaction with AuNPrs, with a decrease in the α-helix and β-sheet contents, as well as an increase in random coil conformations. Changes in the Raman spectrum suggest a modification of the disposition of the protein residues exposed to the gold surface after NIR irradiation; but at the secondary structure level, no relevant changes were observed. This provides possibilities for the use of NPs-BSA for bioapplications based on the photothermal effect promoted by laser irradiation, since the biological identity of the protein is preserved after NIR irradiation.
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http://dx.doi.org/10.1039/d0tb01246gDOI Listing
September 2020

Inhibition of chymotrypsin-like activity of the proteasome by ixazomib prevents mitochondrial dysfunction during myocardial ischemia.

PLoS One 2020 26;15(5):e0233591. Epub 2020 May 26.

Programa de Fisiología y Biofísica, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

The heart is critically dependent on mitochondrial respiration for energy supply. Ischemia decreases oxygen availability, with catastrophic consequences for cellular energy systems. After a few minutes of ischemia, the mitochondrial respiratory chain halts, ATP levels drop and ion gradients across cell membranes collapse. Activation of cellular proteases and generation of reactive oxygen species by mitochondria during ischemia alter mitochondrial membrane permeability, causing mitochondrial swelling and fragmentation and eventually cell death. The mitochondria, therefore, are important targets of cardioprotection against ischemic injury. We have previously shown that ixazomib (IXA), a proteasome inhibitor used for treating multiple myeloma, effectively reduced the size of the infarct produced by global ischemia in isolated rat hearts and prevented degradation of the sarcoplasmic reticulum calcium release channel RyR2. The aim of this work was to further characterize the protective effect of IXA by determining its effect on mitochondrial morphology and function after ischemia. We also quantified the effect of IXA on levels of mitofusin-2, a protein involved in maintaining mitochondrial morphology and mitochondria-SR communication. We found that mitochondria were significantly preserved and functional parameters such as oxygen consumption, the ability to generate a membrane potential, and glutathione content were improved in mitochondria isolated from hearts perfused with IXA prior to ischemia. IXA also blocked the release of cytochrome c observed in ischemia and significantly preserved mitofusin-2 integrity. These beneficial effects resulted in a significant decrease in the left ventricular end diastolic pressure upon reperfusion and a smaller infarct in isolated hearts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233591PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7250417PMC
August 2020

Chitosan-Based Nanoparticles for Intracellular Delivery of ISAV Fusion Protein cDNA into Melanoma Cells: A Path to Develop Oncolytic Anticancer Therapies.

Mediators Inflamm 2020 29;2020:8680692. Epub 2020 Apr 29.

Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile (USACH), Alameda, 3363 Santiago, Chile.

Oncolytic virus therapy has been tested against cancer in preclinical models and clinical assays. Current evidence shows that viruses induce cytopathic effects associated with fusogenic protein-mediated syncytium formation and immunogenic cell death of eukaryotic cells. We have previously demonstrated that tumor cell bodies generated from cells expressing the fusogenic protein of the infectious salmon anemia virus (ISAV-F) enhance crosspriming and display prophylactic antitumor activity against melanoma tumors. In this work, we evaluated the effects of the expression of ISAV-F on the B16 melanoma model, both and , using chitosan nanoparticles as transfection vehicle. We confirmed that the transfection of B16 tumor cells with chitosan nanoparticles (NP-ISAV) allows the expression of a fusogenically active ISAV-F protein and decreases cell viability because of syncytium formation . However, the transfection induces a delay in tumor growth, without inducing changes on the lymphoid populations in the tumor and the spleen. Altogether, our observations show that expression of ISAV fusion protein using chitosan nanoparticles induces cell fusion in melanoma cells and slight antitumor response.
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http://dx.doi.org/10.1155/2020/8680692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206890PMC
April 2020

Gold Nanoparticles Mediate Improved Detection of β-amyloid Aggregates by Fluorescence.

Nanomaterials (Basel) 2020 Apr 6;10(4). Epub 2020 Apr 6.

Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago 8380494, Chile.

The early detection of the amyloid beta peptide aggregates involved in Alzheimer's disease is crucial to test new potential treatments. In this research, we improved the detection of amyloid beta peptide aggregates in vitro and ex vivo by fluorescence combining the use of CRANAD-2 and gold nanorods (GNRs) by the surface enhancement fluorescence effect. We synthetized GNRs and modified their surface with HS-PEG-OMe and HS-PEG-COOH and functionalized them with the D1 peptide, which has the capability to selectively bind to amyloid beta peptide. For an in vitro detection of amyloid beta peptide, we co-incubated amyloid beta peptide aggregates with the probe CRANAD-2 and GNR-PEG-D1 observing an increase in the intensity of the fluorescence signal attributed to surface enhancement fluorescence. Furthermore, the surface enhancement fluorescence effect was observed in brain slices of transgenic mice with Alzheimer´s disease co-incubated with CRANAD-2 and GNR-PEG-D1. An increase in the fluorescence signal was observed allowing the detection of aggregates that cannot be detected with the single use of CRANAD-2. Gold nanoparticles allowed an improvement in the detection of the amyloid aggregated by fluorescence in vitro and ex vivo.
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http://dx.doi.org/10.3390/nano10040690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221977PMC
April 2020

Improving Cell Penetration of Gold Nanorods by Using an Amphipathic Arginine Rich Peptide.

Int J Nanomedicine 2020 17;15:1837-1851. Epub 2020 Mar 17.

Departamento de Química Farmacológica y Toxicológica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.

Introduction: Gold nanorods are highly reactive, have a large surface-to-volume ratio, and can be functionalized with biomolecules. Gold nanorods can absorb infrared electromagnetic radiation, which is subsequently dispersed as local heat. Gold nanoparticles can be used as powerful tools for the diagnosis and therapy of different diseases. To improve the biological barrier permeation of nanoparticles with low cytotoxicity, in this study, we conjugated gold nanorods with cell-penetrating peptides (oligoarginines) and with the amphipathic peptide CLPFFD.

Methods: We studied the interaction of the functionalized gold nanorods with biological membrane models (liposomes) by dynamic light scattering, transmission electron microscopy and the Langmuir balance. Furthermore, we evaluated the effects on cell viability and permeability with an MTS assay and TEM.

Results And Discussion: The interaction study by DLS, the Langmuir balance and cryo-TEM support that GNR-ArgCLPFFD enhances the interactions between GNRs and biological membranes. In addition, cells treated with GNR-ArgCLPFFD internalized 80% more nanoparticles than cells treated with GNR alone and did not induce cell damage.

Conclusion: Our results indicate that incorporation of an amphipathic sequence into oligoarginines for the functionalization of gold nanorods enhances biological membrane nanoparticle interactions and nanoparticle cell permeability with respect to nanorods functionalized with oligoarginine. Overall, functionalized gold nanorods with amphipathic arginine rich peptides might be candidates for improving drug delivery by facilitating biological barrier permeation.
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http://dx.doi.org/10.2147/IJN.S237820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090188PMC
July 2020

Gold nanoparticle based double-labeling of melanoma extracellular vesicles to determine the specificity of uptake by cells and preferential accumulation in small metastatic lung tumors.

J Nanobiotechnology 2020 Jan 23;18(1):20. Epub 2020 Jan 23.

Departamento de Química Farmacológica Y Toxicológica, Universidad de Chile, Santos Dumont 964, 8380494, Santiago, Chile.

Background: Extracellular vesicles (EVs) have shown great potential for targeted therapy, as they have a natural ability to pass through biological barriers and, depending on their origin, can preferentially accumulate at defined sites, including tumors. Analyzing the potential of EVs to target specific cells remains challenging, considering the unspecific binding of lipophilic tracers to other proteins, the limitations of fluorescence for deep tissue imaging and the effect of external labeling strategies on their natural tropism. In this work, we determined the cell-type specific tropism of B16F10-EVs towards cancer cell and metastatic tumors by using fluorescence analysis and quantitative gold labeling measurements. Surface functionalization of plasmonic gold nanoparticles was used to promote indirect labeling of EVs without affecting size distribution, polydispersity, surface charge, protein markers, cell uptake or in vivo biodistribution. Double-labeled EVs with gold and fluorescent dyes were injected into animals developing metastatic lung nodules and analyzed by fluorescence/computer tomography imaging, quantitative neutron activation analysis and gold-enhanced optical microscopy.

Results: We determined that B16F10 cells preferentially take up their own EVs, when compared with colon adenocarcinoma, macrophage and kidney cell-derived EVs. In addition, we were able to detect the preferential accumulation of B16F10 EVs in small metastatic tumors located in lungs when compared with the rest of the organs, as well as their precise distribution between tumor vessels, alveolus and tumor nodules by histological analysis. Finally, we observed that tumor EVs can be used as effective vectors to increase gold nanoparticle delivery towards metastatic nodules.

Conclusions: Our findings provide a valuable tool to study the distribution and interaction of EVs in mice and a novel strategy to improve the targeting of gold nanoparticles to cancer cells and metastatic nodules by using the natural properties of malignant EVs.
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http://dx.doi.org/10.1186/s12951-020-0573-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6979068PMC
January 2020

Inhibition of β-amyloid Aggregation of Ugni molinae Extracts.

Curr Pharm Des 2020 ;26(12):1365-1376

Laboratorio de Productos Naturales, Departamento de Quimica Farmacologica y Toxicologica, Facultad de Ciencias Quimicas y Farmaceuticas, Universidad de Chile. Sergio Livingston 1007, Santiago 8380492, Chile.

The β-amyloid peptide (1-42) is a molecule capable of aggregating into neurotoxic structures that have been implicated as potential etiological factors of Alzheimer's Disease. The aim of this study was to evaluate the inhibition of β-amyloid aggregation of ethyl acetate and ethanolic extracts obtained from Ugni molinae leaves on neurotoxic actions of β-amyloid aggregates. Chemical analyses were carried out with the extracts in order to determine their phenolic profile and its quantification. Both extracts showed a tendency to reduce neuronal deaths caused by β-amyloid. This tendency was inversely proportional to the evaluated concentrations. Moreover, the effect of EAE and ETE on β-amyloid aggregation was studied by fluorimetric T Thioflavin assay and transmission electronic microscopy (TEM); the extracts showed a modulation in the aggregation process. Partly, it is believed that these effects can be attributed to the polyphenolic compounds present in the extracts.
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http://dx.doi.org/10.2174/1381612826666200113160840DOI Listing
November 2020

Gold@Silica Nanoparticles Functionalized with Oligonucleotides: A Prominent Tool for the Detection of the Methylated Reprimo Gene in Gastric Cancer by Dynamic Light Scattering.

Nanomaterials (Basel) 2019 Sep 18;9(9). Epub 2019 Sep 18.

Advanced Center for Chronic Diseases (ACCDiS), Pontificia Universidad Católica de Chile, 8330034 Santiago, Chile.

Reprimo () is a tumor suppressor gene involved in the development of gastric cancer. Hypermethylation of the promoter region has been found in tumor tissue and plasma samples from patients with gastric cancer. These findings suggest that circulating methylated DNA of could be a candidate for a noninvasive detection of gastric cancer. We designed a nanosystem based on the functionalization of silica coated gold nanoparticles with oligonucleotides that recognize a specific DNA fragment of the promoter region. The functionality of the oligonucleotide on the surface of the nanoparticle was confirmed by polymerase chain reaction (PCR). The nanoparticles were incubated with a synthetic DNA fragment of methylated DNA of and changes in the size distribution after hybridization were evaluated by dynamic light scattering (DLS). A difference in the size distribution of nanoparticles hybridized with genomic DNA from the KATO III gastric cancer cell line was observed when was compared with DNA from the GES-1 normal cell line. These results showed that this nanosystem may be a useful tool for the specific and sensitive detection of methylated DNA of in patients at risk of developing gastric cancer.
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http://dx.doi.org/10.3390/nano9091333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781027PMC
September 2019

Capping gold nanoparticles with albumin to improve their biomedical properties.

Int J Nanomedicine 2019 9;14:6387-6406. Epub 2019 Aug 9.

Departamento de Ciencias Quimicas, Facultad de Ciencias Exactas, Universidad Andres Bello, Santiago, Chile.

Nanotechnology is an emerging field which has created great opportunities either through the creation of new materials or by improving the properties of existing ones. Nanoscale materials with a wide range of applications in areas ranging from engineering to biomedicine have been produced. Gold nanoparticles (AuNPs) have emerged as a therapeutic agent, and are useful for imaging, drug delivery, and photodynamic and photothermal therapy. AuNPs have the advantage of ease of functionalization with therapeutic agents through covalent and ionic binding. Combining AuNPs and other materials can result in nanoplatforms, which can be useful for biomedical applications. Biomaterials such as biomolecules, polymers and proteins can improve the therapeutic properties of nanoparticles, such as their biocompatibility, biodistribution, stability and half-life. Serum albumin is a versatile, non-toxic, stable, and biodegradable protein, in which structural domains and functional groups allow the binding and capping of inorganic nanoparticles. AuNPs coated with albumin have improved properties such as greater compatibility, bioavailability, longer circulation times, lower toxicity, and selective bioaccumulation. In the current article, we review the features of albumin, as well as its interaction with AuNPs, focusing on its biomedical applications.
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http://dx.doi.org/10.2147/IJN.S210992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691944PMC
November 2019

Determination of the potency of hexyl-ciprofloxacin molecules that interact with gold nanoparticles in a reversible manner.

IET Nanobiotechnol 2019 May;13(3):320-325

Centro de Biotecnología Daniel Alkalay Lowitt, Universidad Técnica Federico Santa María, General Bari 699, Valparaíso, Chile.

This work determined the potency of hexyl-ciprofloxacin molecules that reversibly interact with gold nanoparticles (AuNPs) passivated with 11-mercaptoundecanoic acid (MUA) on cells. For this, partition of modified antibiotic between different compartments of the gold colloid was determined using analytical techniques. First, concentration of hexyl-ciprofloxacin was determined in the continuous phase of the colloid. Subsequently, the colloid was exposed to a volume of organic immiscible solvent and concentration of the transferred molecules was determined in the organic phase. Comparison of the amount of hexyl-ciprofloxacin in each phase revealed that interaction between molecules and nanoparticles was reversible. Later, this work determined the potency of a population of hexyl-ciprofloxacin molecules contained in a volume of the colloid, and the potency of other population of molecules that only interact with the continuous phase of the colloid. The absolute difference between these two values was proportional to the potency of a number of molecules that interact with the nanoparticles of the colloid.
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http://dx.doi.org/10.1049/iet-nbt.2018.5186DOI Listing
May 2019

The antinociceptive effect of resveratrol in bone cancer pain is inhibited by the Silent Information Regulator 1 inhibitor selisistat.

J Pharm Pharmacol 2019 May 27;71(5):816-825. Epub 2018 Dec 27.

Department of Biology, Laboratory of Neurobiology, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile.

Objectives: To study the antinociceptive effect of single and repeated doses of resveratrol in a bone cancer pain model, and whether this effect is prevented by the Silent Information Regulator 1 (SIRT1) inhibitor selisistat.

Methods: The femoral intercondylar bone of BALB/c mice was injected with 1 000 000 BJ3Z cancer cells. Bone resorption and tumour mass growth (measured by in vivo X-ray and fluorescence imaging), as well as mechanical nociceptive thresholds (von Frey device) and dynamic functionality (rotarod machine), were evaluated during the following 4 weeks. Acute resveratrol (100 mg/kg i.p.) and/or selisistat (10 mg/kg s.c.) were administered on day 14. Chronic resveratrol (100 mg/kg i.p., daily) and/or selisistat (0.5 μg/h s.c., Alzet pump) were administered between days 14 and 20.

Key Findings: Tumour growth gradually incremented until day 31, while mechanical hyperalgesia started on day 3 after cancer cell injection. Acute resveratrol increased the mechanical threshold of pain (peaking at 1.5 h), while the dynamic functionality decreased. Chronic resveratrol produced a sustained antinociceptive effect on mechanical hyperalgesia and improved the loss of dynamic functionality induced by the bone cancer tumour. Selisistat prevented all the effects of resveratrol.

Conclusions: Acute and chronic resveratrol induces antinociceptive effect in the model of metastatic osseous oncological pain, an effect that would be mediated by SIRT1 molecular signalling.
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http://dx.doi.org/10.1111/jphp.13064DOI Listing
May 2019

HAI Peptide and Backbone Analogs-Validation and Enhancement of Biostability and Bioactivity of BBB Shuttles.

Sci Rep 2018 12 18;8(1):17932. Epub 2018 Dec 18.

Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, Barcelona, E-08028, Spain.

Low effectiveness and resistance to treatments are commonplace in disorders of the central nervous system (CNS). These issues concern mainly the blood-brain barrier (BBB), which preserves homeostasis in the brain and protects this organ from toxic molecules and biohazards by regulating transport through it. BBB shuttles-short peptides able to cross the BBB-are being developed to help therapeutics to cross this barrier. BBB shuttles can be discovered by massive exploration of chemical diversity (e.g. computational means, phage display) or rational design (e.g. derivatives from a known peptide/protein able to cross). Here we present the selection of a peptide shuttle (HAI) from several candidates and the subsequent in-depth in vitro and in vivo study of this molecule. In order to explore the chemical diversity of HAI and enhance its biostability, and thereby its bioactivity, we explored two new protease-resistant versions of HAI (i.e. the retro-D-version, and a version that was N-methylated at the most sensitive sites to enzymatic cleavage). Our results show that, while both versions of HAI are resistant to proteases, the retro-D-approach preserved better transport properties.
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http://dx.doi.org/10.1038/s41598-018-35938-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298966PMC
December 2018

Gold nanorods/siRNA complex administration for knockdown of PARP-1: a potential treatment for perinatal asphyxia.

Int J Nanomedicine 2018 25;13:6839-6854. Epub 2018 Oct 25.

Department of Pharmacological and Toxicology Chemistry, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile,

Background: Perinatal asphyxia interferes with neonatal development, resulting in long-term deficits associated with systemic and neurological diseases. Despite the important role of poly (ADP-ribose) polymerase 1 (PARP-1) in the regulation of gene expression and DNA repair, overactivation of PARP-1 in asphyxia-exposed animals worsens the ATP-dependent energetic crisis. Inhibition of PARP-1 offers a therapeutic strategy for diminishing the effects of perinatal asphyxia.

Methods: We designed a nanosystem that incorporates a specific siRNA for PARP-1 knockdown. The siRNA was complexed with gold nanorods (AuNR) conjugated to the peptide CLPFFD for brain targeting.

Results: The siRNA was efficiently delivered into PC12 cells, resulting in gene silencing. The complex was administered intraperitoneally in vivo to asphyxia-exposed rat pups, and the ability of the AuNR-CLPFFD/siRNA complex to reach the brain was demonstrated.

Conclusion: The combination of a nanosystem for delivery and a specific siRNA for gene silencing resulted in effective inhibition of PARP-1 in vivo.
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http://dx.doi.org/10.2147/IJN.S175076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207385PMC
December 2018

Photothermally Controlled Methotrexate Release System Using β-Cyclodextrin and Gold Nanoparticles.

Nanomaterials (Basel) 2018 Nov 28;8(12). Epub 2018 Nov 28.

Department of Pharmacological and Toxicological Chemistry, University of Chile, Sergio Livingston 1007, 8380492 Santiago, Chile.

The inclusion compound (IC) of cyclodextrin (CD) containing the antitumor drug Methotrexate (MTX) as a guest molecule was obtained to increase the solubility of MTX and decrease its inherent toxic effects in nonspecific cells. The IC was conjugated with gold nanoparticles (AuNPs), obtained by a chemical method, creating a ternary intelligent delivery system for MTX molecules, based on the plasmonic properties of the AuNPs. Irradiation of the ternary system, with a laser wavelength tunable with the corresponding surface plasmon of AuNPs, causes local energy dissipation, producing the controlled release of the guest from CD cavities. Finally, cell viability was evaluated using MTS assays for β-CD/MTX and AuNPs + β-CD/MTX samples, with and without irradiation, against HeLa tumor cells. The irradiated sample of the ternary system AuNPs + β-CD/MTX produced a diminution in cell viability attributed to the photothermal release of MTX.
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http://dx.doi.org/10.3390/nano8120985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315352PMC
November 2018

Curcumin-loaded nanoemulsion: a new safe and effective formulation to prevent tumor reincidence and metastasis.

Nanoscale 2018 Dec 28;10(47):22612-22622. Epub 2018 Nov 28.

Laboratory of Cellular Communication, Program of Cell and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Av. Independencia 1027, Santiago 8380453, Chile.

Curcumin is widely considered beneficial to human health, but insolubility and instability greatly hamper reproducible exploitation of the advantageous traits. Here we report on the development, characterization and evaluation of a curcumin-loaded nanoemulsion (CUR-NEM) that is highly effective in preventing post-surgery tumor reincidence and metastasis. The method of fabrication utilized safe excipients and generated particles of 200 nm (PDI ≤ 0.2) with negative zeta potential (-30 mV) and a high yield of curcumin (95%), which can be converted by lyophilization to a dry powder. In vitro assays showed that CUR-NEM is safe in non-cancerous human cells (HEK-293T) and preferentially cytotoxic in gastric (AGS), colon (HT29-ATCC, HT29-US), breast (MDA-MB-231) and melanoma (B16F10) cells. In addition, in melanoma cells the nanoformulation increases intracellular curcumin accumulation and reactive oxygen species (ROS) formation, while preventing cell-migration and invasion. In vivo studies in C57BL/6 mice demonstrated that a single dose, applied topically to the wounded area after surgical excision of primary tumors formed upon subcutaneous injection of syngeneic B16F10 cells, was sufficient to completely prevent reincident tumor growth and spontaneous lung metastasis, while in untreated animals 70% reincidence and metastasis were observed. In vivo experiments also showed that the fluorescence signal due to curcumin was maintained at least 15 days after topical application of CUR-NEM, while when administered in DMSO the curcumin signal disappeared within 4 days. Importantly, the administration of a dose 22 times larger than that applied topically to animals after tumor surgery did not alter biochemical parameters. Due to the safety and efficacy of the formulation, we envisage it as ideal for topical application in cancer patients following surgery, to prevent tumor reincidence and metastasis. In addition, other routes of administration/protocols could also be proposed to treat/prevent malignant tumors in patients.
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http://dx.doi.org/10.1039/c8nr06173dDOI Listing
December 2018

The Ethyl Acetate Extract of Leaves of Ugni molinae Turcz. Improves Neuropathological Hallmarks of Alzheimer's Disease in Female APPswe/PS1dE9 Mice Fed with a High Fat Diet.

J Alzheimers Dis 2018 ;66(3):1175-1191

Departament de Farmacologia, Toxicologia i Química Terapèutica, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain.

The most common type of dementia is Alzheimer's disease (AD), a progressive neurodegenerative disease characterized by impairment in cognitive performance in aged individuals. Currently, there is no effective pharmacological treatment that cures the disease due to the lack of knowledge on the actual mechanisms involved in its pathogenesis. In the last decades, the amyloidogenic hypothesis has been the most studied theory trying to explain the origin of AD, yet it does not address all the concerns relating to its development. In the present study, a possible new preclinical treatment of AD was evaluated using the ethyl acetate extract (EAE) of leaves of Ugni molinae Turcz. (synonym Myrtus ugni Molina Family Myrtacea). The effects were assessed on female transgenic mice from a preclinical model of familial AD (APPswe/PS1dE9) combined with a high fat diet. This preclinical model was selected due to the already available experimental and observational data proving the relationship between obesity, gender, metabolic stress, and cognitive dysfunction; related to characteristics of sporadic AD. According to chemical analyses, EAE would contain polyphenols such as tannins, flavonoid derivatives, and phenolic acids, as well as pentacyclic triterpenoids that exhibit neuroprotective, anti-inflammatory, and antioxidant effects. In addition, the treatment evidenced its capacity to prevent deterioration of memory capacity and reduction of progression speed of AD neuropathology.
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http://dx.doi.org/10.3233/JAD-180174DOI Listing
November 2019

Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: evolution toward prospective theranostic approaches.

Theranostics 2018 9;8(17):4710-4732. Epub 2018 Sep 9.

Advanced Center for Chronic Diseases (ACCDiS), Facultad Ciencias Químicas y Farmaceuticas, Universidad de Chile, Santiago 8380492, Chile.

Cardiovascular diseases are the leading cause of death worldwide. Despite preventive efforts, early detection of atherosclerosis, the common pathophysiological mechanism underlying cardiovascular diseases remains elusive, and overt coronary artery disease or myocardial infarction is often the first clinical manifestation. Nanoparticles represent a novel strategy for prevention, diagnosis, and treatment of atherosclerosis, and new multifunctional nanoparticles with combined diagnostic and therapeutic capacities hold the promise for theranostic approaches to this disease. This review focuses on the development of nanosystems for therapy and diagnosis of subclinical atherosclerosis, coronary artery disease, and myocardial infarction and the evolution of nanosystems as theranostic tools. We also discuss the use of nanoparticles in noninvasive imaging, targeted drug delivery, photothermal therapies together with the challenges faced by nanosystems during clinical translation.
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http://dx.doi.org/10.7150/thno.26284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160774PMC
September 2019

Intranasal delivery of mesenchymal stem cell-derived exosomes reduces oxidative stress and markedly inhibits ethanol consumption and post-deprivation relapse drinking.

Addict Biol 2019 09 21;24(5):994-1007. Epub 2018 Sep 21.

Molecular and Clinical Pharmacology Program, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Chile.

Chronic ethanol consumption leads to brain oxidative stress and neuroinflammation, conditions known to potentiate and perpetuate each other. Several studies have shown that neuroinflammation results in increases in chronic ethanol consumption. Recent reports showed that the intra-cerebroventricular administration of mesenchymal stem cells to rats consuming alcohol chronically markedly inhibited oxidative-stress, abolished neuroinflammation and greatly reduced chronic alcohol intake and post deprivation relapse-like alcohol intake. However, the intra-cerebroventricular administration of living cells is not suitable as a treatment of a chronic condition. The present study aimed at inhibiting ethanol intake by the non-invasive intranasal administration of human mesenchymal stem cell products: exosomes, microvesicles (40 to 150 nm) with marked antioxidant activity extruded from mesenchymal stem cells. The exosome membrane can fuse with the plasma membrane of cells in different tissues, thus delivering their content intracellularly. The study showed that the weekly intranasal administration of mesenchymal stem cell-derived exosomes to rats consuming alcohol chronically (1) inhibited their ethanol intake by 84 percent and blunted the relapse-like 'binge' drinking that follows an alcohol deprivation period and ethanol re-access. (2) Intranasally administered exosomes were found in the brain within 24 hours; (3) fully reversed both alcohol-induced hippocampal oxidative-stress, evidenced by a lower ratio of oxidized to reduced glutathione, and neuroinflammation, shown by a reduced astrocyte activation and microglial density; and (4) increased glutamate transporter GLT1 expression in nucleus accumbens, counteracting the inhibition of glutamate transporter activity, reportedly depressed under oxidative-stress conditions. Possible translational implications are envisaged.
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http://dx.doi.org/10.1111/adb.12675DOI Listing
September 2019