Browsing by Author "Kogan, Marcelo J."

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    Differential Detection of Amyloid Aggregates in Old Animals Using Gold Nanorods by Computerized Tomography: A Pharmacokinetic and Bioaccumulation Study
    (2023) Jara-Guajardo, Pedro; Morales-Zavala, Francisco; Bolanos, Karen; Giralt, Ernest; Araya, Eyleen; Acosta, Gerardo A.; Albericio, Fernando; Alvarez, Alejandra R.; Kogan, Marcelo J.
    Introduction: The development of new materials and tools for radiology is key to the implementation of this diagnostic technique in clinics. In this work, we evaluated the differential accumulation of peptide-functionalized GNRs in a transgenic animal model (APPswe/PSENd1E9) of Alzheimer's disease (AD) by computed tomography (CT) and measured the pharmacokinetic parameters and bioaccumulation of the nanosystem.Methods: The GNRs were functionalized with two peptides, Ang2 and D1, which conferred on them the properties of crossing the blood-brain barrier and binding to amyloid aggregates, respectively, thus making them a diagnostic tool with great potential for AD. The nanosystem was administered intravenously in APPswe/PSEN1dE9 model mice of 4-, 8- and 18-months of age, and the accumulation of gold nanoparticles was observed by computed tomography (CT). The gold accumulation and biodistribution were determined by atomic absorption.Results: Our findings indicated that 18-month-old animals treated with our nanosystem (GNR-D1/Ang2) displayed noticeable differences in CT signals compared to those treated with a control nanosystem (GNR-Ang2). However, no such distinctions were observed in younger animals. This suggests that our nanosystem holds the potential to effectively detect AD pathology.Discussion: These results support the future development of gold nanoparticle-based technology as a more effective and accessible alternative for the diagnosis of AD and represent a significant advance in the development of gold nanoparticle applications in disease diagnosis.
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    Extracellular vesicles through the blood–brain barrier: a review
    (2022) Ramos Zaldívar, Héctor M.; Polakovicova, Iva; Salas-Huenuleo, Edison; Corvalán R., Alejandro; Kogan, Marcelo J.; Yefi Rubio, Claudia Pamela; Andía Kohnenkampf, Marcelo Edgardo
    Extracellular vesicles (EVs) are particles naturally released from cells that are delimited by a lipid bilayer and are unable to replicate. How the EVs cross the Blood–Brain barrier (BBB) in a bidirectional manner between the bloodstream and brain parenchyma remains poorly understood. Most in vitro models that have evaluated this event have relied on monolayer transwell or microfluidic organ-on-a-chip techniques that do not account for the combined effect of all cellular layers that constitute the BBB at different sites of the Central Nervous System. There has not been direct transcytosis visualization through the BBB in mammals in vivo, and evidence comes from in vivo experiments in zebrafish. Literature is scarce on this topic, and techniques describing the mechanisms of EVs motion through the BBB are inconsistent. This review will focus on in vitro and in vivo methodologies used to evaluate EVs transcytosis, how EVs overcome this fundamental structure, and discuss potential methodological approaches for future analyses to clarify these issues. Understanding how EVs cross the BBB will be essential for their future use as vehicles in pharmacology and therapeutics.
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    Formation of Copper Nanoparticles Supported onto Inclusion Compounds of alpha-cyclodextrin: A New Route to Obtain Copper Nanoparticles
    (2010) Silva, Nataly; Moris, Silvana; Herrera Pisani, Bárbara Andrea; Diaz, Maximiliano; Kogan, Marcelo J.; Barrientos, Lorena; Yutronic, Nicolas; Jara, Paul
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    Functionalization of Gold Nanostars with Cationic β-Cyclodextrin-Based Polymer for Drug Co-Loading and SERS Monitoring
    (2021) Donoso-Gonzalez, Orlando; Lodeiro, Lucas; Aliaga, Alvaro E.; Laguna-Bercero, Miguel A.; Bollo, Soledad; Kogan, Marcelo J.; Yutronic, Nicolas; Sierpe, Rodrigo
    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 beta-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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    Gold Nanoparticles Mediate Improved Detection of β-amyloid Aggregates by Fluorescence
    (2020) Jara-Guajardo, Pedro; Cabrera, Pablo; Celis, Freddy; Soler, Monica; Berlanga, Isadora; Parra-Munoz, Nicole; Acosta, Gerardo; Albericio, Fernando; Guzman, Fanny; Campos, Marcelo; Alvarez, Alejandra; Morales-Zavala, Francisco; Kogan, Marcelo J.
    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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    Gold@Silica Nanoparticles Functionalized with Oligonucleotides: A Prominent Tool for the Detection of the Methylated Reprimo Gene in Gastric Cancer by Dynamic Light Scattering
    (2019) Jose Marchant, Maria; Guzman, Leda; Corvalan, Alejandro H.; Kogan, Marcelo J.
    Reprimo (RPRM) is a tumor suppressor gene involved in the development of gastric cancer. Hypermethylation of the RPRM promoter region has been found in tumor tissue and plasma samples from patients with gastric cancer. These findings suggest that circulating methylated DNA of RPRM 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 RPRM 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 RPRM 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 RPRM in patients at risk of developing gastric cancer.
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    In vivo micro computed tomography detection and decrease in amyloid load by using multifunctionalized gold nanorods: a neurotheranostic platform for Alzheimer's disease
    (Royal Soc Chemistry, 2021) Morales Zavala, Francisco; Jara Guajardo, Pedro; Chamorro Veloso, David Daniel; Riveros, Ana L.; Chandia Cristi, América Valeska; Salgado Cortés, Nicole Andrea; Pismante, Paola; Giralt, Ernest; Sanchez Navarro, Macarena; Araya, Eyleen; Vasquez, Rodrigo; Acosta, Gerardo; Albericio, Fernando; Alvarez, Alejandra R.; Kogan, Marcelo J.
    The development and use of nanosystems is an emerging strategy for the diagnosis and treatment of a broad number of diseases, such as Alzheimer's disease (AD). Here, we developed a neurotheranostic nanosystem based on gold nanorods (GNRs) that works as a therapeutic peptide delivery system and can be detected in vivo for microcomputed tomography (micro-CT), being a diagnostic tool. GNRs functionalized with the peptides Ang2 (a shuttle to the Central Nervous System) and D1 (that binds to the A beta peptide, also inhibiting its aggregation) allowed detecting differences in vivo between wild type and AD mice (APPswe/PSEN1dE9) 15 minutes after a single dose by micro-CT. Moreover, after a recurrent treatment for one month with GNRs-D1/Ang2, we observed a diminution of amyloid load and inflammatory markers in the brain. Thus, this new designed nanosystem exhibits promising properties for neurotheranostics of AD.
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    Label-free graphene oxide-based surface plasmon resonance immunosensor for the quantification of galectin-3, a novel cardiac biomarker
    (2018) Primo, Emiliano N.; Kogan, Marcelo J.; Verdejo Pinochet, Hugo; Bollo, Soledad; Rubianes, María D.; Rivas, Gustavo A.
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    Label-Free Oligonucleotide-Based SPR Biosensor for the Detection of the Gene Mutation Causing Prothrombin-Related Thrombophilia
    (2020) Sierpe, Rodrigo; Kogan, Marcelo J.; Bollo, Soledad
    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 Delta mu RIU/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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    Light-induced release of the cardioprotective peptide angiotensin-(1-9) from thermosensitive liposomes with gold nanoclusters
    (2020) Bejarano, Julian; Rojas, Aldo; Ramirez Sagredo, Andrea; Riveros, Ana L.; Morales Zavala, Francisco; Flores, Yvo; Riquelme, Jaime A.; Guzman, Fanny; Araya, Eyleen; Chiong, Mario; Ocaranza, María Paz; Morales, Javier O.; Villamizar Sarmiento, Maria Gabriela; Sanchez, Gina; Lavandero, Sergio; Kogan, Marcelo J.
    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 (LipoThermAuNC) 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 mu M. 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-AuNCbased nanosystem was confirmed using an ex vivo Langendorff heart model.
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    Low-Grade Chronic Inflammation: a Shared Mechanism for Chronic Diseases
    (2025) Cifuentes, Mariana; Verdejo Pinochet, Hugo Eduardo; Castro Gálvez, Pablo Federico; Corvalán Rodríguez, Alejandro; Ferreccio, Catterina; Quest, Andrew F. G.; Kogan, Marcelo J.; Lavandero, Sergio
    Inflammation is an important physiological response of the organism to restore homeostasis upon pathogenic or damaging stimuli. However, the persistence of the harmful trigger or a deficient resolution of the process can evolve into a state of low-grade, chronic inflammation. This condition is strongly associated with the development of several increasingly prevalent and serious chronic conditions, such as obesity, cancer, and cardiovascular diseases, elevating overall morbidity and mortality worldwide. The current pandemic of chronic diseases underscores the need to address chronic inflammation, its pathogenic mechanisms, and potential preventive measures to limit its current widespread impact. The present review discusses the current knowledge and research gaps regarding the association between low-grade chronic inflammation and chronic diseases, focusing on obesity, cardiovascular diseases, digestive diseases, and cancer. We examine the state of the art in selected aspects of the topic and propose future directions and approaches for the field.
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    Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction : evolution toward prospective theranostic approaches
    (2018) Bejarano, Julian; Navarro-Marquez, Mario; Morales-Zavala, Francisco; Morales, Javier O.; Garcia-Carvajal, Ivonne; Araya-Fuentes, Eyleen; Flores, Yvo; Verdejo Pinochet, Hugo; Castro Gálvez, Pablo Federico; Lavandero, Sergio; Kogan, Marcelo J.
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    New Smoothened ligands based on the purine scaffold as potential agents for treating pancreatic cancer
    (2024) Espinosa-Bustos, Christian; Bertrand, Jeanluc; Villegas-Menares, Alondra; Guerrero, Simon; Di Marcotullio, Lucia; Navacci, Shirin; Schulte, Gunnar; Kozielewicz, Pawel; Bloch, Nicolas; Villela, Valentina; Paulino, Margot; Kogan, Marcelo J.; Cantero, Jorge; Salas, Cristian O.
    Aberrant activation of the Hedgehog (Hh) signalling pathway has been associated with the development and progression of pancreatic cancer. For this reason, blockade of Hh pathway by inhibitors targeting the G proteincoupled receptor Smoothened (SMO) has been considered as a therapeutic target for the treatment of this cancer. In our previous work, we obtained a new SMO ligand based on a purine scaffold (compound I), which showed interesting antitumor activity in several cancer cell lines. In this work, we report the design and synthesis of 17 new purine derivatives, some of which showed high cytotoxic effect on Mia-PaCa-2 (Hh-dependent pancreatic cancer cell lines) and low toxicity on non-neoplastic HEK-293 cells compared with gemcitabine, such as 8f, 8g and 8h (IC50 = 4.56, 4.11 and 3.08 mu M, respectively). Two of these purines also showed their ability to bind to SMO through NanoBRET assays (pKi = 5.17 for 8f and 5.01 for 8h), with higher affinities to compound I (pKi = 1.51). In addition, docking studies provided insight the purine substitution pattern is related to the affinity on SMO. Finally, studies of Hh inhibition for selected purines, using a transcriptional functional assay based on luciferase activity in NIH3T3 Shh-Light II cells, demonstrated that 8g reduced GLI activity with a IC50 = 6.4 mu M as well as diminished the expression of Hh target genes in two specific Hh-dependent cell models, Med1 cells and Ptch1- /- mouse embryonic fibroblasts. Therefore, our results provide a platform for the design of SMO ligands that could be potential selective cytotoxic agents for the treatment of pancreatic cancer.
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    Peptide Targeted Gold Nanoplatform Carrying miR-145 Induces Antitumoral Effects in Ovarian Cancer Cells
    (2022) Salas-Huenuleo, Edison; Hernandez, Andrea; Lobos-Gonzalez, Lorena; Polakovicova, Iva; Morales-Zavala, Francisco; Araya, Eyleen; Celis, Freddy; Romero, Carmen; Kogan, Marcelo J.
    One of the recent attractive therapeutic approaches for cancer treatment is restoring downregulated microRNAs. They play an essential muti-regulatory role in cellular processes such as proliferation, differentiation, survival, apoptosis, cell cycle, angiogenesis, and metastasis, among others. In this study, a gold nanoplatform (GNPF) carrying miR-145, a downregulated microRNA in many cancer types, including epithelial ovarian cancer, was designed and synthesized. For targeting purposes, the GNPF was functionalized with the FSH33 peptide, which provided selectivity for ovarian cancer, and loaded with the miR-145 to obtain the nanosystem GNPF-miR-145. The GNPF-mir-145 was selectively incorporated in A2780 and SKOV3 cells and significantly inhibited cell viability and migration and exhibited proliferative and anchor-independent growth capacities. Moreover, it diminished VEGF release and reduced the spheroid size of ovarian cancer through the damage of cell membranes, thus decreasing cell viability and possibly activating apoptosis. These results provide important advances in developing miR-based therapies using nanoparticles as selective vectors and provide approaches for in vivo evaluation.
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    Surface enhanced fluorescence effect improves the in vivo detection of amyloid aggregates
    (2022) Cabrera, Pablo; Jara-Guajardo, Pedro; Oyarzun, Maria Paz; Parra-Munoz, Nicole; Campos, Aldo; Soler, Monica; Alvarez, Alejandra; Morales-Zavala, Francisco; Araya, Eyleen; Minniti, Alicia N.; Aldunate, Rebeca; Kogan, Marcelo J.
    The beta-amyloid (A beta) peptide is one of the key etiological agents in Alzheimer's disease (AD). The in vivo detection of A beta species is challenging in all stages of the illness. Currently, the development of fluorescent probes allows the detection of A beta in animal models in the near-infrared region (NIR). However, considering future applications in biomedicine, it is relevant to develop strategies to improve detection of amyloid aggregates using NIR probes. An innovative approach to increase the fluorescence signal of these fluorophores is the use of plasmonic gold nanoparticles (surface-enhanced fluorescence effect). In this work, we improved the detection of A beta aggregates in C. elegans and mouse models of AD by co-administering functionalized gold nanorods (GNRs-PEG-D1) with the fluorescent probes CRANAD-2 or CRANAD-58, which bind selectively to different amyloid species (soluble and insoluble). This work shows that GNRs improve the detection of A beta using NIR probes in vivo. (C) 2022 Published by Elsevier Inc.
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    Synthesis, antitumoral activity, and in silico studies on Smoothened receptor of new 2,6,9-trisubstituted purine derivatives
    (Elsevier B.V., 2025) Espinosa Bustos, Christian Marcelo; Zarate Méndez, Ana María; Castro Álvarez, Alejandro; Guerrero, Simón; Kogan, Marcelo J.; Salas Sánchez, Cristian Osvaldo
    © 2024 Elsevier B.V.In this work, a series of 30 new 2,6,9-trisubstituted purine derivatives were synthesised and evaluated in silico as potential ligands of the Smoothened (SMO) receptor, as well as their ability to inhibit growth in Hedgehog (Hh)-dependent and Hh-independent cancer cell lines. The synthesis involved a convergent strategy, conventional methods and microwave irradiation. Initial antitumour evaluation was performed by testing cell growth inhibition in seven cancer cell lines and one non-neoplastic cell line (HEK-293) at 50 μM. IC50 values were determined for compounds showing < 50 % cell viability. Compounds 7l and 9j showed promising results with high cytotoxicity in three Hh-dependent cell lines and low cytotoxicity in HEK-293 cells. Compound 7l was more potent and selective than gemcitabine in BxPC-3, AsPc-1 and MIA-PaCa-2 cells and more than 5-fluorouracil in HT-29 cells, while 9j was more potent and selective than 5-fluorouracil in HCT116 and HT-29 cells. Molecular docking studies in SMO allowed the recognition of two binding sites related to ligand size and purine substitution patterns, while 7l bound to the top pocket (TMD-1), 9j bound to a deeper pocket (TMD-2). This study provides new evidence supporting the purine ring as a privileged scaffold for the development of new antitumour drugs targeting the SMO receptor.
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    The case for aflatoxins in the causal chain of gallbladder cancer
    (2016) Foerster, Claudia; Koshiol, Jill; Guerrero, Ariel R.; Kogan, Marcelo J.; Ferreccio Readi, Catterina
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    The Cervical and Meningeal Lymphatic Network as a Pathway for Retrograde Nanoparticle Transport to the Brain
    (2024) Ramos-Zaldivar, Hector; Polakovicova, Iva; Salas-Huenuleo, Edison; Yefi, Claudia P.; Silva-Ancahuail, David; Jara-Guajardo, Pedro; Oyarzun, Juan Esteban; Neira-Troncoso, Alvaro; Burgos, Patricia, V; Cavieres, Viviana A.; Arias-Munoz, Eloisa; Martinez, Carlos; Riveros, Ana L.; Corvalan, Alejandro H.; Kogan, Marcelo J.; Andia, Marcelo E.
    Introduction: The meningeal lymphatic vessels have been described as a pathway that transports cerebrospinal fluid and interstitial fluid in a unidirectional manner towards the deep cervical lymph nodes. However, these vessels exhibit anatomical and molecular characteristics typical of initial lymphatic vessels, with the absence of surrounding smooth muscle and few or absent valves. Given its structure, this network could theoretically allow for bidirectional motion. Nevertheless, it has not been assessed as a potential route for nanoparticles to travel from peripheral tissues to the brain. Methods: We employed superparamagnetic iron oxide nanoparticles (SPIONs), exosomes loaded with SPIONs, gold nanorods, and Chinese ink nanoparticles. SPIONs were prepared via chemical coprecipitation, while exosomes were isolated from the B16F10 melanoma cell line through the Exo-Spin column protocol and loaded with SPIONs through electroporation. Gold nanorods were functionalized with polyethylene glycol. We utilized C57BL/6 mice for post-mortem and in vivo procedures. To evaluate the retrograde directional flow, we injected each nanoparticle solution in the deep cervical lymph node. The head and neck were fixed for magnetic resonance imaging and histological analysis. Results: Here we show that extracellular vesicles derived from the B16F10 melanoma cell line, along with superparamagnetic iron oxide nanoparticles, gold nanorods, and Chinese ink nanoparticles can reach the meningeal lymphatic vessels and the brain of C57BL/6 mice after administration within the deep cervical lymph nodes post-mortem and in vivo, exclusively through lymphatic structures. Discussion: The functional anatomy of dural lymphatics has been found to be conserved between mice and humans, suggesting that our findings may have significant implications for advancing targeted drug delivery systems using nanoparticles. Understanding the retrograde transport of nanoparticles through the meningeal lymphatic network could lead to novel therapeutic approaches in nanomedicine, offering new insights into fluid dynamics in both physiological and neuropathological contexts. Further research into this pathway may unlock new strategies for treating neurological diseases or enhancing drug delivery to the brain.