RESUMEN

Dendrimers and supramolecular chemistry continue to fascinate researchers due to the endless unrevealed potential of their combination. This study investigates the self-assembly process of a series of hydrophobic triazolylferrocenyl dendrimers in aqueous medium. Deep investigation through NMR spectroscopy, absorption UV-vis spectroscopy along with theoretical simulations demonstrates that the ferrocenyl moieties interact intramolecularly and intermolecularly driving the self-assembly process. Data obtained by DLS, NTA, SEM, TEM, and EF-TEM demonstrate that these dendrimers, in water, spontaneously self-assemble through a hierarchical process. The dendrimers first self-assemble into uniform nanovesicles, which in turn self-assemble into larger vesosomes. The resulting vesosomes emit green non-traditional intrinsic fluorescence, which is a property that emerged from the self-assembled architectures. The vesosomes are efficiently uptaken by cancer cells and induce significant cytotoxic activity against the cancer cell line MCF-7, up to the submicromolar concentration. Positive dendritic effects are identified in the fluorescence intensity and in the cytotoxic activity of the vesosomes, which follow the trend G0-9Fc < G1-27Fc < G2-81Fc. This work showcases the remarkable potential of combining the two dynamic fields of dendrimers and supramolecular chemistry, which resulted in green fluorescent vesosomes capable of performing the dual role of cell imaging and killing, with potential applications in nanotheranostics.

RESUMEN

Drug release from hyperbranched Janus dendrimer-drug conjugates and their subsequent activity are influenced by the different drugs in each dendron and the linker. To understand these effects, we synthetized new Janus-type dendrimers of first and second generation. One dendron with 2,2-Bis(hydroxymethyl)propionic acid functionalized with ibuprofen and the second dendron was obtained with 3-aminopropanol-amidoamine and prednisone. The dendrimers were obtained by copper(I)-catalyzed Click azide-alkyne cycloaddition for the formation of a triazole as a dendrimeric nucleus of Janus dendrimer conjugates are reported. The influence of ibuprofen, prednisone, and spacer on cancer activity of Janus dendrimers conjugates is reported. The IC50 values of the anticancer activity on cancer cell lines the Janus dendrimer of second generation was higher in comparison to the first generation dendrimer. Similarly, the anticancer activity was higher compared to the dendron conjugates. Also, no cytotoxic effects of dendrons and dendrimers on non-cancerous kidney COS-7 cell line was observed. The interesting anticancer activity of the prepared prednisone-ibuprofen Janus dendrimer conjugates suggest that the dendrimers could be of potential use as new anticancer drug.

Asunto(s)

Antracenos , Antineoplásicos , Dendrímeros , Antineoplásicos/farmacología , Dendrímeros/farmacología , Ibuprofeno , Prednisona , Cobre/química

RESUMEN

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis that replicates inside human alveolar macrophages. This disease causes significant morbidity and mortality throughout the world. According to the World Health Organization 1.4 million people died of this disease in 2021. This indicates that despite the progress of modern medicine, improvements in diagnostics, and the development of drug susceptibility tests, TB remains a global threat to public health. In this sense, host-directed therapy may provide a new approach to the cure of TB, and the expression of miRNAs has been correlated with a change in the concentration of various inflammatory mediators whose concentrations are responsible for the pathophysiology of M. tuberculosis infection. Thus, the administration of miRNAs may help to modulate the immune response of organisms. However, direct administration of miRNAs, without adequate encapsulation, exposes nucleic acids to the activity of cytosolic nucleases, limiting their application. Dendrimers are a family of highly branched molecules with a well-defined architecture and a branched conformation which gives rise to cavities that facilitate physical immobilization, and functional groups that allow chemical interaction with molecules of interest. Additionally, dendrimers can be easily functionalized to target different cells, macrophages among them. In this sense, various studies have proposed the use of different cell receptors as target molecules to aim dendrimers at macrophages and thus release drugs or nucleic acids in the cell of interest. Based on the considerations, the primary objective of this review is to comprehensively explore the potential of functionalized dendrimers as delivery vectors for miRNAs and other therapeutic agents into macrophages. This work aims to provide insights into the use of functionalized dendrimers as an innovative approach for TB treatment, focusing on their ability to target and deliver therapeutic cargo to macrophages.

RESUMEN

Antimicrobial resistance (AMR) is one of the top ten threats to public health, as reported by the World Health Organization (WHO). One of the causes of the growing AMR problem is the lack of new therapies and/or treatment agents; consequently, many infectious diseases could become uncontrollable. The need to discover new antimicrobial agents that are alternatives to the existing ones and that allow mitigating this problem has increased, due to the rapid and global expansion of AMR. Within this context, both antimicrobial peptides (AMPs) and cyclic macromolecules, such as resorcinarenes, have been proposed as alternatives to combat AMR. Resorcinarenes present multiple copies of antibacterial compounds in their structure. These conjugate molecules have exhibited antifungal and antibacterial properties and have also been used in anti-inflammatory, antineoplastic, and cardiovascular therapies, as well as being useful in drug and gene delivery systems. In this study, it was proposed to obtain conjugates that contain four copies of AMP sequences over a resorcinarene core. Specifically, obtaining (peptide)4-resorcinarene conjugates derived from LfcinB (20-25): RRWQWR and BF (32-34): RLLR was explored. First, the synthesis routes that allowed obtaining: (a) alkynyl-resorcinarenes and (b) peptides functionalized with the azide group were established. These precursors were used to generate (c) (peptide)4-resorcinarene conjugates by azide-alkyne cycloaddition CuAAC, a kind of click chemistry. Finally, the conjugates' biological activity was evaluated: antimicrobial activity against reference strains and clinical isolates of bacteria and fungi, and the cytotoxic activity over erythrocytes, fibroblast, MCF-7, and HeLa cell lines. Our results allowed establishing a new synthetic route, based on click chemistry, for obtaining macromolecules derived from resorcinarenes functionalized with peptides. Moreover, it was possible to identify promising antimicrobial chimeric molecules that may lead to advances in the development of new therapeutic agents.

RESUMEN

Recent studies have shown that the peptide [des-Cys11,Lys12,Lys13-(p-BthTX-I)2K] (p-Bth) is a p-BthTX-I analog that shows enhanced antimicrobial activity, stability and hemolytic activity, and is easy to obtain compared to the wild-type sequence. This molecule also inhibits SARS-CoV-2 viral infection in Vero cells, acting on SARS-CoV-2 PLpro enzymatic activity. Thus, the present study aimed to assess the effects of structural modifications to p-Bth, such as dimerization, dendrimerization and chirality, on the antibacterial activity and inhibitory properties of PLpro. The results showed that the dimerization or dendrimerization of p-Bth was essential for antibacterial activity, as the monomeric structure led to a total loss of, or significant reduction in, bacterial activities. The dimers and tetramers obtained using branched lysine proved to be prominent compounds with antibacterial activity against Gram-positive and Gram-negative bacteria. In addition, hemolysis rates were below 10% at the corresponding concentrations. Conversely, the inhibitory activity of the PLpro of SARS-CoV-2 was similar in the monomeric, dimeric and tetrameric forms of p-Bth. Our findings indicate the importance of the dimerization and dendrimerization of this important class of antimicrobial peptides, which shows great potential for antimicrobial and antiviral drug-discovery campaigns.

RESUMEN

Several human pathogens can cause long-lasting neurological damage. Despite the increasing clinical knowledge about these conditions, most still lack efficient therapeutic interventions. Gene therapy (GT) approaches comprise strategies to modify or adjust the expression or function of a gene, thus providing therapy for human diseases. Since recombinant nucleic acids used in GT have physicochemical limitations and can fail to reach the desired tissue, viral and non-viral vectors are applied to mediate gene delivery. Although viral vectors are associated to high levels of transfection, non-viral vectors are safer and have been further explored. Different types of nanosystems consisting of lipids, polymeric and inorganic materials are applied as non-viral vectors. In this review, we discuss potential targets for GT intervention in order to prevent neurological damage associated to infectious diseases as well as the role of nanosized non-viral vectors as agents to help the selective delivery of these gene-modifying molecules. Application of non-viral vectors for delivery of GT effectors comprise a promising alternative to treat brain inflammation induced by viral infections.

RESUMEN

Nitric oxide (NO) and ursodeoxycholic acid (UDCA) are endogenous molecules involved in physiological processes associated with inflammation. Since inflammatory processes are present in the mechanisms of many diseases, these molecules are important for the development of new drugs. Herein, we describe the synthesis of a well-defined bifunctional dendrimer with 108 termini bearing 54 NO-releasing groups and 54 UDCA units (Dendri-(NO/UDCA)54). For comparison, a lower-generation dendrimer bearing 18 NO-releasing groups and 18 UDCA units (Dendri-(NO/UDCA)18) was also synthesized. The anti-inflammatory activity of these dendrimers was evaluated, showing that the bifunctional dendrimers have an inverse correlation between concentration and anti-inflammatory activity, with an effect dramatically pronounced for Dendri-(NO/UDCA)54 20, which at just 0.25 nM inhibited 76.1% of IL-8 secretion. Data suggest that nanomolar concentrations of these dendrimers aid in releasing NO in a safe and controlled way. This bifunctional dendrimer has great potential as a drug against multifactorial diseases associated with inflammatory processes.

Asunto(s)

Óxido Nítrico , Ácido Ursodesoxicólico , Ácido Ursodesoxicólico/farmacología , Óxido Nítrico/farmacología , Antiinflamatorios/farmacología

RESUMEN

The oral route is the preferred way of drug administration for most drugs, whose treatment success is directly related to the compound intestinal absorption. This absorption process, in its turn, is influenced by several factors impacting the drug bioavailability, which is extremely dependent on the maximum solubility and permeability. However, optimizing these last two factors, without chemical structural modification, is challenging. Although poly(amidoamine) dendrimers (PAMAM) are an innovative and promising strategy as drug delivery compounds, there are few studies that determine the permeability and solubility of PAMAM-drugs derivatives. Considering this scenario, this paper aimed to carry out a literature review of the last five years concerning biopharmaceutical characterizations of dendrimer delivery systems. In vitro methodologies, such as the Parallel artificial membrane permeability assay (PAMPA) (non-cellular based model) and Caco-2 cells (cellular based model), used for the permeability evaluation in the early stages of drug discovery proved to be the most promising methodologies. As a result, we discussed, for instance, that through the usage of PAMPA it was possible to evaluate the higher capacity for transdermal delivery of DNA of TAT-conjugated PAMAM, when in comparison with unmodified PAMAM dendrimer with a P<0.05. We also presented the importance of choosing the best methods of biopharmaceutical characterization, which will be essential to guarantee the efficacy and safety of the drug candidate.

Asunto(s)

Productos Biológicos , Dendrímeros , Células CACO-2 , Dendrímeros/química , Humanos , Membranas Artificiales

RESUMEN

BACKGROUND: Glioblastoma constitutes the most frequent and aggressive primary malignant brain tumor in adults. Despite the advances in its treatment, its prognosis remains very poor. Gene therapy has been proposed as a complementary treatment since it may overcome the problem of the blood-brain barrier for systemic therapies, allowing to target tumor cells and their tumor microenvironment locally, without affecting the normal brain parenchyma. In comparison with viral vectors, non-viral vectors became an attractive tool due to their reduced potential of biosafety risks, lower cost, higher availability, and easy storage. OBJECTIVE: In this article, we aimed to outline the current preclinical and clinical developments of non-viral delivery systems for therapeutic transgene delivery in malignant gliomas. CONCLUSION: Non-viral vectors are efficient tools for gene delivery since they exhibit reduced non-specific cytotoxicity and can go through several modifications in order to achieve high tumor tropism and the ability to cross the blood-brain barrier to access the tumor mass. However, further evaluations in preclinical models and clinical trials are required in order to translate it into the neuro-oncology clinic.

Asunto(s)

Neoplasias Encefálicas , Glioblastoma , Glioma , Barrera Hematoencefálica , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Terapia Genética , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Microambiente Tumoral

RESUMEN

Photodynamic therapy (PDT) is an effective procedure for the treatment of lesions diseases based on the selectivity of a photosensitising compound with the ability to accumulate in the target cell. Atherosclerotic plaque is a suitable target for PDT because of the preferential accumulation of photosensitisers in atherosclerotic plaques. Dendrimers are hyperbranched polymers conjugated to drugs. The dendrimers of ALA hold ester bonds that inside the cells are cleaved and release ALA, yielding PpIX production. The dendrimer 6m-ALA was chosen to perform this study since in previous studies it induced the highest porphyrin macrophage: endothelial cell ratio (Rodriguez et al. in Photochem Photobiol Sci 14:1617-1627, 2015). We transformed Raw 264.7 macrophages to foam cells by exposure to oxidised LDLs, and we employed a co-culture model of HMEC-1 endothelial cells and foam cells to study the affinity of ALA dendrimers for the foam cells. In this work it was proposed an in vitro model of atheromatous plaque, the aim was to study the selectivity of an ALA dendrimer for the foam cells as compared to the endothelial cells in a co-culture system and the type of cell death triggered by the photodynamic treatment. The ALA dendrimer 6m-ALA showed selectivity PDT response for foam cells against endothelial cells. A light dose of 1 J/cm2 eliminate foam cells, whereas less than 50% of HMEC-1 is killed, and apoptosis cell death is involved in this process, and no necrosis is present. We propose the use of ALA dendrimers as pro-photosensitisers to be employed in photoangioplasty to aid in the treatment of obstructive cardiovascular diseases, and these molecules can also be employed as a theranostic agent.

Asunto(s)

Ácido Aminolevulínico/farmacología , Apoptosis/efectos de los fármacos , Células Espumosas/efectos de los fármacos , Macrófagos/efectos de los fármacos , Fármacos Fotosensibilizantes/farmacología , Ácido Aminolevulínico/química , Animales , Línea Celular , Técnicas de Cocultivo , Células Espumosas/fisiología , Humanos , Macrófagos/fisiología , Ratones , Fármacos Fotosensibilizantes/química

RESUMEN

In recent years, polymeric materials with the ability to self-assemble into micelles have been increasingly investigated for application in various fields, mainly in biomedicine. Micellar morphology is interesting in the field of drug transport and delivery since micelles can encapsulate hydrophobic molecules in their nucleus, have active molecules in their outer layer, and due to their nanometric size, can take advantage of the enhanced permeability and retention (EPR) effect, prolong the time in circulation and avoid renal clearance. In addition, nanobioactive molecules (joined in covalent form or by host-host interaction), such as drugs, bioimaging molecules, targeting ligands, "crosslinkable" molecules or bonds, sensitive to internal or external stimuli, can be incorporated into them and showed better activity as anticancer agents, siRNA delivery agents as well as antiviral and antiparasitic compounds. The present work is a review of the information published, which is the most important about the synthesis and biological importance of the confined multivalent cooperation and the ability to modify the dendritic structure, provide the versatility to create and improve the amphiphiles used in the micellar supramolecular field. The most studied structures are the hybrid copolymers formed by the combination of linear polymers and dendrons. However, small dendritic molecules that do not involve linear polymers have also been developed, such as Janus dendrimers, facial dendrons, and dendritic amphiphiles with only one dendron. Amphiphilic dendrimer micelles have achieved efficient and promising results, both in in vitro and in vivo tests, which encourage their research for future application in nanotherapies.

Asunto(s)

Antineoplásicos , Micelas , Sistemas de Liberación de Medicamentos , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ligandos , Polímeros

RESUMEN

Administration of substances through the skin represents a promising alternative, in relation to other drug administration routes, due to its large body surface area, in order to offer ideal and multiple sites for drug administration. In addition, the administration of drugs through the skin avoids the first-pass metabolism, allowing an increase in the bioavailability of drugs, as well as reducing their side effects. However, the stratum corneum (SC) comprises the main barrier of protection against external agents, mainly due to its structure, composition and physicochemical properties, becoming the main limitation for the administration of substances through the skin. In view of the above, pharmaceutical technology has allowed the development of multiple drug delivery systems (DDS), which include liquid crystals (LC), cubosomes, liposomes, polymeric nanoparticles (PNP), nanoemulsions (NE), as well as cyclodextrins (CD) and dendrimers (DND). It appears that the DDS circumvents the problems of drug absorption through the SC layer of the skin, ensuring the release of the drug, as well as optimizing the therapeutic effect locally. This review aims to highlight the DDS that include LC, cubosomes, lipid systems, PNP, as well as CD and DND, to optimize topical skin therapies.

Asunto(s)

Sistemas de Liberación de Medicamentos , Nanopartículas , Administración Cutánea , Portadores de Fármacos , Humanos , Liposomas , Nanotecnología , Piel

RESUMEN

HIV/AIDS, tuberculose, malária e as doenças tropicais negligenciadas representam uma grande preocupação em Saúde em muitas regiões do mundo. Os fármacos disponíveis para o tratamento apresentam diversos problemas, tais como toxicidade e resistência ao parasita. Mesmo com esse triste panorama, o investimento em pesquisa nessa área é, ainda, pouco significativo. Assim, dentre os métodos de modificação molecular para melhorar propriedades farmacêuticas, farmacocinéticas e/ou farmacodinâmica de compostos bioativos destaca-se a latenciação. Já os dendrímeros vêm despertando interesse em aplicações biológicas, principalmente como transportadores de fármacos, além de atuarem como transportadores de genes, imagem em diagnóstico e compostos com ação per se. Face ao exposto e tendo em vista o caráter promissor dos dendrímeros como sistemas de drug delivery, o objetivo deste trabalho foi a síntese de pró-fármacos dendriméricos potencialmente ativos em malária e tuberculose. Os dendrímeros de Bis-MPA (gerações 0, 1 e 2) foram sintetizados pelo grupo do Professor Scott Grayson, da Tulane University (EUA). No Brasil, foram feitas as funcionalizações destes compostos, através do acoplamento do ácido succínico (que funciona como espaçante) e as moléculas ativas. Selecionaram-se as seguintes substâncias: (1) primaquina, com ação antimalárica e (2) isoniazida, de ação nos primeiros estágios da tuberculose. Foram sintetizados os pró-fármacos dendriméricos de isoniazida nas gerações 0 e 1 (G0-Iso e G1-Iso), e primaquina nas gerações 0, 1 e 2 (G0-Pq, G1-Pq e G2Pq). Importante mencionar que os resultados de Ressonância Magnética e Nuclear de 1H e de 13C demostraram as obtenções dos respectivos produtos, porém contendo impurezas. Já a análise do resultado proveniente da espectrometria de massas do composto G0-Iso revelou a presença de um subproduto ciclizado da isonizaida succinoilada (CIso-Suc), o qual pode ser um potencial pró-fármaco ou apresentar atividade per se. Como não se conhece este composto, o laboratório coordenado pela Profas Elizabeth Igne Ferreira e Jeanine Giarolla manifestou interesse em pesquisa-lo, principalmente quanto suas propriedades físico- químicas, bem como quanto à atividade biológica. Assim, utilizando metodologia analítica previamente estabelecida para o G0-Iso, os estudos de estabilidade química da CIso-Suc, em diferentes valores de pH, demonstraram a capacidade da forma ciclizada em se converter no protótipo Iso-Suc, majoritariamente em pH 7,4 e 8,5. Como perspectivas, destaca-se a avaliação da estabilidade enzimática deste potencial derivado. Ressalta-se, ainda, a a avaliação da respectiva atividade antimicobacteriana. Em relação aos pró-fármacos, as necessidades de aprimoramentos das sínteses são, também, evidenciadas. Uma vez sintetizados e caracterizados, estes últimos derivados serão avaliados quanto à atividade biológica. Ademais, estudos computacionais, sobretudo simulações de docking molecular, foram desenvolvidos com intuito de se entender o modo de interação de alguns compostos com alvos biológicos pré-determinados

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HIV/AIDS, tuberculosis, malaria and neglected diseases are a major health concern in many regions of the world. The drugs available present various problems, such as toxicity and parasite resistance. Even with this sad outlook, research investment in this area is still insignificant. Among the molecular modification methods to improve the pharmaceutical, pharmacokinetic and/or pharmacodynamic properties we stands out prodrug design. On the other hand, dendrimers are arousing interest in biological applications, mainly as drug carriers, besides gene delivery, diagnostic imaging, as well as acting as compounds with activity per se. Considering that, added to the promising dendrimer drug delivery features, the aim of this study was to synthesize potentially active dendrimer prodrugs in malaria and tuberculosis. Bis-MPA dendrimers (generations 0, 1 and 2) were synthesized by the group of Professor Scott Grayson of Tulane University (USA). Herein in Brazil, the compounds were functionalized by coupling succinic acid (spacer group), as well as the active molecules. We selected the following substances: (1) primaquine, with antimalarial action and (2) isoniazid, acting in the early stages of tuberculosis. Isoniazid dendrimer prodrugs were synthesized generations 0 and 1 (G0-Iso and G1-Iso), and primaquine in generations 0, 1 and 2 (G0-Pq, G1-Pq and G2-Pq). It is important to mention that the results related to Nuclear and Magnetic Resonance 113C showed chemical structures features, however with impurities. Analysis of the mass spectrometry regarding G0-Iso has revealed the presence of a cyclized by-product of succinylated isonized (CIso-Suc), which may be a potential prodrug or may presentactivity itself. Using the analytical methodology performed for G0-Iso, ICso-Suc demonstrated its ability to convert the Iso-Suc prototype at different pH values, especially at pH 7.4 and 8.5. As perspectives, we highlight the determinations of the chemical stability of ICsoSuc at pH 1.5 and 6.0, as well as the evaluation of the enzymatic stability. We will also investigate the respective antimicobacterial activities. Regarding prodrugs, the needs for synthesis enhancements are also necessary. Once synthesized and characterized, these latter derivatives will be evaluated for biological activity. Moreover, computational studies, especially molecular docking simulations, were developed in order to understand the mode of interaction of some compounds with predetermined biological targets

Asunto(s)

Tuberculosis/patología , Profármacos/análisis , Dendrímeros/efectos adversos , Malaria/patología , Espectrometría de Masas/métodos , Apoyo a la Formación Profesional/clasificación , Preparaciones Farmacéuticas/análisis , Espectroscopía de Resonancia Magnética/métodos , VIH/patogenicidad , Acciones Farmacológicas , Enfermedades Desatendidas/complicaciones , Antimaláricos/análisis

RESUMEN

The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.

Asunto(s)

Antineoplásicos/farmacología , Calixarenos/farmacología , Fenilalanina/análogos & derivados , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Células COS , Calixarenos/síntesis química , Calixarenos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Chlorocebus aethiops , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Fenilalanina/síntesis química , Fenilalanina/química , Fenilalanina/farmacología , Relación Estructura-Actividad

RESUMEN

BACKGROUND: Our research group has developed some Valproic Acid (VPA) derivatives employed as anti-proliferative compounds targeting the HDAC8 enzyme. However, some of these compounds are poorly soluble in water. OBJECTIVE: Employed the four generations of Polyamidoamine (G4 PAMAM) dendrimers as drug carriers of these compounds to increase their water solubility for further in vitro evaluation. METHODS: VPA derivatives were subjected to Docking and Molecular Dynamics (MD) simulations to evaluate their affinity on G4 PAMAM. Then, HPLC-UV/VIS, 1H NMR, MALDI-TOF and atomic force microscopy were employed to establish the formation of the drug-G4 PAMAM complexes. RESULTS: The docking results showed that the amide groups of VPA derivatives make polar interactions with G4 PAMAM, whereas MD simulations corroborated the stability of the complexes. HPLC UV/VIS experiments showed an increase in the drug water solubility which was found to be directly proportional to the amount of G4 PAMAM. 1H NMR showed a disappearance of the proton amine group signals, correlating with docking results. MALDI-TOF and atomic force microscopy suggested the drug-G4 PAMAM dendrimer complexes formation. DISCUSSION: In vitro studies showed that G4 PAMAM has toxicity in the micromolar concentration in MDAMB- 231, MCF7, and 3T3-L1 cell lines. VPA CF-G4 PAMAM dendrimer complex showed anti-proliferative properties in the micromolar concentration in MCF-7 and 3T3-L1, and in the milimolar concentration in MDAMB- 231, whereas VPA MF-G4 PAMAM dendrimer complex didn't show effects on the three cell lines employed. CONCLUSION: These results demonstrate that G4 PAMAM dendrimers are capableof transporting poorly watersoluble aryl-VPA derivate compounds to increase its cytotoxic activity against neoplastic cell lines.

Asunto(s)

Antineoplásicos/farmacología , Dendrímeros/farmacología , Nylons/farmacología , Ácido Valproico/farmacología , Células 3T3-L1 , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Dendrímeros/síntesis química , Dendrímeros/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Ratones , Modelos Moleculares , Estructura Molecular , Nylons/síntesis química , Nylons/química , Relación Estructura-Actividad , Ácido Valproico/síntesis química , Ácido Valproico/química

RESUMEN

Alzheimer's disease has become a public health priority, so an investigation of new therapies is required. Tacrine (TAC) was licensed for treatments; however, its oral administration caused hepatotoxicity, so it is essential to reduce the side effects. PAMAM dendrimer generation 4.0 and 4.5 (DG4.0 and DG4.5) can be used as drug delivery systems and as nanodrugs per se. Our work aims to propose a combined therapy based on TAC and PAMAM dendrimer co-administration. TAC and dendrimer interactions were studied by in vitro drug release, drug stability, and FTIR. The toxicity profile of co-administration was evaluated in human red blood cells, in Neuro-2a cell culture, and in zebrafish larvae. Also, the anti-acetylcholinesterase activity was studied in cell culture. It was possible to obtain DG4.0-TAC and DG4.5-TAC suspensions, without reducing the drug solubility and stability. FTIR and in vitro release studies confirmed that interaction between TAC and DG4.5 was of the electrostatic type. No toxicity effects on human red blood cells were observed, whereas the co-administration with DG4.5 reduced cytotoxicity of TAC on the Neuro-2a cell line. Moreover, in vivo co-administration of both DG4.0-TAC and DG4.5-TAC reduced the morphological and hepatotoxic effects of TAC in zebrafish larvae. The reduction of TAC toxicity was not accompanied by a reduction in its activity since the anti-acetylcholinesterase activity remains when it is co-administrated with dendrimers. In conclusion, the co-administration of TAC with both DG4.0 and DG4.5 is a novel therapy since it was less-toxic, was more biocompatible, and has the same effectiveness than the free drug. Graphical abstract.

Asunto(s)

Enfermedad de Alzheimer/tratamiento farmacológico , Inhibidores de la Colinesterasa/administración & dosificación , Dendrímeros/administración & dosificación , Sistemas de Liberación de Medicamentos , Tacrina/administración & dosificación , Animales , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Estabilidad de Medicamentos , Humanos , Solubilidad , Tacrina/efectos adversos , Tacrina/química , Pez Cebra

RESUMEN

Today, dendrimers are the main nanoparticle applied to drug delivery systems. The physicochemical characteristics of dendrimers and their versatility structural modification make them attractive to applied as a platform to bioactive molecules transport. Nanoformulations based on dendrimers enhance low solubility drugs, arrival to the target tissue, drugs bioavailability, and controlled release. This review describes the latter approaches on the transport of bioactive molecules based on dendrimers. The review focus is on the last therapeutic strategies addressed by dendrimers conjugated with bioactive molecules. A brief review of the latest studies in therapies against cancer and cardiovascular diseases, as well as future projections in the area, are addressed.

RESUMEN

Dendrimers are globular structures, presenting an initiator core, repetitive layers starting radially from the core and terminal groups on the surface, resembling tree architecture. These structures have been studied in many biological applications, as drug, DNA, RNA and proteins delivery, as well as imaging and radiocontrast agents. With reference to that, this review focused in providing examples of dendrimers used in nanomedicine. Although most studies emphasize cancer, there are others which reveal action in the neurosystem, reducing either neuroinflammation or protein aggregation. Dendrimers can carry bioactive compounds by covalent bond (dendrimer prodrug), or by ionic interaction or adsortion in the internal space of the nanostructure. Additionally, dendrimers can be associated with other polymers, as PEG (polyethylene glycol), and with targeting structures as aptamers, antibodies, folic acid and carbohydrates. Their products in preclinical/clinical trial and those in the market are also discussed, with a total of six derivatives in clinical trials and seven products available in the market.

Asunto(s)

Dendrímeros/administración & dosificación , Dendrímeros/química , Nanomedicina/métodos , Nanoestructuras/química , Antineoplásicos/administración & dosificación , Química Farmacéutica , Ensayos Clínicos como Asunto , Medios de Contraste/administración & dosificación , Medios de Contraste/química , Humanos , Nanoestructuras/administración & dosificación , Neoplasias/diagnóstico por imagen , Neoplasias/tratamiento farmacológico , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Enfermedades del Sistema Nervioso/inmunología , Polietilenglicoles/química , Profármacos/administración & dosificación , Profármacos/química , Agregación Patológica de Proteínas/diagnóstico por imagen , Agregación Patológica de Proteínas/tratamiento farmacológico

RESUMEN

A new class of pyrene-based dendrimers, characterized by the presence of a 1,4,7,10-Tetraazacyclododecane (cyclen) unit as the core, was studied by SSF (steady-state fluorescence) and SPC (single-photon counting fluorescence). The photophysical behavior of these dendrimers was studied in THF, DMF and DMSO solution. The typical signals for pyrene-labeled molecules were recorded in each solvent, showing the representative fluorescence spectra: the corresponding emissions of monomer and excimer of the pyrene chromophore are observed. Unexpectedly, the typical quenching of tertiary amine on the pyrene emission was not observed in these dendrimers. Quenching studies were performed by adding up to 3 equivalents of trifluoroacetic acid (TFA). To our knowledge, this is the first report of pyrene's unquenching behavior by a tertiary amine.

Asunto(s)

Aminas/química , Dendrímeros/química , Fluorescencia , Pirenos/química , Estructura Molecular , Espectrometría de Fluorescencia

RESUMEN

The peptide-receptor radionuclide therapy (PRRT) is a successful approach for selectively delivering radiation within tumor sites through specific recognition of radiolabeled peptides by overexpressed receptors on cancer cell surfaces. The efficacy of PRRT could be improved by using polymeric radio- and drug- therapy nanoparticles for a concomitant therapeutic effect on malignant cells. This research aimed to prepare and evaluate, a novel drug and radiation delivery nanosystem based on the 177Lu-labeled polyamidoamine (PAMAM) dendrimer (DN) loaded with paclitaxel (PTX) and functionalized on the surface with the Lys1Lys3(DOTA)-bombesin (BN) peptide for specific targeting to gastrin-releasing peptide receptors (GRPr) overexpressed on breast cancer cells. DN was first conjugated covalently to BN and DOTA (chemical moiety for lutetium-177 complexing) and subsequently loaded with PTX. The characterization by microscopic and spectroscopic techniques, in-vitro drug delivery tests as well as in in-vitro and in-vivo cellular uptake of 177Lu-DOTA-DN(PTX)-BN by T47D breast cancer cells (GRPr-positive), indicated the formation of an improved delivery nanosystem with target-specific recognition by GRPr. Results of the 177Lu-DOTA-DN(PTX)-BN effect on T47D cell viability (1.3%, compared with 10.9% of 177Lu-DOTA-DN-BN and 14.0% of DOTA-DN-(PTX)-BN) demonstrated the concomitant radiotherapeutic and chemotherapeutic properties of the polymeric nanosystem as a potential agent for the treatment of GRPr-positive tumors.