RESUMO
Radioguidance that makes use of ß-emitting radionuclides is gaining in popularity and could have potential to strengthen the range of existing radioguidance techniques. While there is a strong tendency to develop new PET radiotracers, due to favorable imaging characteristics and the success of theranostics research, there are practical challenges that need to be overcome when considering use of ß-emitters for surgical radioguidance. In this position paper, the EANM identifies the possibilities and challenges that relate to the successful implementation of ß-emitters in surgical guidance, covering aspects related to instrumentation, radiation protection, and modes of implementation.
Assuntos
Partículas beta , Partículas beta/uso terapêutico , Humanos , Radioisótopos/química , Medicina Nuclear , Compostos Radiofarmacêuticos , Cirurgia Assistida por Computador/métodos , Proteção Radiológica/métodosRESUMO
Evidence that Huntington's disease (HD) is characterized by impaired cholesterol biosynthesis in the brain has led to strategies to increase its level in the brain of the rapidly progressing R6/2 mouse model, with a positive therapeutic outcome. Here we tested the long-term efficacy of chronic administration of cholesterol to the brain of the slowly progressing zQ175DN knock-in HD mice in preventing ("early treatment") or reversing ("late treatment") HD symptoms. To do this we used the most advanced formulation of cholesterol loaded brain-permeable nanoparticles (NPs), termed hybrid-g7-NPs-chol, which were injected intraperitoneally. We show that one cycle of treatment with hybrid-g7-NPs-chol, administered in the presymptomatic ("early treatment") or symptomatic ("late treatment") stages is sufficient to normalize cognitive defects up to 5 months, as well as to improve other behavioral and neuropathological parameters. A multiple cycle treatment combining both early and late treatments ("2 cycle treatment") lasting 6 months generates therapeutic effects for more than 11 months, without severe adverse reactions. Sustained cholesterol delivery to the brain of zQ175DN mice also reduces mutant Huntingtin aggregates in both the striatum and cortex and completely normalizes synaptic communication in the striatal medium spiny neurons compared to saline-treated HD mice. Furthermore, through a meta-analysis of published and current data, we demonstrated the power of hybrid-g7-NPs-chol and other strategies able to increase brain cholesterol biosynthesis, to reverse cognitive decline and counteract the formation of mutant Huntingtin aggregates. These results demonstrate that cholesterol delivery via brain-permeable NPs is a therapeutic option to sustainably reverse HD-related behavioral decline and neuropathological signs over time, highlighting the therapeutic potential of cholesterol-based strategies in HD patients. DATA AVAILABILITY: This study does not include data deposited in public repositories. Data are available on request to the corresponding authors.
Assuntos
Doença de Huntington , Camundongos , Animais , Doença de Huntington/tratamento farmacológico , Doença de Huntington/patologia , Encéfalo/patologia , Colesterol , Corpo Estriado/patologia , Cognição , Modelos Animais de Doenças , Camundongos TransgênicosRESUMO
Glioblastoma multiforme (GBM) is the most common malignant brain tumor, associated with low long-term survival. Nanoparticles (NPs) developed against GBM are a promising strategy to improve current therapies, by enhancing the brain delivery of active molecules and reducing off-target effects. In particular, NPs hold high potential for the targeted delivery of chemotherapeutics both across the blood-brain barrier (BBB) and specifically to GBM cell receptors, pathways, or the tumor microenvironment (TME). In this review, the most recent strategies to deliver drugs to GBM are explored. The main focus is on how surface functionalizations are essential for BBB crossing and for tumor specific targeting. We give a critical analysis of the various ligand-based approaches that have been used to target specific cancer cell receptors and the TME, or to interfere with the signaling pathways of GBM. Despite the increasing application of NPs in the clinical setting, new methods for ligand and surface characterization are needed to optimize the synthesis, as well as to predict their in vivo behavior. An expert opinion is given on the future of this research and what is still missing to create and characterize a functional NP system for improved GBM targeting.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Humanos , Glioblastoma/metabolismo , Ligantes , Nanopartículas/uso terapêutico , Transporte Biológico , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Barreira Hematoencefálica/metabolismo , Sistemas de Liberação de Medicamentos , Microambiente TumoralRESUMO
Hyaluronic acid (HA) is a Glycosaminoglycan made of disaccharide units containing N-acetyl-D-glucosamine and glucuronic acid. Its molecular mass can reach 10 MDa and its physiological properties depend on its polymeric property, polyelectrolyte feature and viscous nature. HA is a ubiquitous compound found in almost all biological tissues and fluids. So far, HA grades are produced by biotechnology processes, while in the human organism it is a major component of the extracellular matrix (ECM) in brain tissue, synovial fluid, vitreous humor, cartilage and skin. Indeed, HA is capable of forming hydrogels, polymer crosslinked networks that are very hygroscopic. Based on these considerations, we propose an overview of HA-based scaffolds developed for brain cancer treatment, central and peripheral nervous systems, discuss their relevance and identify the most successful developed systems.
Assuntos
Acetilglucosamina , Ácido Hialurônico , Humanos , Polieletrólitos , Hidrogéis , Glicosaminoglicanos , Ácido Glucurônico , Dissacarídeos , Sistema Nervoso , Alicerces Teciduais , Engenharia TecidualRESUMO
Tunneling nanotubes (TNTs), discovered in 2004, are thin, long protrusions between cells utilized for intercellular transfer and communication. These newly discovered structures have been demonstrated to play a crucial role in homeostasis, but also in the spreading of diseases, infections, and metastases. Gaining much interest in the medical research field, TNTs have been shown to transport nanomedicines (NMeds) between cells. NMeds have been studied thanks to their advantageous features in terms of reduced toxicity of drugs, enhanced solubility, protection of the payload, prolonged release, and more interestingly, cell-targeted delivery. Nevertheless, their transfer between cells via TNTs makes their true fate unknown. If better understood, TNTs could help control NMed delivery. In fact, TNTs can represent the possibility both to improve the biodistribution of NMeds throughout a diseased tissue by increasing their formation, or to minimize their formation to block the transfer of dangerous material. To date, few studies have investigated the interaction between NMeds and TNTs. In this work, we will explain what TNTs are and how they form and then review what has been published regarding their potential use in nanomedicine research. We will highlight possible future approaches to better exploit TNT intercellular communication in the field of nanomedicine.
Assuntos
Estruturas da Membrana Celular/metabolismo , Animais , Transporte Biológico/fisiologia , Humanos , Nanomedicina/métodos , Nanotubos , Distribuição Tecidual/fisiologiaRESUMO
Increasing life expectancy has led to an aging population, which has consequently increased the prevalence of dementia. Alzheimer's disease (AD), the most common form of dementia worldwide, is estimated to make up 50-80% of all cases. AD cases are expected to reach 131 million by 2050, and this increasing prevalence will critically burden economies and health systems in the next decades. There is currently no treatment that can stop or reverse disease progression. In addition, the late diagnosis of AD constitutes a major obstacle to effective disease management. Therefore, improved diagnostic tools and new treatments for AD are urgently needed. In this review, we investigate and describe both well-established and recently discovered AD biomarkers that could potentially be used to detect AD at early stages and allow the monitoring of disease progression. Proteins such as NfL, MMPs, p-tau217, YKL-40, SNAP-25, VCAM-1, and Ng / BACE are some of the most promising biomarkers because of their successful use as diagnostic tools. In addition, we explore the most recent molecular strategies for an AD therapeutic approach and nanomedicine-based technologies, used to both target drugs to the brain and serve as devices for tracking disease progression diagnostic biomarkers. State-of-the-art nanoparticles, such as polymeric, lipid, and metal-based, are being widely investigated for their potential to improve the effectiveness of both conventional drugs and novel compounds for treating AD. The most recent studies on these nanodevices are deeply explained and discussed in this review.
Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/tratamento farmacológico , Biomarcadores/metabolismo , Nanomedicina/métodos , Envelhecimento , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides , Animais , Encéfalo , Sistemas de Liberação de Medicamentos , Humanos , Nanopartículas Metálicas , Estresse OxidativoRESUMO
Marek's disease (MD) is a lymphoproliferative disease caused by Gallid alphaherpesvirus 2 (GaHV-2), which primarily affects chickens. However, the virus is also able to induce tumours in turkeys, albeit less frequently than in chickens. This study reports the molecular characterization of a GaHV-2 strain detected in a flock of Italian meat-type turkeys exhibiting visceral lymphomas. Sequencing and phylogenetic analysis of the meq gene revealed that the turkey GaHV-2 has molecular features of high virulence and genetic similarity with GaHV-2 strains recently detected in Italian commercial and backyard chickens. GaHV-2 is ubiquitous among chickens despite vaccination, and chicken-to-turkey transmission is hypothesized due to the presence of broilers in neighbouring pens.RESEARCH HIGHLIGHTS A GaHV-2 strain from Italian turkeys was molecularly characterized.The turkey strain presented molecular characteristics of high virulence in its meq gene.The turkey strain was closely related to previously detected chicken strains.
Assuntos
Herpesvirus Galináceo 2 , Doença de Marek/virologia , Neoplasias/veterinária , Perus , Animais , Regulação Viral da Expressão Gênica , Herpesvirus Galináceo 2/genética , Doença de Marek/patologia , Neoplasias/virologia , Proteínas Oncogênicas Virais/isolamento & purificação , Filogenia , Reação em Cadeia da Polimerase/veterinária , Doenças das Aves Domésticas/virologiaRESUMO
Central nervous system (CNS) compartments remain one of the most difficult districts for drug delivery. This is due to the presence of the blood-brain barrier (BBB) that hampers 90% of drug passage, dramatically requiring non-invasive treatment strategies. Here, for the first time, the use of opioid-derived deltorphin-derivative peptides to drive biodegradable and biocompatible polymeric (i.e. poly-lactide-co-glycolide, PLGA) nanomedicines delivery across the BBB was described. Opioid-derived peptides were covalently conjugated to furnish activated polymers which were further used for fluorescently tagged nanoformulations. Beyond reporting production, formulation methodology and full physico-chemical characterization, in vivo tests generated clear proof of BBB crossing and CNS targeting by engineered nanomedicines opening the research to further applications of drug delivery and targeting in CNS disease models.
Assuntos
Nanomedicina/métodos , Peptídeos/química , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Sistema Nervoso Central , Sistemas de Liberação de Medicamentos/métodos , Humanos , Oligopeptídeos/químicaRESUMO
Enzymes have gained attention for their role in numerous disease states, calling for research for their efficient delivery. Loading enzymes into polymeric nanoparticles to improve biodistribution, stability, and targeting in vivo has led the field with promising results, but these enzymes still suffer from a degradation effect during the formulation process that leads to lower kinetics and specific activity leading to a loss of therapeutic potential. Stabilizers, such as bovine serum albumin (BSA), can be beneficial, but the knowledge and understanding of their interaction with enzymes are not fully elucidated. To this end, the interaction of BSA with a model enzyme B-Glu, part of the hydrolase class and linked to Gaucher disease, was analyzed. To quantify the natural interaction of beta-glucosidase (B-Glu,) and BSA in solution, isothermal titration calorimetry (ITC) analysis was performed. Afterwards, polymeric nanoparticles encapsulating these complexes were fully characterized, and the encapsulation efficiency, activity of the encapsulated enzyme, and release kinetics of the enzyme were compared. ITC results showed that a natural binding of 1:1 was seen between B-Glu and BSA. Complex concentrations did not affect nanoparticle characteristics which maintained a size between 250 and 350 nm, but increased loading capacity (from 6% to 30%), enzyme activity, and extended-release kinetics (from less than one day to six days) were observed for particles containing higher B-Glu:BSA ratios. These results highlight the importance of understanding enzyme:stabilizer interactions in various nanoparticle systems to improve not only enzyme activity but also biodistribution and release kinetics for improved therapeutic effects. These results will be critical to fully characterize and compare the effect of stabilizers, such as BSA with other, more relevant therapeutic enzymes for central nervous system (CNS) disease treatments.
Assuntos
Nanopartículas/química , Soroalbumina Bovina/química , Animais , Calorimetria , Estabilidade Enzimática/fisiologia , NanomedicinaRESUMO
Crenosoma vulpis, the fox lungworm, is a nematode parasite of wild and domestic canids belonging to the super-family Metastrongyloidea. A survey of infection was carried out examining 88 red foxes (Vulpes vulpes) obtained during the regular hunting season (2014-2015) from the Emilia-Romagna region of Italy. Carcasses were stored frozen (- 21 °C) prior to necropsy. Lungs were examined for the presence of adult worms by dissection of the trachea, bronchi, and bronchioles, and then the lung tissue was examined for first-stage larvae (L1) by the Baermann method. No adult stages were detected, but L1, identified based on morphology as Crenosoma vulpis, were recovered from 28.4% (25/88) of the fox lungs. No significant differences in infection were found based on sex or geographical distribution. A brief review on C. vulpis report in red foxes in Italy and other European countries was also carried out.
Assuntos
Raposas/parasitologia , Pneumopatias Parasitárias/veterinária , Pulmão/parasitologia , Metastrongyloidea/isolamento & purificação , Infecções por Strongylida/veterinária , Animais , Europa (Continente) , Feminino , Itália , Larva/classificação , Pneumopatias Parasitárias/diagnóstico , Pneumopatias Parasitárias/parasitologia , Masculino , Metastrongyloidea/classificação , Infecções por Strongylida/diagnóstico , Infecções por Strongylida/parasitologiaRESUMO
Mucopolysaccharidosis type II (MPSII) is a lysosomal storage disorder due to the deficit of the enzyme iduronate 2-sulfatase (IDS), which leads to the accumulation of glycosaminoglycans in most organ-systems, including the brain, and resulting in neurological involvement in about two-thirds of the patients. The main treatment is represented by a weekly infusion of the functional enzyme, which cannot cross the blood-brain barrier and reach the central nervous system. In this study, a tailored nanomedicine approach based on brain-targeted polymeric nanoparticles (g7-NPs), loaded with the therapeutic enzyme, was exploited. Fibroblasts from MPSII patients were treated for 7 days with NPs loaded with the IDS enzyme; an induced IDS activity like the one detected in healthy cells was measured, together with a reduction of GAG content to non-pathological levels. An in vivo short-term study in MPSII mice was performed by weekly administration of g7-NPs-IDS. Biochemical, histological, and immunohistochemical evaluations of liver and brain were performed. The 6-weeks treatment produced a significant reduction of GAG deposits in liver and brain tissues, as well as a reduction of some neurological and inflammatory markers (i.e., LAMP2, CD68, GFAP), highlighting a general improvement of the brain pathology. The g7-NPs-IDS approach allowed a brain-targeted enzyme replacement therapy. Based on these positive results, the future aim will be to optimize NP formulation further to gain a higher efficacy of the proposed approach.
Assuntos
Encéfalo/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Sistemas de Liberação de Medicamentos , Iduronato Sulfatase/administração & dosagem , Mucopolissacaridose II/tratamento farmacológico , Nanopartículas/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Animais , Encéfalo/enzimologia , Encéfalo/metabolismo , Encéfalo/patologia , Portadores de Fármacos/química , Terapia de Reposição de Enzimas , Glicopeptídeos/química , Glicopeptídeos/metabolismo , Humanos , Iduronato Sulfatase/uso terapêutico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mucopolissacaridose II/enzimologia , Mucopolissacaridose II/metabolismo , Mucopolissacaridose II/patologia , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/químicaRESUMO
Salmonella enterica serotype Enteritidis and S. enterica serotype Typhimurium are frequently present among poultry and are associated with outbreaks of human salmonellosis. The study investigated the in vitro antimicrobial activity of essential oils (EOs) obtained from Aloysia triphylla, Cinnamomum zeylanicum, Cymbopogon citratus, Litsea cubeba, Mentha piperita, Syzygium aromaticum against S. Enteritidis and S. Thyphimurium strains previously isolated from poultry. A 1:1 mixture of C. zeylanicum and S. aromaticum was also tested. The activity of all compounds was evaluated against the yeast Saccharomyces cerevisiae, commonly used as probiotic. The highest antibacterial activity was observed for C. zeylanicum (minimum inhibitory concentrations (MICs) ranging from 1.26 mg/mL to 0.63 mg/mL), S. aromaticum (MICs from 2.637 mg/mL to 0.164 mg/mL) and the mixture (MICs from 1.289 mg/mL to 0.322 mg/mL). No activity was recorded against S. cerevisiae. The results suggest a possible use of C. zeylanicum and S. aromaticum, alone or in combination, in the farm environment for disinfection and in poultry diet, combined with S. cerevisiae administration, for an integrated approach to avoid Salmonella intestinal colonization.
Assuntos
Anti-Infecciosos/farmacologia , Óleos Voláteis/química , Aves Domésticas/microbiologia , Salmonella enteritidis/efeitos dos fármacos , Salmonella typhimurium/efeitos dos fármacos , Animais , Anti-Infecciosos/isolamento & purificação , Cinnamomum zeylanicum/química , Cymbopogon/química , Quimioterapia Combinada , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/efeitos dos fármacos , Sorogrupo , Syzygium/química , Traqueófitas/químicaRESUMO
Trans-resveratrol (RSV) was microencapsulated in Eudragit® RS100 and RL100 resin blends. Lyophilized microspheres were characterized in the solid state for their micromeritic properties and drug loading. FT-IR, PXRD, and DSC analyzes suggested that RSV formed an intimate microcrystalline dispersion within the polymer network, also confirmed by SEM analysis. This produced a reduced degradation of RSV after storage at 40 °C, compared to the neat drug, and a protection of the drug from UV light-induced trans-cis isomerization (60% intact drug was found after 60 s irradiation at 350 nm, compared to 37% for the pure drug). Solubility and in vitro dissolution studies indicated that microencapsulation did not improve the dissolution pattern of RSV in simulated gastric and intestinal aqueous fluids. Evaluation of the in vitro antioxidant activity showed that, compared to the neat drug in aqueous solution, RSV loaded in the microspheres retained for a longer time, up to 22 days of incubation, the initial ORAC capacity. The present study thus demonstrated that Eudragit® Retard resins can be used to easily produce micro-sized solid dispersions with RSV, for potential oral administration, contributing to ameliorate the physico-chemical stability and antioxidant activity of this compound.
Assuntos
Acrilatos/química , Antioxidantes/química , Polímeros/química , Resveratrol/química , Resinas Acrílicas/química , Varredura Diferencial de Calorimetria/métodos , Composição de Medicamentos/métodos , Microesferas , Ácidos Polimetacrílicos/química , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodosRESUMO
Glycogenosis type II, or Pompe Disease, is a lysosomal storage disease caused by the deficiency of acid alpha-glucosidase (GAA), leading to glycogen accumulation in muscles. A recombinant human GAA (rhGAA, Myozyme®) is currently used for enzyme replacement therapy. Despite its efficacy in most of patients, some of them show a diminished response to the treatment with rapidly progressive clinical deterioration, due to immuno-mediated enzyme inactivation. To demonstrate that Nanoparticles (NPs) could be profitably exploited to carry macromolecules, PLGA NPs loaded with rhGAA (GAA-NPs) were prepared by double emulsion solvent evaporation. Their surface morphology, particle size, zeta-potential and biochemical activity were assessed. "Pulse and chase" experiments were made by administrating GAA-NPs on patients' fibroblasts. Biochemical activity tests showed a more efficient cellular uptake of rhGAA loaded to NPs and a more significant stability of the enzyme (up to 7 days) in vitro, if compared to the same amount of rhGAA free enzyme. This data allows to envision in vivo experiments, in significant animal models, to further characterize lysosomal enzyme loaded-NPs' efficacy and toxicity.
Assuntos
Doença de Depósito de Glicogênio Tipo II , Ácido Láctico/química , Lisossomos/metabolismo , Nanopartículas/química , Ácido Poliglicólico/química , RNA/química , alfa-Glucosidases/química , Células Cultivadas , Sistemas de Liberação de Medicamentos , Fibroblastos , Humanos , Ácido Láctico/farmacocinética , Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , RNA/farmacocinética , alfa-Glucosidases/farmacocinéticaRESUMO
The development of smart delivery systems able to deliver and target a drug to the site of action is one of the major challenges in the field of pharmaceutical technology. The surface modification of nanocarriers, such as liposomes, is widely investigated either for increasing the blood circulation time (by pegylation) or for interacting with specific tissues or cells (by conjugation of a selective ligand as a monoclonal antibody, mAb). Microscopical analysis thereby is a useful approach to evaluate the morphology and the size owing to resolution and versatility in defining either surface modification or the architecture and the internal structure of liposomes. This contribution aims to connect the outputs obtained by transmission electron (TEM) and atomic force (AFM) microscopical techniques for identifying the modifications on the liposomal surface. To reach this objective, we prepared liposomes applying two different pegylation technologies and further modifying the surface by mAb conjugation. This work demonstrates the feasibility to apply the combined approach (TEM and AFM analysis) in the evaluation of the efficacy of a surface engineering process.
Assuntos
Lipossomos/química , Microscopia de Força Atômica , Tamanho da Partícula , Propriedades de SuperfícieRESUMO
INTRODUCTION: Neurometabolic disorders remain challenging to treat, largely due to the limited availability of drugs that can cross the blood-brain barrier (BBB) and effectively target brain impairment. Key reasons for inadequate treatment include a lack of coordinated knowledge, few studies on BBB status in these diseases, and poorly designed therapies. AREAS COVERED: This paper provides an overview of current research on neurometabolic disorders and therapeutic options, focusing on the treatment of neurological involvement. It highlights the limitations of existing therapies, describes innovative protocols recently developed, and explores new opportunities for therapy design and testing, some of which are already under investigation. The goal is to guide researchers toward innovative and potentially more effective treatments. EXPERT OPINION: Advancing research on neurometabolic diseases is crucial for designing effective treatment strategies. The field suffers from a lack of collaboration, and a strong collective effort is needed to enhance synergy, increase knowledge, and develop a new therapeutic paradigm for neurometabolic disorders.
Assuntos
Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Humanos , Barreira Hematoencefálica/metabolismo , Animais , Desenho de Fármacos , Enzimas/metabolismo , Enzimas/administração & dosagem , Desenvolvimento de MedicamentosRESUMO
Purpose: In recent years, microfluidic technologies have become mainstream in producing gene therapy nanomedicines (NMeds) following the Covid-19 vaccine; however, extensive optimizations are needed for each NMed type and genetic material. This article strives to improve LNPs for pDNA loading, protection, and delivery, while minimizing toxicity. Methods: The microfluidic technique was optimized to form cationic or neutral LNPs to load pDNA. Classical "post-formulation" DNA addition vs "pre" addition in the aqueous phase were compared. All formulations were characterized (size, homogeneity, zeta potential, morphology, weight yield, and stability), then tested for loading efficiency, nuclease protection, toxicity, and cell uptake. Results: Optimized LNPs formulated with DPPC: Chol:DOTAP 1:1:0.1 molar ratio and 10 µg of DOPE-Rhod, had a size of 160 nm and good homogeneity. The chemico-physical characteristics of cationic LNPs worsened when adding 15 µg/mL of pDNA with the "post" method, while maintaining their characteristics up to 100 µg/mL of pDNA with the "pre" addition remaining stable for 30 days. Interestingly, neutral LNPs formulated with the same method loaded up to 50% of the DNA. Both particles could protect the DNA from nucleases even after one month of storage, and low cell toxicity was found up to 40 µg/mL LNPs. Cell uptake occurred within 2 hours for both formulations with the DNA intact in the cytoplasm, outside of the lysosomes. Conclusion: In this study, the upcoming microfluidic technique was applied to two strategies to generate pDNA-LNPs. Cationic LNPs could load 10x the amount of DNA as the classical approach, while neutral LNPs, which also loaded and protected DNA, showed lower toxicity and good DNA protection. This is a big step forward at minimizing doses and toxicity of LNP-based gene therapy.
Assuntos
Cátions , DNA , Plasmídeos , Plasmídeos/administração & dosagem , Plasmídeos/química , Humanos , Cátions/química , DNA/química , DNA/administração & dosagem , Terapia Genética/métodos , Microfluídica/métodos , Tamanho da Partícula , Nanomedicina , COVID-19/prevenção & controle , Lipossomos/química , Transfecção/métodos , Nanopartículas/química , SARS-CoV-2 , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/química , Compostos de Amônio Quaternário/química , Ácidos Graxos MonoinsaturadosRESUMO
Enzyme-based therapy has garnered significant attention for its current applications in various diseases. Despite the notable advantages associated with the use of enzymes as therapeutic agents, that could have high selectivity, affinity, and specificity for the target, their application faces challenges linked to physico-chemical and pharmacological properties. These limitations can be addressed through the encapsulation of enzymes in nanoplatforms as a comprehensive solution to mitigate their degradation, loss of activity, off-target accumulation, and immunogenicity, thus enhancing bioavailability, therapeutic efficacy, and circulation time, thereby reducing the number of administrations, and ameliorating patient compliance. The exploration of novel nanomedicine-based enzyme therapeutics for the treatment of challenging diseases stands as a paramount goal in the contemporary scientific landscape, but even then it is often not enough. Combining an enzyme with another therapeutic (e.g., a small molecule, another enzyme or protein, a monoclonal antibody, or a nucleic acid) within a single nanocarrier provides innovative multidrug-integrated therapy and ensures that both the actives arrive at the target site and exert their therapeutic effect, leading to synergistic action and superior therapeutic efficacy. Moreover, this strategic approach could be extended to gene therapy, a field that nowadays has gained increasing attention, as enzymes acting at genomic level and nucleic acids may be combined for synergistic therapy. This multicomponent therapeutic approach opens opportunities for promising future developments. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
Assuntos
Terapia Enzimática , Nanomedicina , Humanos , AnimaisRESUMO
Caseous lymphadenitis is a chronic debilitating disease typical of small ruminants, but it is also noted in several other domestic and wild species. In this report, we present the first documented case in Italy of pseudotuberculosis in a roe deer (Capreolus capreolus, Linnaeus 1758) found dead in the mountains of Forlì-Cesena province, Emilia Romagna region. The carcass underwent necropsy according to standard protocols, revealing generalized lymphadenopathy and severe apostematous pneumonia with multifocal and encapsulated abscesses. Corynebacterium pseudotuberculosis was isolated from the lung parenchyma, lymph nodes and abscesses. Additionally, severe parasitic bronchopneumonia of the caudal lobes and gastrointestinal strongyle infestation were detected. To our knowledge, this is the first documented case of CLA referable to C. pseudotubercolosis in a roe deer in Italy.
RESUMO
Small interfering RNA (siRNA) holds great potential to treat many difficult-to-treat diseases, but its delivery remains the central challenge. This study aimed at investigating the suitability of polymer-lipid hybrid nanomedicines (HNMeds) as novel siRNA delivery platforms for locoregional therapy of glioblastoma. Two HNMed formulations were developed from poly(lactic-co-glycolic acid) polymer and a cationic lipid: 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) or 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol (DC-Chol). After characterization of the HNMeds, a model siRNA was complexed onto their surface to form HNMed/siRNA complexes. The physicochemical properties and siRNA binding ability of complexes were assessed over a range of nitrogen-to-phosphate (N/P) ratios to optimize the formulations. At the optimal N/P ratio of 10, complexes effectively bound siRNA and improved its protection from enzymatic degradation. Using the NIH3T3 mouse fibroblast cell line, DOTAP-based HNMeds were shown to possess higher cytocompatibility in vitro over the DC-Chol-based ones. As proof-of-concept, uptake and bioefficacy of formulations were also assessed in vitro on U87MG human glioblastoma cell line expressing luciferase gene. Complexes were able to deliver anti-luciferase siRNA and induce a remarkable suppression of gene expression. Noteworthy, the effect of DOTAP-based formulation was not only about three-times higher than DC-Chol-based one, but also comparable to lipofectamine model transfection reagent. These findings set the basis to exploit this nanosystem for silencing relevant GB-related genes in further in vitro and in vivo studies.