RESUMO
BACKGROUND: Insufficient solubility and stability of bioactive small molecules as well as poor biocompatibility may cause low bioavailability and are common obstacles in drug development. One example of such problematic molecules is 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE), a hydrophobic indirubin derivative. 6BIGOE potently modulates the release of inflammatory cytokines and lipid mediators from isolated human monocytes through inhibition of glycogen synthase kinase-3 in a favorable fashion. However, 6BIGOE suffers from poor solubility and short half-lives in biological aqueous environment and exerts cytotoxic effects in various mammalian cells. In order to overcome the poor water solubility, instability and cytotoxicity of 6BIGOE, we applied encapsulation into poly(D,L-lactide-co-glycolide) (PLGA)-based nanoparticles by employing formulation methods using the sustainable solvents Cyrene™ or 400 g/mol poly(ethylene glycol) as suitable technology for efficient drug delivery of 6BIGOE. RESULTS: For all preparation techniques the physicochemical characterization of 6BIGOE-loaded nanoparticles revealed comparable crystallinity, sizes of about 230 nm with low polydispersity, negative zeta potentials around - 15 to - 25 mV, and biphasic release profiles over up to 24 h. Nanoparticles with improved cellular uptake and the ability to mask cytotoxic effects of 6BIGOE were obtained as shown in human monocytes over 48 h as well as in a shell-less hen's egg model. Intriguingly, encapsulation into these nanoparticles fully retains the anti-inflammatory properties of 6BIGOE, that is, favorable modulation of the release of inflammation-relevant cytokines and lipid mediators from human monocytes. CONCLUSIONS: Our formulation method of PLGA-based nanoparticles by applying sustainable, non-toxic solvents is a feasible nanotechnology that circumvents the poor bioavailability and biocompatibility of the cargo 6BIGOE. This technology yields favorable drug delivery systems for efficient interference with inflammatory processes, with improved pharmacotherapeutic potential.
Assuntos
Indóis , Sistemas de Liberação de Fármacos por Nanopartículas , Nanopartículas/química , Oximas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Adolescente , Adulto , Idoso , Animais , Sobrevivência Celular/efeitos dos fármacos , Fluoresceína/química , Fluoresceína/farmacocinética , Humanos , Indóis/química , Indóis/farmacocinética , Indóis/toxicidade , Leucócitos/efeitos dos fármacos , Pessoa de Meia-Idade , Sistemas de Liberação de Fármacos por Nanopartículas/química , Sistemas de Liberação de Fármacos por Nanopartículas/farmacocinética , Sistemas de Liberação de Fármacos por Nanopartículas/farmacologia , Nanopartículas/toxicidade , Nanotecnologia , Oximas/química , Oximas/farmacocinética , Oximas/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Solventes/química , Adulto JovemRESUMO
Nanotechnology is a very promising technological tool to combat health problems associated with the loss of effectiveness of currently used antibiotics. Previously, we developed a formulation consisting of a chitosan and tween 80-decorated alginate nanocarrier that encapsulates rifampicin and the antioxidant ascorbic acid (RIF/ASC), intended for the treatment of respiratory intracellular infections. Here, we investigated the effects of RIF/ASC-loaded NPs on the respiratory mucus and the pulmonary surfactant. In addition, we evaluated their cytotoxicity for lung cells in vitro, and their biodistribution on rat lungs in vivo after their intratracheal administration. Findings herein demonstrated that RIF/ASC-loaded NPs display a favorable lung biocompatibility profile and a uniform distribution throughout lung lobules. RIF/ASC-loaded NPs were mainly uptaken by lung macrophages, their primary target. In summary, findings show that our novel designed RIF/ASC NPs could be a suitable system for antibiotic lung administration with promising perspectives for the treatment of pulmonary intracellular infections.
Assuntos
Alginatos/química , Ácido Ascórbico/química , Pneumopatias/tratamento farmacológico , Pneumopatias/metabolismo , Nanopartículas/química , Rifampina/metabolismo , Rifampina/toxicidade , Células A549 , Alginatos/metabolismo , Alginatos/toxicidade , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Antioxidantes/toxicidade , Ácido Ascórbico/metabolismo , Ácido Ascórbico/toxicidade , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/fisiologia , Linhagem Celular , Linhagem Celular Tumoral , Quitosana/metabolismo , Quitosana/toxicidade , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Portadores de Fármacos/toxicidade , Sistemas de Liberação de Medicamentos/métodos , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/metabolismo , Masculino , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Polímeros/metabolismo , Polímeros/toxicidade , Ratos , Ratos Wistar , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Rifampina/farmacologia , Suínos , Distribuição TecidualRESUMO
BACKGROUND: Bone defects are often combined with the risk of infection in the clinic, and artificial bone substitutes are often implanted to repair the defective bone. However, the implant materials are carriers for bacterial growth, and biofilm can form on the implant surface, which is difficult to eliminate using antibiotics and the host immune system. Magnesium (Mg) was previously reported to possess antibacterial potential. METHODS: In this study, Mg was incorporated into poly(lactide-co-glycolic acid) (PLGA) to fabricate a PLGA/Mg scaffold using a low-temperature rapid-prototyping technique. All scaffolds were divided into three groups: PLGA (P), PLGA/10 wt% Mg with low Mg content (PM-L) and PLGA/20 wt% Mg with high Mg content (PM-H). The degradation test of the scaffolds was conducted by immersing them into the trihydroxymethyl aminomethane-hydrochloric acid (Tris-HCl) buffer solution and measuring the change of pH values and concentrations of Mg ions. The antibacterial activity of the scaffolds was investigated by the spread plate method, tissue culture plate method, scanning electron microscopy and confocal laser scanning microscopy. Additionally, the cell attachment and proliferation of the scaffolds were evaluated by the cell counting kit-8 (CCK-8) assay using MC3T3-E1 cells. RESULTS: The Mg-incorporated scaffolds degraded and released Mg ions and caused an increase in the pH value. Both PM-L and PM-H inhibited bacterial growth and biofilm formation, and PM-H exhibited higher antibacterial activity than PM-L after incubation for 24 and 48 h. Cell tests revealed that PM-H exerted a suppressive effect on cell attachment and proliferation. CONCLUSIONS: These findings demonstrated that the PLGA/Mg scaffolds possessed favorable antibacterial activity, and a higher content of Mg (20%) exhibited higher antibacterial activity and inhibitory effects on cell attachment and proliferation than low Mg content (10%).
Assuntos
Antibacterianos/química , Antibacterianos/farmacologia , Magnésio/química , Teste de Materiais , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacologia , Células 3T3 , Animais , Antibacterianos/toxicidade , Adesão Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Camundongos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Alicerces Teciduais/químicaRESUMO
Aptamer based drug delivery systems are gaining the importance in anticancer therapy due to their targeted drug delivery efficiency without harming the normal cells. The present work formulated the pH-dependent aptamer functionalized polymer-based drug delivery system against human lung cancer. The prepared aptamer functionalized doxorubicin (DOX) loaded poly (D, L-lactic-co-glycolic acid) (PLGA), poly (N-vinylpyrrolidone) (PVP) nanoparticles (APT-DOX-PLGA-PVP NPs) were spherical in shape with an average size of 87.168â¯nm. The crystallography and presence of the PLGA (poly (D, L-lactic-co-glycolic acid)) and DOX (doxorubicin) in APT-DOX-PLGA-PVP NPs were indicated by the X-ray diffraction (XRD), Fourier transforms infrared spectroscopy (FTIR), and 1H and 13C nuclear magnetic resonance spectrometer (NMR). The pH-dependent aptamer AS1411 based drug release triggered the cancer cell death was evidenced by cytotoxicity assay, flow cytometry, and fluorescent microscopic imaging. In addition, the cellular uptake of the DOX was determined and the apoptosis-related signaling pathway in the A549â¯cells was studied by Western blot analysis. Further, the in vivo study revealed that mice treated with APT-DOX-PLGA-PVP NPs were significantly recovered from cancer as evident by mice weight and tumor size followed by the histopathological study. It was reported that the APT-DOX-PLGA-PVP NPs induced the apoptosis through the activation of the apoptosis-related proteins. Hence, the present study revealed that the APT-DOX-PLGA-PVP NPs improved the therapeutic efficiency through the nucleolin receptor endocytosis targeted drug release.
Assuntos
Antineoplásicos/uso terapêutico , Aptâmeros de Nucleotídeos/química , Doxorrubicina/uso terapêutico , Nanopartículas/química , Neoplasias/tratamento farmacológico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Células A549 , Animais , Antineoplásicos/farmacocinética , Aptâmeros de Nucleotídeos/toxicidade , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Liberação Controlada de Fármacos , Feminino , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Células NIH 3T3 , Nanopartículas/toxicidade , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Povidona/química , Povidona/toxicidade , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nicotine vaccines have been investigated to assist with smoking cessation. Because smoking cessation is a long process, past nicotine vaccines required multiple injections to achieve long-term efficacy. It would be of great significance if extended efficacy can be achieved with fewer injections. Here, we report the assembly of lipid-polylactic acid (PLA) and lipid-poly(lactic-co-glycolic acid) (PLGA) hybrid nanoparticle (NP) based nicotine vaccines. Mice immunized with the lipid-PLGA vaccine produced higher titers of nicotine-specific antibodies than the lipid-PLA vaccine in short-term. However, the lipid-PLA vaccine was found to induce long-lasting antibodies. Three months after the immunization, only mice that received first two injections of the lipid-PLGA vaccine and a third injection of the lipid-PLA vaccine achieved a significantly lower brain nicotine concentration of 65.13 ± 20.59 ng/mg than 115.88 ± 37.62 ng/mg from the negative controls. The results indicate that not only the stability of the vaccines but also the combination of the vaccines impacted the long-term efficacy of the immunization. Lastly, both the body weight and the histopathology study suggest that the vaccines were safe to mice. These findings suggest that long-term immunity against nicotine can be realized by a rational administration of nanovaccines of different levels of stability.
Assuntos
Imunidade Humoral/efeitos dos fármacos , Nanopartículas/química , Nicotina/imunologia , Vacinas/imunologia , Animais , Encéfalo/metabolismo , Feminino , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Camundongos Endogâmicos BALB C , Nanopartículas/toxicidade , Nicotina/metabolismo , Poliésteres/química , Poliésteres/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Vacinas/química , Vacinas/toxicidadeRESUMO
Sustained release nanoformulations of second line antitubercular drugs levofloxacin and ethionamide had shown promise in pharmacokinetics and acute and sub-acute toxicity studies. The present study evaluated the clastogenicity potential of the nanoformulations of these antitubercular agents. Clastogenicity was evaluated by (a) in vitro micronucleus assay (b) in vivo micronucleus assay in Swiss albino mice and (c) sister chromatid exchange (SCE) in CHO cell lines. Ethionamide and levofloxacin loaded nanoparticles were 312 ± 64 nm and 245 ± 24 nm in size respectively and drug encapsulation was 35.2 ± 3.1% w/w and 45.6 ± 9.4% w/w, respectively. The frequency of MN-NCE/1000 NCE and MN-PCE/1000 PCE were significantly reduced in mice treated with ethionamide nanoparticle (3.5 ± 0.9, 13.8 ± 16.68) and levofloxacin nanoparticles (5.6 ± 2.7, 16.7 ± 12.7) compared to the mice treated with free ethionamide (11.5 ± 4.1, p = 0.23 and 45.19 ± 19.21, p = 0.38) and free levofloxacin (14.7 ± 1.88, p < 0.0001 and 54.6 ± 18.1, p = 0.0017), respectively. For in vitro, micronucleus assay frequencies of micronuclei per thousand bi-nucleated cells (MN-BN/1000 BN) was 188.3 ± 20.20 and 148 ± 20.42 for ethionamide and levofloxacin nanoparticles as compared to 232.6 ± 16.04 (p = 0.52) and 175 ± 5.56 (p = 0.45) for free ethionamide and levofloxacin, respectively. The average number of SCE per cell for nanoformulation of ethionamide were not different from that of free drug (4.9 ± 0.51 vs 4.1 ± 0.55, p = 0.86). The SCE per cells were not significant difference for nanoformulation of levofloxacin (2.33 ± 1.36 vs 5.46 ± 0.25, p = 0.88). In vitro and in vivo assays have shown relatively less clastogenic potential of equivalent dose of ethionamide nanoparticles as compared to the conventional formulation.
Assuntos
Antituberculosos/toxicidade , Células Cultivadas/efeitos dos fármacos , Etionamida/toxicidade , Levofloxacino/toxicidade , Mutagênese/efeitos dos fármacos , Nanopartículas/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Animais , Camundongos , Testes para Micronúcleos , Modelos AnimaisRESUMO
Administration of drugs via the buccal route has attracted much attention in recent years. However, developing systems with satisfactory adhesion under wet conditions and adequate drug bioavailability still remains a challenge. Here, we propose a mussel-inspired mucoadhesive film. Ex vivo models show that this film can achieve strong adhesion to wet buccal tissues (up to 38.72 ± 10.94 kPa). We also demonstrate that the adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Additionally, the film with incorporated polydopamine nanoparticles shows superior advantages for transport across the mucosal barrier, with improved drug bioavailability (~3.5-fold greater than observed with oral delivery) and therapeutic efficacy in oral mucositis models (~6.0-fold improvement in wound closure at day 5 compared with that observed with no treatment). We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.
Assuntos
Biomimética , Bivalves/química , Sistemas de Liberação de Medicamentos , Mucosa Bucal/fisiologia , Adesividade , Administração Bucal , Animais , Linhagem Celular , Dexametasona/farmacologia , Di-Hidroxifenilalanina/química , Liberação Controlada de Fármacos , Humanos , Indóis/toxicidade , Masculino , Mucinas/química , Muco/química , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Polímeros/toxicidade , Álcool de Polivinil/química , Álcool de Polivinil/toxicidade , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta , Suínos , Distribuição TecidualRESUMO
Although nitric oxide (NO) has been emerging as a novel local anticancer agent because of its potent cytotoxic effects and lack of off-target side effects, its clinical applications remain a challenge because of the short effective diffusion distance of NO that limits its anticancer activity. In this study, we synthesized albumin-coated poly(lactic-co-glycolic acid) (PLGA)-conjugated linear polyethylenimine diazeniumdiolate (LP/NO) nanoparticles (Alb-PLP/NO NPs) that possess tumor-penetrating and NO-releasing properties for an effective local treatment of melanoma. Sufficient NO-loading and prolonged NO-releasing characteristics of Alb-PLP/NO NPs were acquired through PLGA-conjugated LP/NO copolymer (PLP/NO) synthesis, followed by nanoparticle fabrication. In addition, tumor penetration ability was rendered by the electrostatic adsorption of the albumin on the surface of the nanoparticles. The Alb-PLP/NO NPs showed enhanced intracellular NO delivery efficiency and cytotoxicity to B16F10 murine melanoma cells. In B16F10-tumor-bearing mice, the Alb-PLP/NO NPs showed improved extracellular matrix penetration and spatial distribution in the tumor tissue after intratumoral injection, resulting in enhanced antitumor activity. Taken together, the results suggest that Alb-PLP/NO NPs represent a promising new modality for the local treatment of melanoma.
Assuntos
Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Nanopartículas/uso terapêutico , Doadores de Óxido Nítrico/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Compostos Azo/síntese química , Compostos Azo/uso terapêutico , Compostos Azo/toxicidade , Bovinos , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Melanoma/patologia , Camundongos Endogâmicos C57BL , Nanopartículas/química , Nanopartículas/toxicidade , Óxido Nítrico/metabolismo , Doadores de Óxido Nítrico/síntese química , Doadores de Óxido Nítrico/toxicidade , Polietilenoimina/análogos & derivados , Polietilenoimina/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/síntese química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Soroalbumina Bovina/química , Soroalbumina Bovina/toxicidadeRESUMO
Polymeric nanoparticles (NPs) are produced using bio-compatible and bio-degradable materials such as PLGA (Poly(lactic-co-glycolic acid)). This technology provides a valuable tool to deliver molecules to the subcellular level with a relatively low risk of cytotoxicity. However their use in the field of reproductive biotechnology is not yet scientifically substantiated. The aim of the present study was to test if PLGA NPs can be taken-up by cumulus-enclosed oocytes as a first step towards potential oocyte-targeted applications to enhance oocyte quality and fertility. We conducted a series of experiments using bovine in vitro oocyte maturation as a model to study FITC-conjugated PLGA internalization (using laser-scanning confocal microscopy) and the effect of some important physical (particle size) and chemical (conjugation with PEG) modifications. We show evidence that PLGA NPs can be taken-up by cumulus cells and to a less extent by the enclosed oocytes regardless of the NP size. The NP transfer to the oocyte appear to be transcellular (via cumulus cells and transzonal projections) and paracellular (via zona pellucida). The PLGA NPs were detected in the vicinity of the oocyte as quick as 2 h post-exposure in a protein-free medium and did not compromise cumulus cell viability nor subsequent early embryo development or embryo quality. These results suggest that PLGA NPs may have promising applications as carriers for drug or molecule delivery targeting cumulus cells and oocytes.
Assuntos
Portadores de Fármacos/farmacocinética , Técnicas de Maturação in Vitro de Oócitos/métodos , Nanopartículas/toxicidade , Oócitos/crescimento & desenvolvimento , Oogênese/efeitos dos fármacos , Animais , Bovinos , Sobrevivência Celular/efeitos dos fármacos , Células do Cúmulo/efeitos dos fármacos , Portadores de Fármacos/química , Portadores de Fármacos/toxicidade , Técnicas de Cultura Embrionária/métodos , Embrião de Mamíferos , Feminino , Microscopia Intravital , Masculino , Microscopia Confocal , Nanopartículas/química , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/farmacocinética , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Espermatozoides/fisiologia , Testes de Toxicidade AgudaRESUMO
Cardiovascular diseases (CVD) are the leading cause of death worldwide. Growth factor therapy has emerged as novel therapeutic strategy under investigation for CVD. In this sense, adrenomedullin-2 (ADM-2) has been recently identified as a new angiogenic factor able to regulate the regional blood flow and cardiovascular function. However, the therapeutic value of ADM-2 is limited by its short biological half-life and low plasma stability. Poly (lactic-co-glycolic acid) (PLGA) micro- and nanoparticles have been investigated as growth factor delivery systems for cardiac repair. In this study, we aimed to develop PLGA nanoparticles containing ADM-2 intended for therapeutic angiogenesis. PLGA nanoparticles containing ADM-2 were prepared by a double emulsion modified method, resulting in 300 nm-sized stable particles with zeta potential around - 30 mV. Electron microscopy analysis by SEM and TEM revealed spherical particles with a smooth surface. High encapsulation efficiency was reached (ca.70%), as quantified by ELISA. ADM-2 associated to polymer nanoparticles was also determined by EDS elemental composition analysis, SDS-PAGE and LC-MS/MS for peptide identification. In vitro release assays showed the sustained release of ADM-2 from polymer nanoparticles for 21 days. Cell viability experiments were performed in J774 macrophages and H9c2 cardiomyocyte cells, about which PLGA nanoparticles loaded with ADM-2 did not cause toxicity in the range 0.01-1 mg/ml. Of note, encapsulated ADM-2 significantly induced cell proliferation in EA.hy926 endothelial cells, indicating the ADM-2 bioactivity was preserved after the encapsulation process. Collectively, these results demonstrate the feasibility of using PLGA nanoparticles as delivery systems for the angiogenic peptide ADM-2, which could represent a novel approach for therapeutic angiogenesis in CVD using growth factor therapy.
Assuntos
Indutores da Angiogênese/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos , Células Endoteliais/efeitos dos fármacos , Hormônios Peptídicos/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Indutores da Angiogênese/química , Indutores da Angiogênese/toxicidade , Animais , Linhagem Celular , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Cinética , Camundongos , Nanopartículas , Hormônios Peptídicos/química , Hormônios Peptídicos/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Ratos , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , SolubilidadeRESUMO
Gadolinium as a contrast agent in MRI technique combined with DTPA causes contrast induced nephropathy (CIN) and nephrogenic systemic fibrosis (NSF) which can reduce by usage of antioxidants such as N-acetyl cysteine by increasing the membrane's permeability leads to lower cytotoxicity. In this study, N-acetyl cysteine-PLGA Nano-conjugate was synthesized according to stoichiometric rules of molar ratios andafter assessment by FTIR, NMR spectroscopy and Atomic Force Microscopy (AFM) imaging was combined with Magnevist® (gadopentetate dimeglumine) and its effects on the renal cells were evaluated. MTT [3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide] and cellular uptake assays have indicated relatively significant toxicity of magnevist (P < 0.05) on three cell lines including HEK293, MCF7 and L929 compared to other synthesized ligands that shown no toxicity. Moreover, systemic evaluation has shown no notable changes of blood urea nitrogen (BUN) and creatinine in kidney of mice. In consequence, antioxidant effect was increased as well as the renal toxicity of the contrast agent reduced at the cell level. As a result, PLGA-NAC nano-conjugate can be a promising choice for decreasing the magnevist toxicity for treatment and prevention of CIN and will be able to open a new horizon to research on reduction of toxicity of contrast agents by using nanoparticles.
Assuntos
Acetilcisteína , Gadolínio DTPA , Nanoconjugados , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Acetilcisteína/química , Acetilcisteína/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Meios de Contraste/química , Meios de Contraste/farmacocinética , Sistemas de Liberação de Medicamentos , Gadolínio DTPA/química , Gadolínio DTPA/farmacocinética , Células HEK293 , Humanos , Rim/citologia , Rim/metabolismo , Células MCF-7 , Camundongos , Nanoconjugados/química , Nanoconjugados/toxicidade , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidadeRESUMO
Infection and resulting bone defects caused by Staphylococcus aureus is one of the major issues in orthopaedic surgeries. Vancomycin hydrochloride (VaH) is largely used to manage these events. Here, a human derived bone paste supplemented with biopolymer microcarriers for VaH sustained delivery to merge osteoinductive and antimicrobial actions is described. In detail, different emulsion formulations were tested to fabricate micro-carriers of poly-lactic-co-glycolic acid (PLGA) and hydroxyapatite (HA) by a proprietary technology (named Supercritical Emulsion Extraction). These carriers (mean size 827 ± 68 µm; loading 47 mgVaH/gPLGA) were assembled with human demineralized bone matrix (DBM) to obtain an antimicrobial bone paste system (250 mg/0.5 cm3 w/v, carrier/DBM). Release profiles in PBS indicated a daily drug average release of about 4 µg/mL over two weeks. This concentration was close to the minimum inhibitory concentration and able to effectively inhibit the S. aureus growth in our experimental sets. Carriers cytotoxicity tests showed absence of adverse effects on cell viability at the concentrations used for paste assembly. This approach points toward the potential of the DBM-carrier-antibiotic system in hampering the bacterial growth with accurately controlled antibiotic release and opens perspectives on functional bone paste with PLGA carriers for the controlled release of bioactive molecules.
Assuntos
Antibacterianos/farmacologia , Materiais Biomiméticos , Matriz Óssea/química , Portadores de Fármacos , Durapatita/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Staphylococcus aureus/efeitos dos fármacos , Vancomicina/farmacologia , Antibacterianos/química , Antibacterianos/toxicidade , Técnica de Desmineralização Óssea , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Preparações de Ação Retardada , Composição de Medicamentos , Liberação Controlada de Fármacos , Durapatita/toxicidade , Humanos , Cinética , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Staphylococcus aureus/crescimento & desenvolvimento , Vancomicina/química , Vancomicina/toxicidadeRESUMO
AIM: The aim of this study was to assess the local and systemic response to poly-lactic co-glycolic acid (PLGA) 50:50 membranes, developed as synthetic biodegradable alternatives to the use of human donor amniotic membrane in the treatment of limbal stem cell deficiency. METHODS: PLGA membranes of 2 cm diameter and 50 µm thickness were placed on one eye of rabbits and secured in place using fibrin glue and a bandage contact lens, suturing the eye close with a single stitch. Control animals were treated identically, with the absence of the membranes. Plain and microfabricated electrospun membranes (containing micropockets which roughly emulate the native limbal niche) were examined over 29 days. All animals were subjected to a detailed gross and histopathological observation as well as a detailed examination of the eye. RESULTS: Application of the membranes both with and without microfabricated pockets did not adversely affect animal welfare. There was complete degradation of the membranes by day 29. The membranes did not induce any significant local or systemic toxicity. Conjunctival congestion and corneal vascularisation were noted in a few control and PLGA-treated animals. Intraocular pressure was normal and the retinal status was unaltered. The ocular surface was clear and intact in all animals by the end of 29 days. CONCLUSION: Membranes of 50:50 PLGA can be safely applied to rabbit corneas without inducing any local or systemic toxicity and these break down completely within 29 days.
Assuntos
Implantes Absorvíveis , Âmnio/transplante , Materiais Biocompatíveis/uso terapêutico , Córnea/fisiologia , Doenças da Córnea/cirurgia , Regeneração Tecidual Guiada , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/uso terapêutico , Animais , Materiais Biocompatíveis/toxicidade , Feminino , Masculino , Membranas Artificiais , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , CoelhosRESUMO
Aim: The manuscript describes the performance of nanoparticles loaded with antidepressant drug for nose-to-brain drug delivery. Materials & methods: Poly-lactic-co-glycolic acid-loaded nanoparticles of agomelatine were prepared by nanoprecipitation method using poloxamer 407 as stabilizer. The process parameters were optimized using factorial design. Results: The drug-loaded nanoparticles having low particle size (<200 nm) with narrow size distribution and required zeta potential (-22.7 mV) to avoid aggregation showed sustained release profile and were found to have higher permeability as observed from ex vivo studies when compared with plain drug suspension. Histopathology test showed that the optimized formulation was free from nasal toxicity on the goat nasal mucosa. Pharmacodynamic study showed significant reduction in immobility time in rats treated with the formulation which indicated antidepressant activity of the formulation. Conclusion: The prepared agomelatin-loaded poly-lactic-co-glycolic acid nanoparticles showed prominent antidepressant activity by nose-to-brain delivery as observed from various studies.
Assuntos
Acetamidas/administração & dosagem , Antidepressivos/administração & dosagem , Depressão/tratamento farmacológico , Portadores de Fármacos/química , Nanopartículas/química , Acetamidas/farmacocinética , Acetamidas/toxicidade , Administração Intranasal , Animais , Antidepressivos/farmacocinética , Antidepressivos/toxicidade , Técnicas de Observação do Comportamento , Comportamento Animal/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Depressão/diagnóstico , Depressão/etiologia , Modelos Animais de Doenças , Portadores de Fármacos/toxicidade , Composição de Medicamentos/métodos , Cabras , Humanos , Nanopartículas/toxicidade , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Ratos , Testes de ToxicidadeRESUMO
Modified nanoparticles (NPs) can interact with the immune system by causing its activation to fight tumors or for vaccination. During this activation, dendritic cells (DCs) are effective in generating robust immune response. However, the effect of nanomaterials on dendritic cell (DC) maturation, and the associated adjuvant effect, should be assessed as a novel biocompatibility criteria for biomaterials since immune consequences may constitute potential complications in nanomedicine. Among emerging biomaterials, poly(lactic-co-glycolic acid) NPs (PLGA NPs) are widely explored for various applications in which the degree of desired adjuvant effect may vary. As contradictory results are reported regarding their effects on DCs, we aimed at clarifying this point with particular emphasis on the relative impact of particle surface properties. To that end, NP uptake and effects on the viability, phenotype, and secretory activity of DC primary cultures. Intracellular signaling pathways were explored and evaluated. Immature human and murine DCs were exposed to cationic, neutral, or anionic PLGA NPs. Particle uptake was assessed by both confocal microscopy and flow cytometry. Cell viability was then evaluated prior to the study of maturation by examination of both surface marker expression and cytokine release. Our results demonstrate that PLGA NPs are rapidly engulfed by DCs and do not exert cytotoxic effects. However, upon exposure to PLGA NPs, DCs showed phenotypes and cytokine secretion profiles consistent with maturation which resulted, at least in part, from the transient intracellular activation of mitogen-activated protein kinases (MAPKs). Interestingly, NP-specific stimulation patterns were observed since NP surface properties had a sensible influence on the various parameters measured.
Assuntos
Materiais Biocompatíveis/toxicidade , Células Dendríticas/efeitos dos fármacos , Nanopartículas/toxicidade , Fagocitose/efeitos dos fármacos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Animais , Materiais Biocompatíveis/química , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/imunologia , Técnicas de Cocultura , Citocinas/metabolismo , Células Dendríticas/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Nanopartículas/química , Fagocitose/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Propriedades de SuperfícieRESUMO
Nano-sized particles (NPs) of various materials have been extensively used as therapeutic and diagnostic agents, drug delivery systems, and biomedical devices. However, the biological impacts of NP exposure during early embryogenesis on following development and next generations have not been investigated. Here, we demonstrated that polylactic-co-glycolic acid (PLGA)-NPs were not toxic and did not perturb development of preimplantation mouse embryos in vitro. Moreover, subsequent fetal development in vivo after embryo transfer proceeded normally and healthy pups were born without any genetic aberrations, suggesting biosafety of PLGA-NPs during developmental processes. TRITC-labeled PLGA-NPs, named TRITC nano-tracer (TnT) were used to visualize the successful delivery of the NPs into sperms, oocytes and early embryos. Various molecular markers for early embryogenesis demonstrated that TnT treatment at various developmental stages did not compromise embryo development to the blastocyst. mRNA-Seq analyses reinforced that TnT treatment did not significantly affect mRNA landscapes of blastocysts which undergo embryo implantation critical for following developmental processes. Moreover, when 2-cell embryos exposed to TnT were transferred into pseudopregnant recipients, healthy offspring were born without any distinct morphologic and chromosomal abnormalities. TnT treatment did not affect the sex ratio of the exposed embryos after birth. When mated with male mice, female mice that were exposed to TnT during early embryogenesis produced a comparable number of pups as control females. Furthermore, the phenotypes of the offspring of mice experienced TnT at their early life clearly demonstrated that TnT did not elicit any negative transgenerational effects on mammalian development.