RESUMO
Vaccine technology is still facing challenges regarding some infectious diseases, which can be addressed by innovative drug delivery systems. In particular, nanoparticle-based vaccines combined with new types of adjuvants are actively explored as a platform for improving the efficacy and durability of immune protection. Here, biodegradable nanoparticles carrying an antigenic model of HIV were formulated with two combinations of poloxamers, 188/407, presenting or not presenting gelling properties, respectively. The study aimed to determine the influence of poloxamers (as a thermosensitive hydrogel or a liquid solution) on the adaptive immune response in mice. The results showed that poloxamer-based formulations were physically stable and did not induce any toxicity using a mouse dendritic cell line. Then, whole-body biodistribution studies using a fluorescent formulation highlighted that the presence of poloxamers influenced positively the dissemination profile by dragging nanoparticles through the lymphatic system until the draining and distant lymph nodes. The strong induction of specific IgG and germinal centers in distant lymph nodes in presence of poloxamers suggested that such adjuvants are promising components in vaccine development.
Assuntos
Poloxâmero , Vacinas , Poloxâmero/metabolismo , Adjuvantes de Vacinas , Distribuição Tecidual , Antígenos , Linfonodos/metabolismo , Adjuvantes Imunológicos/química , Células DendríticasRESUMO
Osteoarthritis (OA) is a degenerative joint disorder associated with inflammation, functional disability, and high socioeconomic costs. The development of effective therapies against inflammatory OA has been limited owing to its complex and multifactorial nature. The efficacy of Prussian blue nanozymes coated with Pluronic (PPBzymes), US Food and Drug Administration-approved components, and their mechanisms of action have been described in this study, and PPBzymes have been characterized as a new OA therapeutic. Spherical PPBzymes were developed via nucleation and stabilization of Prussian blue inside Pluronic micelles. A uniformly distributed diameter of approximately 204 nm was obtained, which was maintained after storage in an aqueous solution and biological buffer. This indicates that PPBzymes are stable and could have biomedical applications. In vitro data revealed that PPBzymes promote cartilage generation and reduce cartilage degradation. Moreover, intra-articular injections with PPBzymes into mouse joints revealed their long-term stability and effective uptake into the cartilage matrix. Furthermore, intra-articular PPBzymes injections attenuated cartilage degradation without exhibiting cytotoxicity toward the synovial membrane, lungs, and liver. Notably, based on proteome microarray data, PPBzymes specifically block the JNK phosphorylation, which modulates inflammatory OA pathogenesis. These findings indicate that PPBzymes might represent a biocompatible and effective nanotherapeutic for obstructing JNK phosphorylation.
Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Fosforilação , Poloxâmero/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/uso terapêutico , Osteoartrite/patologia , Cartilagem Articular/metabolismo , Injeções Intra-ArticularesRESUMO
Drug absorption is improved by the intranasal route's wide surface area and avoidance of first-pass metabolism. For the treatment of central nervous system diseases such as migraine, intranasal administration delivers the medication to the brain. The study's purpose was to develop an in situ nasal hydrogel that contained liposomes that were loaded with sumatriptan succinate (SS). A thin-film hydration approach was used to create liposomes, and a 32 factorial design was used to optimize them. The optimized liposomes had a spherical shape, a 171.31 nm particle size, a high drug encapsulation efficiency of 83.54%, and an 8-h drug release of 86.11%. To achieve in situ gel formation, SS-loaded liposomes were added to the liquid gelling system of poloxamer-407, poloxamer-188, and sodium alginate. The final product was tested for mucoadhesive strength, viscosity, drug content, gelation temperature, and gelation time. Following intranasal delivery, in vivo pharmacokinetic investigations showed a significant therapeutic concentration of the medication in the brain with a Cmax value of 167 ± 78 ng/mL and an area under the curve value of 502 ± 63 ng/min·mL. For SS-loaded liposomal thermosensitive nasal hydrogel, significantly higher values of the nose-to-brain targeting parameters, that is, drug targeting index (2.61) and nose-to-brain drug direct transport (57.01%), confirmed drug targeting to the brain through the nasal route. Liposomes containing thermosensitive in situ hydrogel demonstrated potential for intranasal administration of SS.
Assuntos
Lipossomos , Sumatriptana , Sumatriptana/farmacocinética , Hidrogéis/metabolismo , Poloxâmero/metabolismo , Encéfalo/metabolismoRESUMO
The mechanism of action of excipients eliciting sex differences in drug bioavailability is poorly understood. In this study, the excipients Cremophor RH 40 (PEG 40 hydrogenated castor oil), Poloxamer 188 (2-methyloxirane) and Tween 80 (polyoxyethylene (80) sorbitan monooleate) were screened at 0.07 - 5% concentrations for their effect on ranitidine bioavailability in male and female Wistar rats. We show that all excipient concentrations significantly increased ranitidine bioavailability in male, but not female, rats. The effect of these excipients on the intestinal efflux transporters P-glycoprotein (P-gp), breast cancer resistant protein (BCRP) and multi-drug resistant protein 2 (MRP2) were also monitored. Measured by ELISA assay, in male rats, peak reductions in intestinal P-gp protein expression occurred in the presence of 1% Cremophor RH 40 and Poloxamer 188 and 0.5% Tween 80. In contrast, no distinct changes were observed in female intestinal P-gp expression. Unlike P-gp, all excipients had a positive effect on MRP2 protein expression - albeit only in males - in a concentration-dependent manner. The excipients did not modulate intestinal BCRP protein expression in either sex. Endogenous hormones and a nuclear receptor (testosterone, oestradiol and pregnane X receptor; PXR) that are purported to regulate intestinal efflux membrane transporter expression were also quantified. In the presence of all excipients, testosterone levels significantly elevated in males, although PXR levels reduced at similar rates in both sexes. No significant effects were identified in oestradiol levels in male and female rats. It is clear that excipients are not inert and their pathway for modulating drug response is multi-dimensional and specific between sexes. This study showed that excipients increased drug bioavailability of a P-gp drug substrate due to its reductive effect on intestinal P-gp expression; we propose that this link may be due to the excipients modulating fundamental testosterone levels. Understanding the implication of excipients on intestinal physiology and hormone levels can therefore improve pharmaceutical design, clinical efficacy and instigate next generation personalised, sex-specific formulations.
Assuntos
Excipientes , Polissorbatos , Masculino , Feminino , Ratos , Animais , Excipientes/farmacologia , Disponibilidade Biológica , Polissorbatos/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ranitidina , Poloxâmero/metabolismo , Ratos Wistar , Proteínas de Neoplasias/metabolismo , Estradiol , TestosteronaRESUMO
Ocular health may strongly benefit from the supply of antioxidant agents that counteract free radicals and reactive oxygen species responsible for long-term eye diseases. Additionally, natural antioxidants like resveratrol can inhibit bacteria growth and restore natural microbiota. However, their use is hindered by limited solubility, fast degradation, and low ocular permeability. This work aimed to overcome these limitations by preparing single and mixed micelles of Pluronic® F127 and casein that serve as resveratrol nanocarriers. Single and mixed (0.1 % casein) micelles (0.0 to -17.0 mV; 2.4 to 32.7 nm) increased 50-fold resveratrol solubility, remained stable for one month at 4 °C, withstood fast dilution, underwent sol-to-gel transitions in the 23.9-27.1 °C range, and exhibited potent antioxidant properties. All formulations successfully passed the HET-CAM assay but showed Pluronic®-casein dose-dependent toxicity in the zebrafish embryo model. Resveratrol-loaded single and mixed micelles (10-15 mM Pluronic® F127) displayed antimicrobial activity against S. aureus and P. aeruginosa. The micelles favored resveratrol accumulation in cornea and sclera, but mixed micelles showed larger lag times and provided lower amount of resveratrol permeated through sclera. In vivo (rabbit) tests confirmed the safety of resveratrol-loaded single micelles and their capability to supply resveratrol to anterior and posterior eye segments.
Assuntos
Micelas , Poloxâmero , Animais , Coelhos , Poloxâmero/metabolismo , Resveratrol , Caseínas/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Staphylococcus aureus , Peixe-Zebra , Córnea/metabolismo , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/metabolismoRESUMO
Polymeric nanocarriers (NCs) are efficient vehicles to prevent drug unspecific biodistribution and increase the drug amounts delivered to tumor tissues. However, some toxicological aspects of NCs still lack a comprehensive assessment, such as their effects on cellular processes that lead to toxicity. We evaluate the interaction of poly(lactic-co-glycolic acid) (PLGA) NCs prepared using dextran (Dex) and Pluronic®-F127 as stabilizing agents with myocardial cells (H9C2), breast adenocarcinoma cells (MCF-7) and macrophages (RAW 264.7) to address the effect of Dex in PLGA NC formulations. By an emulsion diffusion method, doxorubicin-loaded NCs were prepared with no Dex (PLGA-DOX), 1% (w/v) Dex (Dex1/PLGA-DOX) and 5% (w/v) Dex (Dex5/PLGA-DOX). Uptake analyses revealed a significant reduction in Dex5/PLGA-DOX NC uptake by H9C2 and MCF-7, as in the case of Dex1/PLGA-DOX NCs in the absence of in vitro protein corona, revealing an effect of dextran concentration on the formation of protein corona. RAW 264.7 cells presented a greater uptake of Dex5/PLGA-DOX NCs than the other NCs likely because of receptor mediated endocytosis, since C-type lectins like SIGN-R1, mannose receptors and scavenger receptor type 1 that are expressed in RAW 264.7 can mediate Dex uptake. Despite the lower uptake, Dex5/PLGA-DOX NCs promote the generation of reactive oxygen species and oxidative membrane damage in MCF-7 and H9C2 even though cellular metabolic activity assessed by MTT was comparable among all the NCs. Our results highlight the importance of an in-depth investigation of the NC-cell interaction considering additional mechanisms of damage apart from metabolic variations, as nanoparticle-induced damage is not limited to imbalance in metabolic processes, but also associated with other mechanisms, e.g., membrane and DNA damage.
Assuntos
Antineoplásicos , Coroa de Proteína , Humanos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Dextranos , Portadores de Fármacos/metabolismo , Antineoplásicos/farmacologia , Distribuição Tecidual , Poloxâmero/metabolismo , Emulsões/metabolismo , Excipientes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Doxorrubicina/farmacologia , Doxorrubicina/metabolismo , Membrana Celular/metabolismo , Lectinas Tipo C/metabolismoRESUMO
Antibiotic combinations remain the frontline therapy for severe infections to reduce mortality. However, conventional antibiotic combinations have some limitations such as the low bioavailability and the rise of resistant strains. Nanoparticles are increasingly used as antibiotic delivery systems to promote bioavailability and hence improve efficacy of antibiotics. In this work, we hypothesize that the simultaneous delivery of two antibiotic-loaded nanoparticles will improve the intracellular bioavailability and thus inhibit emergence of resistance. Accordingly, Chitosan-pluronic nanoparticles were used to construct nanosized ciprofloxacin and meropenem and the antibacterial activity of nanosized combined antibiotics were compared versus unloaded single, unloaded combined, and nanosized single antibiotics. Thirty-six stepwise mutants were selected by exposing two E. coli strains to increasing concentrations of free-unloaded and nanosized antibiotics, and mutants were tested for antimicrobial susceptibilities using broth microdilution and disc diffusion methods. The change in expression levels of acrB efflux pump and porins (ompC and ompF) was assessed by real-time reverse transcription-PCR. The in vitro evaluation of combined ciprofloxacin and meropenem-loaded nanoparticles demonstrated that this nanosystem exhibited enhanced antibacterial effect. Step mutants selected with nanosized combined antibiotics showed higher sensitivity to both drugs, exhibited lower mutation frequencies, and less cross-resistance to other antimicrobial classes. Moreover, for all steps of selection, nanosized combined antibiotic mutants expressed significantly lower levels of acrB as well as higher levels of ompC and ompF (p-value <0.01). In view of these results, the use of nanosized combined antibiotics may be considered among the new promising strategies to combat infections through their potential efficacy in reducing microorganisms' ability to form resistant mutants.
Assuntos
Anti-Infecciosos , Quitosana , Infecções por Escherichia coli , Proteínas de Escherichia coli , Humanos , Escherichia coli , Antibacterianos/farmacologia , Testes de Sensibilidade Microbiana , Meropeném/farmacologia , Quitosana/farmacologia , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Infecções por Escherichia coli/tratamento farmacológico , Porinas/metabolismo , Ciprofloxacina/farmacologia , Anti-Infecciosos/farmacologia , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismoRESUMO
Owing to the similarity of hydrogels to cartilage extracellular matrix, they have been extensively utilized in the chondral lesions. Moreover, their tunable administration properties are desirable for reducing injuries in lesion sites. Generally, injectable hydrogels are mechanically weak, requiring some modifications for being used as a cell carrier in place of articular cartilage. In this study, a combination ofß-cyclodextrin-grafted alginate (Alg-ß-CD) and pluronic-amine with multiple physical crosslinking was used for the first time. Supramolecular interactions, including electrostatic forces, host-guest interaction, and hydrophobic interaction with increasing temperature maintain injectability of hydrogels while these interactions boost mechanical properties to the extent that shear modulus surpassed 40 kPa. Vacantß-CD cavities in conjunction with gel network were exploited for kartogenin (KGN) loading. All groups had gel time of less than one minute and gel temperature was 28 °C. No toxic effect of hydrogels on encapsulated cells was observed. While the optimum combination of polymers provided a sustainable release for KGN, it also extended thein vitrodegradation time of hydrogels from six days to two weeks. KGN facilitated encapsulated mesenchymal stem cells differentiation towards chondrocytes. Taken together, the synthesized hydrogel proved to be a promising candidate for being utilized in cartilage regeneration.
Assuntos
Cartilagem Articular , Ciclodextrinas , Células-Tronco Mesenquimais , Alginatos , Aminas , Anilidas , Ciclodextrinas/metabolismo , Ciclodextrinas/farmacologia , Hidrogéis/química , Ácidos Ftálicos , Poloxâmero/metabolismo , Poloxâmero/farmacologiaRESUMO
BACKGROUND: Large area skin trauma has always been a great challenge for both patients and clinicians. Exosomes originating from human adipose-derived mesenchymal stem cells (hADSCs) have been a novel promising cell-free treatment in cutaneous damage repair. Nevertheless, the low retention rate of exosomes post-transplantation in vivo remains a significant challenge in clinical applications. Herein, we purposed to explore the potential clinical application roles of hADSCs-Exos encapsulated in functional PF-127 hydrogel in wound healing. METHODS: hADSCs-Exos were isolated from human hADSCs by ultracentrifugation. An injectable, biocompatible, and thermo-sensitive hydrogel Pluronic F-127 hydrogel was employed to encapsulate allogeneic hADSCs-Exos, and this complex was topically applied to a full-thickness cutaneous wound in mice. On different days post-transplantation, the mice were sacrificed, and the skin tissue was excised for histological and immunohistochemical analysis. RESULTS: Compared with hADSCs-Exos or PF-127 only, PF-127/hADSCs-Exos complexes enhanced skin wound healing, promoted re-epithelialization, increased expression of Ki67, α-SMA, and CD31, facilitated collagen synthesis (Collagen I, Collagen III), up-regulated expression of skin barrier proteins (KRT1, AQP3), and reduced inflammation (IL-6, TNF-α, CD68, CD206). By using PF-127/hADSCs-Exos complexes, hADSCs-Exos can be administrated at lower doses frequency while maintaining the same therapeutic effects. CONCLUSION: Administration of hADSCs-Exos in PF-127 improves the efficiency of exosome delivery, maintains the bioactivity of hADSCs-Exos, and optimizes the performance of hADSCs-Exos. Thus, this biomaterial-based exosome will be a promising treatment approach for the cutaneous rejuvenation of skin wounds.
Assuntos
Exossomos , Células-Tronco Mesenquimais , Animais , Colágeno/metabolismo , Exossomos/metabolismo , Humanos , Hidrogéis/farmacologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Poloxâmero/metabolismo , Poloxâmero/farmacologia , CicatrizaçãoRESUMO
The oxidative stress and activation of the fibrosis pathway are essential pathological mechanisms of acute kidney injury (AKI). In this article, we designed a drug delivery system that could effectively improve oxidative stress and relieve fibrosis by the combination of precise targeting, solubilization, and reducing the toxicity of nano-transport system to strengthen the efficacy of AKI. Folic acid (FA) was used as the targeting molecule, and curcumin (Cur) and resveratrol (Res), which are Chinese medicine monomers with anti-inflammatory and antioxidant effects, were used as model drugs. Here, the targeting nanosystem (Cur/Res@FA-F127/TPGS) co-loaded with Cur and Res was successfully synthesized. Finally, the comprehensive therapeutic effect of the nanosystem was evaluated through the targeted and pharmacodynamic researches on the AKI models induced by cisplatin (CDDP) in vitro and in vivo. The studies in vitro proved that the nanosystem could not only specifically target HK-2 cells and promote the effective accumulation of Cur and Res in the kidney, but also effectively improve oxidative stress by eliminating reactive oxygen species (ROS), stabilizing mitochondrial membrane potential (MMP), and reducing the expression of apoptosis-related proteins. The studies in vivo showed that the nanosystem could effectively play the role of anti-oxidation, anti-inflammatory and alleviate fibrosis to reduce the apoptosis and necrosis of renal tubular cells. The nanosystem could coordinately repair damaged HK-2 cells by improving oxidative stress, inhibiting inflammation and tissue fibrosis, which provided a new idea for the treatment of AKI.
Assuntos
Injúria Renal Aguda , Curcumina , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/metabolismo , Apoptose , Cisplatino/farmacologia , Curcumina/farmacologia , Curcumina/uso terapêutico , Fibrose , Ácido Fólico/farmacologia , Humanos , Micelas , Estresse Oxidativo , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Poloxâmero/uso terapêutico , Resveratrol/farmacologiaRESUMO
Treatment for CNS related diseases are limited by the difficulty of the drugs to cross the blood-brain barrier (BBB). The functionalization of polymeric nanoparticles (NPs) coated with the surfactants polysorbate 80 (PS80) and poloxamer 188 (P188), have shown promising results as drugs carriers are able to cross the BBB on animal models. In this study, poly(lactide-co-glycolide) (PLGA) NPs coated with PS80 and P188, labelled with a fluorescent dye were tested on human pre-clinical in vitro model to evaluate and compare their uptake profiles, mechanisms of transport and crossing over human brain-like endothelial cells (BLECs) mimicking the human BBB. In addition, these NPs were produced using a method facilitating their reproducible production at high scale, the MicroJet reactor® technology. Results showed that both formulations were biocompatible and able to be internalized within the BLECs in different uptake profiles depending on their coating: P188 NP showed higher internalization capacity than PS80 NP. Both NPs uptakes were ATP-dependent, following more than one endocytosis pathway with colocalization in the early endosomes, ending with a NPs release in the brain compartment. Thus, both surfactant-coated PLGA NPs are interesting formulations for delivery to the brain through the BBB, presenting different uptake profiles.
Assuntos
Nanopartículas , Surfactantes Pulmonares , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Portadores de Fármacos/metabolismo , Células Endoteliais/metabolismo , Excipientes/metabolismo , Humanos , Poloxâmero/metabolismo , Polissorbatos , Surfactantes Pulmonares/metabolismo , Tensoativos/metabolismoRESUMO
BACKGROUND: Alzheimer's disease (AD) is initiated by aberrant accumulation of amyloid beta (Aß) protein in the brain parenchyma. The microenvironment surrounding amyloid plaques is characterized by the swelling of presynaptic terminals (dystrophic neurites) associated with lysosomal dysfunction, microtubule disruption, and impaired axonal transport. Aß-induced plasma membrane damage and calcium influx could be potential mechanisms underlying dystrophic neurite formation. OBJECTIVE: We tested whether promoting membrane integrity by brain administration of a safe FDA approved surfactant molecule poloxamer-188 (P188) could attenuate AD pathology in vivo. METHODS: Three-month-old 5XFAD male mice were administered several concentrations of P188 in the brain for 42 days with mini-osmotic pumps. After 42 days, mice were euthanized and assessed for amyloid pathology, dystrophic neurites, pathogenic microglia activation, tau phosphorylation, and lysosomal / vesicular trafficking markers in the brain. RESULTS: P188 was lethal at the highest concentration of 10mM. Lower concentrations of P188 (1.2, 12, and 120µM) were well tolerated. P188 increased brain Aß burden, potentially through activation of the γ-secretase pathway. Dystrophic neurite pathology was exacerbated in P188 treated mice as indicated by increased LAMP1 accumulation around Aß deposits. Pathogenic microglial activation was increased by P188. Total tau levels were decreased by P188. Lysosomal enzyme cathepsin D and calciumdependent vesicular trafficking regulator synaptotagmin-7 (SYT7) were dysregulated upon P188 administration. CONCLUSION: P188 brain delivery exacerbated amyloid pathology, dystrophic neurites, and pathogenic microglial activation in 5XFAD mice. These effects correlated with lysosomal dysfunction and dysregulation of plasma membrane vesicular trafficking. P188 is not a promising therapeutic strategy against AD pathogenesis.
Assuntos
Doença de Alzheimer , Amiloidose , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/toxicidade , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Proteínas Amiloidogênicas/metabolismo , Amiloidose/metabolismo , Animais , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Placa Amiloide/patologia , Poloxâmero/metabolismo , Poloxâmero/toxicidadeRESUMO
BACKGROUND: Balloon angioplasty, stent implantation, and application of an arterial clamp during surgery can induce artery injury such as elastin breaks and endothelium injury, but there is little research focused on the injury induced by these therapeutic manipulations. We established a simple and reproducible small animal aortic injury model and examined intramural injection as a potential therapeutic method to alleviate injury. MATERIALS AND METHODS: The abdominal aorta of male Sprague Dawley (SD) rats or C57BL/6 J mice was clamped sequentially throughout its length. Transforming growth factor ß1 (TGFß1), SB431542, lipopolysaccharide (LPS), Necrostatin-1 (Nec-1), rapamycin, or MHY1485 contained in Pluronic gel was injected intramurally at day 0 or day 7. Animals were fed with chow containing 0.25% beta-aminopropionitrile (BAPN) to evaluate the influence of BAPN. All samples were harvested and examined by immunohistochemistry and immunofluorescence. RESULTS: The clamped rat aorta showed luminal dilation, elastin fiber breaks, neointimal hyperplasia, and dissection (days 0-90). Intramural injection of TGFß1, rapamycin and Nec-1 showed a protective effect on the injured aorta, whereas SB431542, MHY1485 and LPS showed more severe wall damage. The aortic lumen in rats fed with BAPN was significantly larger than in control rats (day 7). Mouse aorta showed similar injury with neointimal hyperplasia and elastin fiber breaks. CONCLUSIONS: The rodent arterial injury model is reproducible and may mimic early changes of arterial injury. The model accommodates intramural injection of different drugs that may show mechanisms of arterial injury. Although this is a preliminary animal model, the intramural injection method may have potential clinical application in the future.
Assuntos
Aminopropionitrilo , Poloxâmero , Aminopropionitrilo/metabolismo , Animais , Aorta Abdominal/patologia , Modelos Animais de Doenças , Elastina/metabolismo , Hiperplasia/metabolismo , Hiperplasia/patologia , Lipopolissacarídeos/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neointima/metabolismo , Neointima/patologia , Poloxâmero/metabolismo , Ratos , Ratos Sprague-Dawley , Sirolimo/metabolismo , Sirolimo/farmacologiaRESUMO
Previous studies have shown that reconstructive surgery alone following injury to the anterior cruciate ligament (ACL) does not prevent the development of post-traumatic osteoarthritis (PTOA). Poloxamer 188 (P188) has been shown to prevent cell death following trauma in both articular cartilage and meniscal tissue. This study aims to test the efficacy of single or multiple administrations of P188 in conjunction with reconstructive surgery to help prevent or delay the onset of the disease. Thirty skeletally mature rabbits underwent closed-joint trauma that resulted in ACL rupture and meniscal damage and were randomly assigned to one of four treatment groups with varying doses of P188. ACL reconstruction was then performed using an autograft from the semitendinosus tendon. Animals were euthanized 1-month following trauma, meniscal tissue was assessed for changes in morphology, mechanical properties, and proteoglycan content. Femurs and tibias were scanned using microcomputed tomography to determine changes in bone quality, architecture, and osteophyte formation. The medial meniscus experienced more damage and a decrease in the instantaneous modulus regardless of treatment group, while P188 treatment tended to limit degenerative changes in the lateral meniscus. Both lateral and medial menisci had documented decreases in the equilibrium modulus and inconsistent changes in proteoglycan content. Minimal changes were documented in the tibias and femurs, with the only significant change being the formation of osteophytes in both bones regardless of treatment group. The data suggest that P188 was able to limit some degenerative changes in the meniscus associated with PTOA and may warrant future studies.
Assuntos
Lesões do Ligamento Cruzado Anterior , Cartilagem Articular , Traumatismos do Joelho , Osteoartrite , Animais , Lesões do Ligamento Cruzado Anterior/complicações , Lesões do Ligamento Cruzado Anterior/metabolismo , Lesões do Ligamento Cruzado Anterior/cirurgia , Traumatismos do Joelho/complicações , Meniscos Tibiais/metabolismo , Poloxâmero/metabolismo , Proteoglicanas/metabolismo , Coelhos , Microtomografia por Raio-XRESUMO
Brachial plexus avulsion (BPA) is a devastating traumatic peripheral nerve injury complicated with paralysis of the upper extremity. We previously reported that leucine-rich repeat and immunoglobulin-like domain-containing NOGO receptor-interacting protein 1 (LINGO-1) has a potent role in inhibiting neuron survival and axonal regeneration after the central nervous system (CNS) damage and miR-615 is a potential microRNA (miRNA) negatively regulated LINGO-1. However, the effect of miR-615 in BPA remains to be elucidated. Accumulating evidence indicates that pluronic F-127 (PF-127) hydrogel could serve as a promising vehicle for miRNA encapsulation. Thus, to further explore the potential role of hydrogel-miR-615 in BPA-reimplantation, the present study established the BPA rat model and injected miR-615 agomir encapsulated by PF-127 hydrogel into the reimplantation site using a microsyringe. In this study, results indicated that hydrogel-miR-615 agomir effectively alleviated motoneuron loss by LINGO-1 inhibition, promoted musculocutaneous nerve regeneration and myelination, reduced astrocytes activation, promoted angiogenesis and attenuated peripheral amyotrophy, leading to improved motor functional rehabilitation of the upper extremity. In conclusion, our findings demonstrate that miR-615-loaded PF-127 hydrogel may represent a novel therapeutic strategy for BPA treatment.
Assuntos
Plexo Braquial , MicroRNAs , Animais , Plexo Braquial/lesões , MicroRNAs/genética , MicroRNAs/metabolismo , Neurônios Motores/metabolismo , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Poloxâmero/uso terapêutico , Ratos , Recuperação de Função FisiológicaRESUMO
Pluronic polymers (pluronics) are a unique class of synthetic triblock copolymers containing hydrophobic polypropylene oxide (PPO) and hydrophilic polyethylene oxide (PEO) arranged in the PEO-PPO-PEO manner. Due to their excellent biocompatibility and amphiphilic properties, pluronics are an ideal and promising biological material, which is widely used in drug delivery, disease diagnosis, and treatment, among other applications. Through self-assembly or in combination with other materials, pluronics can form nano carriers with different morphologies, representing a kind of multifunctional pharmaceutical excipients. In recent years, the utilization of pluronic-based multi-functional drug carriers in tumor treatment has become widespread, and various responsive drug carriers are designed according to the characteristics of the tumor microenvironment, resulting in major progress in tumor therapy. This review introduces the specific role of pluronic-based polymer drug delivery systems in tumor therapy, focusing on their physical and chemical properties as well as the design aspects of pluronic polymers. Finally, using newer literature reports, this review provides insights into the future potential and challenges posed by different pluronic-based polymer drug delivery systems in tumor therapy.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Propilenoglicóis/química , Propilenoglicóis/farmacologia , Portadores de Fármacos/química , Humanos , Interações Hidrofóbicas e Hidrofílicas , Neoplasias/tratamento farmacológico , Poloxâmero/química , Poloxâmero/metabolismo , Poloxâmero/farmacologia , Polietilenoglicóis/metabolismo , Polímeros/química , Polipropilenos/química , Polipropilenos/farmacologia , Propilenoglicóis/metabolismo , Microambiente Tumoral/efeitos dos fármacosRESUMO
A new indole based chalcone molecule MOMIPP induced methuosis mediated cell death in gliobastoma and other cancer cell lines. But the drug was insoluble in water and had a very short plasma half-life. The purpose of this work was to develop a formulation that can provide sustained levels of MOMIPP in vivo. Initial studies established drug solubility in various solvents. N-methyl pyrrolidone (NMP) was determined as an excellent solvent for the drug. Subsequently a poloxamer-407 based thermoreversible gel containing NMP was used to develop the formulation. Rheological studies were performed via oscillatory temperature mode, continuous shear analysis, and oscillatory frequency mode experiments. The mechanical properties of the formulations were tested using a texture profile analyzer. The gelation temperature and time of formulations increased with increasing amounts of NMP. However, the viscosity at 20 °C and storage modulus decreased as the amount of NMP increased. Characterization studies helped to identify the gel formulation that was used to administer the drug orally, sub-cutaneously, and intra-peritoneally. When the gel was given intraperitoneally the target plasma and brain levels of over 5 µM was maintained for about 8 h. Thus, a thermoreversible gel formulation that can deliver MOMIPP in animal studies was successfully developed.
Assuntos
Antineoplásicos , Hidrogéis , Animais , Encéfalo/metabolismo , Géis , Indóis , Poloxâmero/metabolismo , Piridinas , Reologia , Temperatura , ViscosidadeRESUMO
Background: Glycyrrhizic acid (GL), a pentacyclic triterpenoid glycoside, has been used as a hepatoprotective agent for the treatment of acute and chronic hepatitis. However, its poor solubility and permeability across the gastrointestinal mucosa limit its clinical efficacy. This study aimed to develop mixed micelles based on pluronic F127 and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) to improve the oral bioavailability of GL.Methods: GL loaded pluronic F127/TPGS mixed micelles (GL-F127/TPGS-MMs) were prepared by thin film hydration method, and their physicochemical properties including particle size, zeta potential, entrapment efficiency (EE), drug loading (DL), X-ray diffraction (XRD) analysis, differential scanning calorimetry (DSC), and drug release were characterized. Furthermore, the pharmacokinetic and biodistribution studies of GL-F127/TPGS-MMs were evaluated in rats and compared with GL solution.Results: GL-F127/TPGS-MMs were found to be of spherical shape with particle size of (27.41 ± 4.90) nm, EE% of 95.38% and DL% of 12.99%. The results of XRD and DSC indicated that GL was encapsulated in the micelles. Drug release of GL-F127/TPGS-MMs demonstrated a sustained release behavior as compared to GL solution. The pharmacokinetic and biodistribution studies showed a significantly higher oral absorption and liver accumulation of glycyrrhetinic acid (GA) after oral administration of GL-F127/TPGS-MMs as compared to GL solution.Conclusion: These results suggested F127/TPGS-MMs might be a potential nanocarrier for oral delivery of GL.
Assuntos
Ácido Glicirrízico/química , Micelas , Poloxâmero , Vitamina E/química , Administração Oral , Animais , Portadores de Fármacos , Tamanho da Partícula , Poloxâmero/metabolismo , Polietilenoglicóis/química , Ratos , Distribuição TecidualRESUMO
The purpose of this study was to investigate the nasal absorption rate and nasal mucosal toxicity of thermosensitive ketamine in situ gels containing various absorption enhancers. The optimal composition ratio for the gel matrix was determined to be 17.2% Poloxamer 407 and 2% Poloxamer 188, as this combination resulted in solutions with a gelation point within the range found in the nasal cavity. Ketamine gels containing the tested enhancers, namely, ethylenediaminetetraacetic acid disodium salt, hydroxypropyl-ß-cyclodextrin, propylene glycol, or Tween-80, were compared with enhancer-free counterparts to determine the absorption of the drug, in vivo by measuring its plasma levels in rats and in vitro using a Franz diffusion cell. Moreover, the toxicity of each gel type was assessed by microscopic observation of the morphology of rat nasal mucosa as well as by determining the mobility of the mucosal cilia using an established toad model. The results showed that gels containing hydroxypropyl-ß-cyclodextrin could promote the absorption of ketamine without added toxicity compared to enhancer-free gels. Thus, we consider hydroxypropyl-ß-cyclodextrin as the most promising absorption enhancer for the nasal administration of ketamine using in situ gels.
Assuntos
Portadores de Fármacos/toxicidade , Ketamina/toxicidade , Absorção Nasal/efeitos dos fármacos , Mucosa Nasal/efeitos dos fármacos , Poloxâmero/toxicidade , Administração Intranasal/métodos , Analgésicos/síntese química , Analgésicos/metabolismo , Analgésicos/toxicidade , Animais , Anuros , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Feminino , Géis , Ketamina/síntese química , Ketamina/metabolismo , Masculino , Absorção Nasal/fisiologia , Mucosa Nasal/metabolismo , Técnicas de Cultura de Órgãos , Poloxâmero/síntese química , Poloxâmero/metabolismo , Ratos , Ratos Sprague-Dawley , TemperaturaRESUMO
Budesonide is a glucocorticoid for the treatment of ulcerative colitis (UC). The current study aims to develop a thermosensitive in situ and adhesive gel for rectal delivery of budesonide. HPMC K4M was selected as the adhesive agent based on the adhesive force and the effect on gel performance. The formulation of gel was optimized by using the central composite design-response surface methodology (CCD-RSM); a mathematical model was successfully developed to predict desired formulations as well as to analyze relationships between the amount of Pluronic F-127, Pluronic F-68, and HPMC K4M and the performances of gel. Based on CCD-RSM, a thermosensitive in situ and adhesive gel consisting of 0.002% budesonide, 0.74% HPMC, 4.87% F-68, and 19.0% F-127 was developed. Furthermore, the in vivo behavior of gel was evaluated in Sprague-Dawley rats. In comparison with budesonide solution, rectal administration of budesonide gel at 0.1 mg/kg in rats showed relative bioavailability of 230% with significant increase in rectum uptake.