RESUMO
Radiation-induced brain injury is a major adverse event in head and neck tumor treatment, influencing the quality of life for the more than 50% of patients who undergo radiation therapy and experience long-term survival. However, no effective treatments are available for these patients, and preventative drugs and effective drug-delivery methods must be developed. Based on our results, miR-122-5p was upregulated in the mouse radiation-induced brain injury (RBI) model and patients with nasopharyngeal carcinoma (NPC) who received radiation therapy. Intranasal administration of a single antagomiR-122-5p dose before irradiation effectively alleviated radiation-induced cognitive impairment, neuronal injury, and neuroinflammation in the mouse RBI model. Results further indicated that miR-122-5p inhibition in microglia reduced the levels of proinflammatory cytokines and enhanced the phagocytic function to protect against radiation-induced neuronal injury in cell models. Further, we profiled transcriptome data and verified that Tensin 1 (TNS1) may be the target of miR-122-5p in RBI. In summary, our results reveal a distinct role for miR-122-5p in regulating neuroinflammation in RBI, indicating that a non-invasive strategy for intranasal miR-122-5p administration may be an attractive therapeutic target in RBI, providing new insights for clinical trials. Further systematic safety assessment, optimization of drug administration, and clarity of mechanism will accelerate the process into clinical practice.
Assuntos
Lesões Encefálicas , MicroRNAs , Neoplasias Nasofaríngeas , Animais , Antagomirs , Humanos , Camundongos , MicroRNAs/genética , Neoplasias Nasofaríngeas/radioterapia , Qualidade de VidaRESUMO
BACKGROUND: Dysbiosis or imbalance of gut microbiota in Alzheimer's disease (AD) affects the production of short-chain fatty acids (SCFAs), whereas exogenous SCFAs supplementation exacerbates brain Aß burden in APP/PS1 mice. Bifidobacterium is the main producer of SCFAs in the gut flora, but oral administration of Bifidobacterium is ineffective due to strong acids and bile salts in the gastrointestinal tract. Therefore, regulating the levels of SCFAs in the gut is of great significance for AD treatment. METHODS: We investigated the feasibility of intranasal delivery of MSNs-Bifidobacterium (MSNs-Bi) to the gut and their effect on behavior and brain pathology in APP/PS1 mice. RESULTS: Mesoporous silica nanospheres (MSNs) were efficiently immobilized on the surface of Bifidobacterium. After intranasal administration, fluorescence imaging of MSNs-Bi in the abdominal cavity and gastrointestinal tract revealed that intranasally delivered MSNs-Bi could be transported through the brain to the peripheral intestine. Intranasal administration of MSNs-Bi not only inhibited intestinal inflammation and reduced brain Aß burden but also improved olfactory sensitivity in APP/PS1 mice. CONCLUSIONS: These findings suggested that restoring the balance of the gut microbiome contributes to ameliorating cognitive impairment in AD, and that intranasal administration of MSNs-Bi may be an effective therapeutic strategy for the prevention of AD and intestinal disease.
Assuntos
Doença de Alzheimer , Nanopartículas , Transtornos do Olfato , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Bifidobacterium/metabolismo , Ácidos e Sais Biliares , Encéfalo/metabolismo , Modelos Animais de Doenças , Ácidos Graxos Voláteis , Camundongos , Camundongos Transgênicos , Transtornos do Olfato/patologia , Dióxido de SilícioRESUMO
Chitosan (CS) is a linear polysaccharide obtained by the deacetylation of chitin, which, after cellulose, is the second biopolymer most abundant in nature, being the primary component of the exoskeleton of crustaceans and insects. Since joining the pharmaceutical field, in the early 1990s, CS attracted great interest, which has constantly increased over the years, due to its several beneficial and favorable features, including large availability, biocompatibility, biodegradability, non-toxicity, simplicity of chemical modifications, mucoadhesion and permeation enhancer power, joined to its capability of forming films, hydrogels and micro- and nanoparticles. Moreover, its cationic character, which renders it unique among biodegradable polymers, is responsible for the ability of CS to strongly interact with different types of molecules and for its intrinsic antimicrobial, anti-inflammatory and hemostatic activities. However, its pH-dependent solubility and susceptibility to ions presence may represent serious drawbacks and require suitable strategies to be overcome. Presently, CS and its derivatives are widely investigated for a great variety of pharmaceutical applications, particularly in drug delivery. Among the alternative routes to overcome the problems related to the classic oral drug administration, the mucosal route is becoming the favorite non-invasive delivery pathway. This review aims to provide an updated overview of the applications of CS and its derivatives in novel formulations intended for different methods of mucosal drug delivery.
Assuntos
Quitosana , Nanopartículas , Quitina , Quitosana/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Preparações FarmacêuticasRESUMO
A brain tumor (BT) is a condition in which there is growth or uncontrolled development of the brain cells, which usually goes unrecognized or is diagnosed at the later stages. Since the mechanism behind BT is not clear, and the various physiological conditions are difficult to diagnose, the success rate of BT is not very high. This is the central issue faced during drug development and clinical trials with almost all types of neurodegenerative disorders. In the first part of this review, we focus on the concept of brain tumors, their barriers, and the types of delivery possible to target the brain cells. Although various treatment methods are available, they all have side effects or toxic effects. Hence, in the second part, a correlation was made between the use of resveratrol, a potent antioxidant, and its advantages for brain diseases. The relationship between brain disease and the blood-brain barrier, multi-drug resistance, and the use of nanomedicine for treating brain disorders is also mentioned. In short, a hypothetical concept is given with a background investigation into the use of combination therapy with resveratrol as an active ingredient, the possible drug delivery, and its formulation-based approach.
Assuntos
Neoplasias Encefálicas , Estilbenos , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Encéfalo , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Humanos , Preparações Farmacêuticas , Resveratrol/uso terapêutico , Estilbenos/farmacologia , Estilbenos/uso terapêuticoRESUMO
In the current study, a composite in-situ gel formulation containing aripiprazole (APZ) loaded transfersomes (TFS) was developed for the intranasal brain targeting of APZ. APZ loaded TFS were prepared by applying the film hydration method and optimized using an irregular factorial design. The prepared formulations were optimized based on different parameters including particle size, polydispersity index (PdI), zeta potential, encapsulation efficiency (EE) and release efficiency (RE). The optimized APZ-TFS were distributed in an ion-triggered deacetylated gellan gum solution (APZ-TFS-Gel) and evaluated in terms of pH, gelling time, rheological properties and in-vitro release study. The therapeutic efficacy of the best APZ-TFS-Gel was then tested in the mice model of schizophrenia induced by ketamine by evaluating various behavioral parameters. The optimized formulation showed the particle size of 72.12 ± 0.72 nm, the PdI of 0.19 ± 0.07, the zeta potential of -55.56 ± 1.9 mV, the EE of 97.06 ± 0.10%, and the RE of 70.84 ± 1.54%. The in-vivo results showed that compared with the other treatment groups, there was a considerable increase in swimming and climbing time and a decrease in locomotors activity and immobility time in the group receiving APZ-TFS-Gel. Thus, APZ-TFS-Gel was found to have desirable characteristics for therapeutic improvement.
Assuntos
Antipsicóticos/administração & dosagem , Aripiprazol/administração & dosagem , Nanogéis/administração & dosagem , Administração Intranasal , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Sistemas de Liberação de Fármacos por Nanopartículas/administração & dosagem , Tamanho da Partícula , Esquizofrenia/tratamento farmacológico , Espectroscopia de Infravermelho com Transformada de FourierRESUMO
The crucial challenge in tuberculosis (TB) as a chronic infectious disease is to present a novel vaccine candidate that improves current vaccination and provides efficient protection in individuals. The present study aimed to evaluate the immune efficacy of multi-subunit vaccines containing chitosan (CHT)- or trimethyl chitosan (TMC)-coated PLGA nanospheres to stimulate cell-mediated and mucosal responses against Mycobacterium Tuberculosis (Mtb) in an animal model. The surface-modified PLGA nanoparticles (NPs) containing tri-fusion protein from three Mtb antigens were produced by the double emulsion technique. The subcutaneously or nasally administered PLGA vaccines in the absence or presence of BCG were assessed to compare the levels of mucosal IgA, IgG1, and IgG2a production as well as secretion of IFN-γ, IL-17, IL-4, and TGF-ß cytokines. According to the release profile, the tri-fusion encapsulated in modified PLGA NPs demonstrated a biphasic release profile including initial burst release on the first day and sustained release within 18 days. All designed PLGA vaccines induced a shift of Th1/Th2 balance toward Th1-dominant response. Although immunized mice through subcutaneous injection elicited higher cell-mediated responses relative to the nasal vaccination, the intranasally administered groups stimulated robust mucosal IgA immunity. The modified PLGA NPs using TMC cationic polymer were more efficient to elevate Th1 and mucosal responses in comparison with the CHT-coated PLGA nanospheres. Our findings highlighted that the tri-fusion loaded in TMC-PLGA NPs may represent an efficient prophylactic vaccine and can be considered as a novel candidate against TB.
Assuntos
Quitosana , Nanosferas , Tuberculose , Administração Intranasal , Animais , Camundongos , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Tuberculose/prevenção & controle , Vacinas de Subunidades AntigênicasRESUMO
The major challenge associated with the treatment of neurological disorders is the inefficiency of drugs to enter the Central Nervous System (CNS). Polymer-drug conjugates are now being tailored to overcome this hindrance associated with conventional drugs. The study aimed at developing polymer hybrid nasal nanocomposite for enhanced delivery of Centella to the CNS. Thiolated chitosan was complexed with Centella to form a composite using EDAC hydrochloride. The composite was characterized by FTIR, XRD, NMR, and MS. Further, this composite was converted into a nanoformulation by the ionic-gelation method, characterized, and subjected to ex vivo permeation studies. Additionally, MTT assay was performed using Human Uumbilical cord Vein Endothelial Cells (HUVECs) mimicking Blood-Brain Barrier (BBB) to establish the safety of nanocomposite. The targeting efficacy was predicted by molecular docking studies against receptors associated with BBB. The FTIR, XRD, NMR, and MS studies confirmed the chemical conjugation of thiolated chitosan with Centella. Nanocomposite characterization through SEM, AFM, and DLS confirmed the size and stability of the developed nanocomposite having a zeta potential of - 14.5 mV and PDI of 0.260. The nanocomposite showed no signs of nasal ciliotoxicity and good permeation of 89.44 ± 1.75% (mean ± SD, n = 3) at 8 h across the nasal mucosa. MTT assay showed that the nanocomposite had lesser toxicity compared to the free drug (IC50 of Centella-269.1 µg/mL and IC50 of CTC nanocomposite-485.375 µg/mL). The affinity of polymer to the BBB receptors as proved by docking studies suggests the ability of polymer-based nanocomposite to concentrate in the brain post nasal administration.
Assuntos
Centella , Quitosana , Nanocompostos , Nanopartículas , Administração Intranasal , Barreira Hematoencefálica , Células Endoteliais , Humanos , Simulação de Acoplamento Molecular , Mucosa NasalRESUMO
Obesity and metabolic syndrome are threats to the health of large population worldwide as they are associated with high mortality, mainly linked to cardiovascular diseases. Recently, CPN-116 (CPN), which is an agonist peptide specific to neuromedin-U receptor 2 (NMUR2) that is expressed predominantly in the brain, has been developed as a new therapeutic candidate for the treatment of obesity and metabolic syndrome. However, treatment with CPN poses a challenge due to the limited delivery of CPN to the brain. Recent studies have clarified that the direct anatomical connection of the nasal cavity with brain allows delivery of several drugs to the brain. In this study, we confirm the nasal cavity as a promising CPN delivery route to the brain for the treatment of obesity and metabolic syndrome. According to the pharmacokinetic study, the clearance of CPN from the blood was very rapid with a half-life of 3 min. In vitro study on its stability in the serum and cerebrospinal fluid (CSF) indicates that CPN was more stable in the CSF than in the blood. The concentration of CPN in the brain was higher after nasal administration, despite its lower concentrations in the plasma than that after intravenous administration. The study on its pharmacological potency suggests the effective suppression of increased body weight in mice in a dose-dependent manner due to the direct activation of NMUR2 by CPN. This results from the higher concentration of corticosterone in blood after nasal administration of CPN as compared to nasal application of saline. In conclusion, the above findings indicate that the nasal cavity is a promising CPN delivery route to the brain to treat obesity and metabolic syndrome.
Assuntos
Fármacos Antiobesidade/administração & dosagem , Encéfalo/efeitos dos fármacos , Obesidade/tratamento farmacológico , Peptídeos/administração & dosagem , Receptores de Neurotransmissores/agonistas , Administração Intranasal , Animais , Fármacos Antiobesidade/sangue , Fármacos Antiobesidade/líquido cefalorraquidiano , Fármacos Antiobesidade/farmacocinética , Corticosterona/sangue , Células HEK293 , Humanos , Camundongos , Obesidade/sangue , Obesidade/líquido cefalorraquidiano , Peptídeos/sangue , Peptídeos/líquido cefalorraquidiano , Peptídeos/farmacocinética , Ratos , Ratos WistarRESUMO
Quercetin (Que) is a flavonoid associated with high oxygen radical scavenging activity and potential neuroprotective activity against Alzheimer's disease. Que's oral bioavailability is limited by its low water solubility and extended peripheral metabolism; thus, nasal administration may be a promising alternative to achieve effective Que concentrations in the brain. The formation of Que-2-hydroxypropylated-ß-cyclodextrin (Que/HP-ß-CD) complexes was previously found to increase the molecule's solubility and stability in aqueous media. Que-methyl-ß-cyclodextrin (Que/Me-ß-CD) inclusion complexes were prepared, characterized, and compared with the Que/HP-ß-CD complex using biophysical and computational methods (phase solubility, fluorescence and NMR spectroscopy, differential scanning calorimetry (DSC), and molecular dynamics simulations (MDS)) as candidates for the preparation of nose-to-brain Que's delivery systems. DSC thermograms, NMR, fluorescence spectroscopy, and MDS confirmed the inclusion complex formation of Que with both CDs. Differences between the two preparations were observed regarding their thermodynamic stability and inclusion mode governing the details of molecular interactions. Que's solubility in aqueous media at pH 1.2 and 4.5 was similar and linearly increased with both CD concentrations. At pH 6.8, Que's solubility was higher and positively deviated from linearity in the presence of HP-ß-CD more than with Me-ß-CD, possibly revealing the presence of more than one HP-ß-CD molecule involved in the complex. Overall, water solubility of lyophilized Que/Me-ß-CD and Que/HP-ß-CD products was approximately 7-40 times and 14-50 times as high as for pure Que at pH 1.2-6.8. In addition, the proof of concept experiment on ex vivo permeation across rabbit nasal mucosa revealed measurable and similar Que permeability profiles with both CDs and negligible permeation of pure Que. These results are quite encouraging for further ex vivo and in vivo evaluation toward nasal administration and nose-to-brain delivery of Que.
Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Encéfalo/efeitos dos fármacos , Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/efeitos dos fármacos , Quercetina/administração & dosagem , Quercetina/química , beta-Ciclodextrinas/química , Administração Intranasal/métodos , Animais , Disponibilidade Biológica , Estabilidade de Medicamentos , Concentração de Íons de Hidrogênio , Quercetina/farmacocinética , Coelhos , Solubilidade , Temperatura de TransiçãoRESUMO
Ondansetron HCl is a (5-HT3) serotonin receptor antagonist, used as anti-emetic drug in combination with anticancer agents. Conventional dosage forms have poor bioavailability and patient compliance. These problems can be reduced by the use of nasal niosomal thermo-reversible in situ gelling system. Niosomes were formulated using various surfactants (Span 60, Span 80, Tween 20, and Tween 80) in different ratios using the thin-film hydration technique. Niosomes were evaluated for particle size, zeta potential, transmission electron microscopy (TEM) imaging, drug entrapment efficiency, and in vitro drug release. Niosomes prepared using Span 60 and cholesterol in the ratio 1:1 (F5) showed higher entrapment efficiency (76.13 ± 1.2%) and in vitro drug release (91.76%) after 12 h was optimized. The optimized niosomes were developed into thermo-reversible in situ gel, composed of Poloxamer 407 and sodium carboxymethyl cellulose, prepared by cold method technique. Compatibility study (FTIR, DSC) was made for drugs and excipients that showed no significant interaction. The gel formulation G5 showed the most suitable gelation temperature (31 °C), viscosity (1250 mpoise), bioadhesion force (5860 ± 28 dyne/cm2), and in vitro drug release (70.6%) after 12 h. Comparative in vivo pharmacokinetic study on rabbits showed a sustained release and higher relative bioavailability of the prepared nasal in situ gel compared to similar dose of oral tablets (202.4%) which make ondansetron HCl niosomal nasal thermo-sensitive in situ gel a more convenient dosage form for the administration of ondansetron HCl than oral tablets.
Assuntos
Composição de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/métodos , Mucosa Nasal/efeitos dos fármacos , Ondansetron/administração & dosagem , Ondansetron/síntese química , Administração Intranasal/métodos , Animais , Antieméticos/administração & dosagem , Antieméticos/síntese química , Antieméticos/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Liberação Controlada de Fármacos/fisiologia , Lipossomos , Masculino , Mucosa Nasal/metabolismo , Ondansetron/metabolismo , CoelhosRESUMO
Non-invasive brain therapy for chronic neurological disorders is in high demand. Vinpocetine (VIN) tablets for cerebrovascular degenerative disorders ensued < 7% oral bioavailability. The olfactory pathway (providing direct brain access) can improve VIN pharmacokinetic/pharmacodynamic profile. In this context, VIN hydrogels based on temperature-, pH-, and ion-triggered gelation in physiological milieu were formulated. Poloxamer-chitosan (PLX-CS) and carbopol-HPMC-alginate (CP-HPMC-SA) systems were optimized for appropriate gelation time, temperature, and pH. PLX-CS-hydrogels exhibited strong mucoadhesion for > 8 h, while CP-HPMC-SA hydrogels were mucoadhesive in simulated nasal fluid, owing to pH and ion-activated gelation. Along with prolonged mucosal residence, hydrogels confirmed sustained VIN release (> 24 h), especially from CP-HPMC-SA hydrogels. As proof of concept, brain exposure of intranasal VIN hydrogels was investigated in rats versus VIN-IV bolus. PLX-CS provided 146% increase in AUC0-30 and 3-fold maximum brain concentration (BCmax) relative to IV bolus. BCmax was reached after 4 h versus 1 h (IV bolus). CP-HPMC-SA hydrogel showed superior brain targeting efficiency (460%) and brain direct transport percentage (78.23%). VIN plasma pharmacokinetics confirmed 45-60% reduction in AUCplasma versus IV bolus, while PCmax of CP-HPMC-SA and PLX-CS represented 17 and 28% that of IV bolus, respectively. Olfactory-targeted hydrogels grant effective, sustainable VIN brain level with minimal systemic exposure, thus, assuring lower dose, dose frequency, side effects, and per se better patient compliance.
Assuntos
Encefalopatias/tratamento farmacológico , Encéfalo/metabolismo , Sistemas de Liberação de Medicamentos , Hidrogéis , Administração Intranasal , Alginatos/química , Animais , Encefalopatias/metabolismo , Quitosana/metabolismo , Derivados da Hipromelose/química , Masculino , Ratos , Temperatura , Alcaloides de Vinca/administração & dosagemRESUMO
Synaptic NMDA receptors activating nuclear calcium-driven adaptogenomics control a potent body-own neuroprotective mechanism, referred to as acquired neuroprotection. Viral vector-mediated gene transfer in conjunction with stereotactic surgery has previously demonstrated the proficiency of several nuclear calcium-regulated genes to protect in vivo against brain damage caused by toxic extrasynaptic NMDA receptor signaling following seizures or stroke. Here we used noninvasive nose-to-brain administration of Activin A and SerpinB2, two secreted nuclear calcium-regulated neuroprotectants, for post-injury treatment of brain damage following middle cerebral artery occlusion (MCAO) in C57BL/6N mice. The observed reduction of the infarct volume was comparable to the protection obtained by intracerebroventricular injection of recombinant Activin A or SerpinB2 or by stereotactic delivery 3 weeks prior to the injury of a recombinant adeno-associated virus containing an expression cassette for the potent neuroprotective transcription factor Npas4. These results establish post-injury, nose-to-brain delivery of Activin A and SerpinB2 as effective and possibly clinically applicable treatments of acute and chronic neurodegenerative conditions.
Assuntos
Ativinas/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Isquemia Encefálica/terapia , Inibidor 2 de Ativador de Plasminogênio/genética , Acidente Vascular Cerebral/terapia , Ativinas/administração & dosagem , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/administração & dosagem , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Cálcio/metabolismo , Dependovirus/genética , Modelos Animais de Doenças , Terapia Genética/métodos , Humanos , Infarto da Artéria Cerebral Média/genética , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/terapia , Infusões Intraventriculares , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Neuroproteção/genética , Fármacos Neuroprotetores/administração & dosagem , Inibidor 2 de Ativador de Plasminogênio/administração & dosagem , Receptores de N-Metil-D-Aspartato/genética , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/genética , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologiaRESUMO
Glioblastoma (GBM) is the most lethal form of brain tumor, being characterized by the rapid growth and invasion of the surrounding tissue. The current standard treatment for glioblastoma is surgery, followed by radiotherapy and concurrent chemotherapy, typically with temozolomide. Although extensive research has been carried out over the past years to develop a more effective therapeutic strategy for the treatment of GBM, efforts have not provided major improvements in terms of the overall survival of patients. Consequently, new therapeutic approaches are urgently needed. Overcoming the blood-brain barrier (BBB) is a major challenge in the development of therapies for central nervous system (CNS) disorders. In this context, the intranasal route of drug administration has been proposed as a non-invasive alternative route for directly targeting the CNS. This route of drug administration bypasses the BBB and reduces the systemic side effects. Recently, several formulations have been developed for further enhancing nose-to-brain transport, mainly with the use of nano-sized and nanostructured drug delivery systems. The focus of this review is to provide an overview of the strategies that have been developed for delivering anticancer compounds for the treatment of GBM while using nasal administration. In particular, the specific properties of nanomedicines proposed for nose-to-brain delivery will be critically evaluated. The preclinical and clinical data considered supporting the idea that nasal delivery of anticancer drugs may represent a breakthrough advancement in the fight against GBM.
Assuntos
Antineoplásicos/farmacologia , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Mucosa Nasal/metabolismo , Administração Intranasal , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , HumanosRESUMO
This work is devoted to design a novel nanostructured hybrid vesicle (NHV) made of lecithin and an acrylate/C10-C30 alkyl acrylate for the nasal delivery of a model active indomethacin (IND), and further to probe its microstructure, intermolecular interactions, drug release behavior, ex vivo permeation, and stability. NHVs were prepared by cavitation technology employing RSM-based central composite design (CCD). Amount of lecithin (X1), power of ultrasound (X2), and sonication time (X3) were selected as three independent variables while the studied response included Z-Avg (nm), polydispersity index (PDI), and zeta potential (mV). The designed system (NHV) was investigated through dynamic (DLS) and electrophoretic light scattering (ELS), attenuated total reflectance (ATR-FTIR), oscillatory measurement (stress and frequency sweep), and transmission electron microscopy (TEM). CCD was found useful in optimizing NHV. An optimized formulation (S6) had Z-Avg 80 nm, PDI 0.2, and zeta potential of - 43.26 mV. Morphology investigation revealed spherical vesicles with smaller TEM diameters (the largest particle being 52.26 nm). ATR analysis demonstrated significant intermolecular interactions among the drug (IND) and the components of vesicles. The designed vesicles had an elastic predominance and displayed supercase II (n > 1) type of drug release. Besides, the vesicles possessed potential to transport IND across the nasal mucosa with the steady-state flux (µg/cm2/h) and permeability coefficient (cm/h) of 26.61 and 13.30 × 10-3, respectively. NHV exhibited an exceptional stability involving a combination of electrostatic and steric interactions while the histopathology investigation confirmed their safety for nasal administration.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Indometacina/administração & dosagem , Administração Intranasal , Animais , Anti-Inflamatórios não Esteroides/química , Indometacina/química , Lecitinas/análise , Microscopia Eletrônica de Transmissão , Mucosa Nasal/metabolismo , Tamanho da Partícula , Permeabilidade , Ovinos , Espectroscopia de Infravermelho com Transformada de Fourier , Propriedades de SuperfícieRESUMO
BACKGROUND: Due to initiation of Mycobacterium tuberculosis infection via the mucosal tissue of the respiratory tract, intranasal administration of new tuberculosis vaccines is highly regarded to enhance mucosal immunity. Our outline was evaluation of mucosal and systemic immune responses in BALB/c mice after nasal delivery of HspX/EsxS fused antigen of Mycobacterium tuberculosis along with MPLA adjuvant entrapped in PLGA:DDA hybrid nanoparticles. METHODS: In this study, the double emulsion solvent evaporation method (w/o/w) was used to prepare different nanoparticle formulations containing HspX/EsxS protein and MPLA. Three weeks after the last nasal immunization of BALB/c mice, IgA antibody levels in nasal lavage and IFN-γ, IL-4, IL-17 and TGF-ß cytokines in supernatant of cultured splenocytes and also serum IgG1 and IgG2a titers were evaluated using ELISA method. RESULTS: Our results indicated that nasal vaccination with PLGA:DDA nanoparticles loaded with HspX/EsxS protein±MPLA, both with and without a prime dose of BCG could provide efficient Th1, Th17, IgA, IgG1 and IgG2a immune responses. CONCLUSION: These findings demonstrate that both PLGA:DDA hybrid nanoparticles as carrier/adjuvant and MPLA as adjuvant, could efficiently induce mucosal and systemic immune responses against HspX/EsxS antigen, alone or as a booster for BCG.
Assuntos
Imunidade Adaptativa , Adjuvantes Imunológicos/administração & dosagem , Antígenos de Bactérias/imunologia , Imunidade nas Mucosas , Nanopartículas/administração & dosagem , Vacinas contra a Tuberculose/imunologia , Administração Intranasal , Animais , Anticorpos Antibacterianos/análise , Anticorpos Antibacterianos/sangue , Antígenos de Bactérias/genética , Proteínas de Bactérias/genética , Proteínas de Bactérias/imunologia , Células Cultivadas , Citocinas/análise , Portadores de Fármacos/administração & dosagem , Ensaio de Imunoadsorção Enzimática , Imunoglobulina A/análise , Imunoglobulina G/sangue , Leucócitos Mononucleares/imunologia , Camundongos Endogâmicos BALB C , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Compostos de Amônio Quaternário/administração & dosagem , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Vacinas contra a Tuberculose/administração & dosagem , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/imunologiaRESUMO
It has become important to explore more efficient and feasible influenza vaccines, since epidemics of influenza virus cause hundreds of thousands of deaths all around the world. Improving immunogenicity of parentral influenza vaccines has given rise to mucosal delivery routes. In this study, alginate nanoparticles (NPs) were efficiently synthetized by ionic gelation method and influenza virus and CpG ODN or Quillaja Saponin (QS) adjuvants were actively incorporated into alginate NPs. The prepared particles were evaluated for both humoral and cellular immune responses in rabbits' nostrils. The vaccination started with a prime dose and followed by three boosters (two intranasal (IN) on days 45 and 60 and the last dose, intramuscular (IM) on day 75). HAI titer had increased in all the samples; although, only in the group received WV + CPG suspension reached to the protective HAI titer. All the immunized rabbits elicited significantly high sIgA levels on day 75, compared to the negative and the IM groups. At the end of the study, IN administration of CpG ODN adjuvant with virus antigen induced higher IgG level than the groups vaccinated with alginate NPs with or without CpG ODN (P < 0.001). As for the cellular immunity, CpG ODN was capable of inducing significant levels of IL-4 and TNF-α, either through inoculation along with the virus suspension or as incorporated in alginate NPs. According to the obtained data, CpG ODN adjuvant showed higher immunogenic potential as part of a vaccine delivery system than QS. Moreover, applying alginate polymer as a nasal delivery system carrier was not deemed immunogenic against influenza whole virus.
Assuntos
Alginatos/química , Imunização , Vacinas contra Influenza/química , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Nanopartículas/química , Adjuvantes Imunológicos/administração & dosagem , Administração Intranasal , Animais , Anticorpos Antivirais , Antígenos Virais/imunologia , Modelos Animais de Doenças , Feminino , Ácido Glucurônico/química , Ácido Glucurônico/imunologia , Ácidos Hexurônicos/química , Ácidos Hexurônicos/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Vacinas contra Influenza/administração & dosagem , Interleucina-4/metabolismo , Oligodesoxirribonucleotídeos , Orthomyxoviridae/imunologia , Pós , Saponinas de Quilaia , Coelhos , Fator de Necrose Tumoral alfa/metabolismo , Vacinação , Vacinas de Produtos InativadosRESUMO
Exosomes represent an attractive vehicle for the delivery of biomolecules. However, mechanisms for loading functional molecules into exosomes are relatively unexplored. Here we report the use of the evolutionarily conserved late-domain (L-domain) pathway as a mechanism for loading exogenous proteins into exosomes. We demonstrate that labeling of a target protein, Cre recombinase, with a WW tag leads to recognition by the L-domain-containing protein Ndfip1, resulting in ubiquitination and loading into exosomes. Our results show that Ndfip1 expression acts as a molecular switch for exosomal packaging of WW-Cre that can be suppressed using the exosome inhibitor GW4869. When taken up by floxed reporter cells, exosomes containing WW-Cre were capable of inducing DNA recombination, indicating functional delivery of the protein to recipient cells. Engineered exosomes were administered to the brain of transgenic reporter mice using the nasal route to test for intracellular protein delivery in vivo. This resulted in the transport of engineered exosomes predominantly to recipient neurons in a number of brain regions, including the olfactory bulb, cortex, striatum, hippocampus, and cerebellum. The ability to engineer exosomes to deliver biologically active proteins across the blood-brain barrier represents an important step for the development of therapeutics to treat brain diseases.
Assuntos
Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Engenharia Genética , Transporte Proteico , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Vesículas Extracelulares/metabolismo , Expressão Gênica , Engenharia Genética/métodos , Integrases/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Absorção Nasal , Permeabilidade , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
The aim was to prepare an optimized zolmitriptan (ZT)-loaded transfersome formulation using Box-Behnken design for improving the bioavailability by nasal route for quick relief of migraine and further to compare with a marketed nasal spray. Here, three factors were evaluated at three levels. Independent variables include: amount of soya lecithin (X1), amount of drug (X2) and amount of tween 80 (X3). The dependent responses were vesicle size (Y1), flexibility index (Y2) and regression coefficient of drug release kinetics (Y3). Prepared formulations were evaluated for physical characters and an optimal system was identified. Further, in vivo pharmacokinetic study was performed in male wistar rats to compare the amount of drug in systemic circulation after intranasal administration. Optimized ZT-transfersome formulation containing 82.74 mg of lecithin (X1), 98.37 mg of zolmitriptan (X2) and 32.2 mg of Tween 80 (X3) and had vesicle size of 93.3 nm, flexibility index of 20.25 and drug release regression coefficient of 0.992. SEM picture analysis revealed that the vesicles were spherical in morphology and had a size more than 1 µm. The formulations were found to be physically stable upon storage at room temperature up to 2 months period, as there were no significant changes noticed in size and ZP. The nasal bioavailability of optimized transfersome formulation was found to be increased by 1.72 times than that of marketed nasal spray (Zolmist®). The design and development of zolmitriptan as transfersome provided improved nasal delivery over a conventional nasal spray for a better therapeutic effect.
Assuntos
Oxazolidinonas/administração & dosagem , Oxazolidinonas/química , Triptaminas/administração & dosagem , Triptaminas/química , Administração Intranasal/métodos , Animais , Disponibilidade Biológica , Química Farmacêutica/métodos , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/efeitos dos fármacos , Lecitinas/química , Masculino , Transtornos de Enxaqueca/tratamento farmacológico , Tamanho da Partícula , Polissorbatos/química , Ratos , Ratos Wistar , Solubilidade , Tensoativos/químicaRESUMO
BACKGROUND: Iron deficiency in children can have significant neurological consequences, and iron supplementation is an effective treatment of choice. However, traditional routes of iron supplementation do not allow efficient iron delivery to the brain due to the presence of the blood-brain barrier. So an easily delivered iron formulation with high absorption efficiency potentially could find widespread application in iron deficient infants. RESULTS: In this study, we have developed and characterized a nanovesicular formulation of ferric ammonium citrate (ferric ammonium citrate nanoliposomes, FAC-LIP) and have shown that it can increase brain iron levels in rats following nasal administration. FAC was incorporated into liposomes with high efficiency (97%) and the liposomes were small (40 nm) and stable. Following intranasal delivery in rats, FAC-LIP significantly increased the iron content in the olfactory bulb, cerebral cortex, striatum, cerebellum and hippocampus, and was more efficient at doing so than FAC alone. No signs of apoptosis or abnormal cell morphology were observed in the brain following FAC-LIP administration, and there were no significant changes in the levels of SOD and MDA, except in the cerebellum and hippocampus. No obvious morphological changes were observed in lung epithelial cells or tracheal mucosa after nasal delivery, suggesting that the formulation was not overtly toxic. CONCLUSIONS: In this study, nanoscale FAC-LIP proved an effective system delivering iron to the brain, with high encapsulation efficiency and low toxicity in rats. Our studies provide the foundation for more detailed investigations into the applications of niosomal nasal delivery of liposomal formulations of iron as a simple and safe therapy for iron deficiency anemia. Graphical abstract The diagrammatic sketch of "Nasal delivery of nanoliposome-encapsulated ferric ammonium citrate can increase the iron content of rat brain". Nanoliposome-encapsulated ferric ammonium citrate (FAC-LIP) was successfully prepared and intranasal administration of FAC-LIP increased both the total iron contents and iron storage protein (FTL) expression in rat olfactory bulb, cerebral cortex, striatum and hippocampus, compared with those of FAC groups. Moreover, there was not overtly toxic affects to brain, lung epithelial cells and tracheal mucosa.
Assuntos
Encéfalo/metabolismo , Compostos Férricos/administração & dosagem , Compostos Férricos/farmacocinética , Compostos de Amônio Quaternário/administração & dosagem , Compostos de Amônio Quaternário/farmacocinética , Administração Intranasal , Animais , Apoptose/efeitos dos fármacos , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Ferro/administração & dosagem , Ferro/farmacocinética , Lipossomos/química , Lipossomos/ultraestrutura , Masculino , Malondialdeído/metabolismo , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismoRESUMO
PURPOSE: Thickening polymers have been used as excipients in nasal formulations to avoid nasal run-off (nasal drip) post-administration. However, increasing the viscosity of the formulation can have a negative impact on the quality of the aerosols generated. Therefore, the study aims to investigate the use of a novel smart nano-cellulose excipient to generate suitable droplets for nasal drug delivery that simultaneously has only marginally increased viscosity while still reducing nasal drips. METHODS: Nasal sprays containing nano-cellulose at different concentrations were investigated for the additive's potential as an excipient. The formulations were characterized for their rheological and aerosol properties. This was then compared to conventional nasal spray formulation containing the single-component hydroxyl-propyl methyl cellulose (HPMC) viscosity enhancing excipient. RESULTS: The HPMC-containing nasal formulations behave in a Newtonian manner while the nano-cellulose formulations have a yield stress and shear-thinning properties. At higher excipient concentrations and shear rates, the nano-cellulose solutions have significantly lower viscosities compared to the HPMC solution, resulting in improved droplet formation when actuated through conventional nasal spray. CONCLUSIONS: Nano-cellulose materials could potentially be used as a suitable excipient for nasal drug delivery, producing consistent aerosol droplet size, and enhanced residence time within the nasal cavity with reduced run-offs compared to conventional polymer thickeners.