RÉSUMÉ
Guillain-Barre syndrome (GBS) is an autoimmune disease of demyelination and inflammation of peripheral nerves. Current treatments are limited to plasma exchange and intravenous immunoglobulins. Cargo-free nanoparticles (NPs) have been evaluated here for their therapeutic benefit on the disease course of experimental autoimmune neuritis (EAN), mimicking the human GBS. NPs prepared from poly-lactic co-glycolic acid (PLGA) with variable size and surface charge (i.e., 500 nm vs. 130 nm, polyvinyl alcohol (PVA) vs. sodium cholate), were intravenously administered in before- or early-onset treatment schedules in a rat EAN model. NP treatment mitigated distinctly the clinical severity of EAN as compared to the P2-peptide control group (P2) in all treatments and reduced the trafficking of inflammatory monocytes at inflammatory loci and diverted them towards the spleen. Therapeutic treatment with NPs reduced the expression of proinflammatory markers (CD68 (P2: 34.8 ± 6.6 vs. NP: 11.9 ± 2.3), IL-1ß (P2: 18.3 ± 0.8 vs. NP: 5.8 ± 2.2), TNF-α (P2: 23.5 ± 3.7 vs. NP: 8.3 ± 1.7) and elevated the expression levels of anti-inflammatory markers CD163 (P2: 19.7 ± 3.0 vs. NP: 41.1 ± 6.5; all for NP-PVA of 130 nm; relative to healthy control). These results highlight the therapeutic potential of such cargo-free NPs in treating EAN, which would be easily translatable into clinical use due to their well-known low-toxicity profile.
RÉSUMÉ
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract with increasing incidence worldwide. Although a deeper understanding of the underlying mechanisms of IBD has led to new therapeutic approaches, treatment options are still limited. Severe adverse events in conventional drug therapy and poor drug targeting are the main cause of early therapy failure. Nanoparticle-based targeting approaches can selectively deliver drugs to the site of inflammation and reduce the risk of side effects by decreasing systemic availability. Here, we developed a nanoparticulate platform for the delivery of the anti-TNF-α antibody adalimumab (ADA) by covalent crosslinking to the particle surface. ADA binding to nanoparticles improved the stability of ADA against proteolytic degradation in vitro and led to a significantly better therapeutic outcome in a murine colitis model. Moreover, immobilization of ADA reduced systemic exposure, which can lead to enhanced therapeutic safety. Thus, nanoparticle protein decoration constitutes a platform through which epithelial delivery of any biological of interest to the inflamed gut and hence a local treatment can be achieved.
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Polymeric nanoparticles can passively target inflamed tissues. How their physicochemical properties affect their distribution pattern among the infiltrating immune cells is unknown. Polyvinyl acetate nanoparticles with different particle size (100 and 300â¯nm) and surface charge (cationic, non-ionic, and anionic) were prepared and incubated with either LPS-activated or unactivated murine splenocytes. Nanoparticle association with macrophages, dendritic cells, neutrophils, B and T cells was investigated using flow cytometry. Cells associated with nanoparticles as follows: cationic>anionic>non-ionic and 300â¯nmâ¯>â¯100â¯nm. 40% of ionic nanoparticles were distributed among unactivated macrophages, reduced to 25% for activated macrophages. 60% of 100â¯nm and 40% of 300â¯nm non-ionic nanoparticles were distributed among unactivated and LPS-activated macrophages. This study highlights that particles' physicochemical properties impact the number of nanoparticles associating with immune cells more than their distribution pattern, which is principally determined by the cell activation state. This suggests a disease-dependent distribution pattern for therapeutic nanoparticles.
Sujet(s)
Système immunitaire/effets des médicaments et des substances chimiques , Macrophages/effets des médicaments et des substances chimiques , Nanoparticules/effets indésirables , Rate/effets des médicaments et des substances chimiques , Animaux , Lignée cellulaire , Cytométrie en flux , Humains , Macrophages/anatomopathologie , Macrophages/ultrastructure , Souris , Nanoparticules/usage thérapeutique , Taille de particule , Polymères/effets indésirables , Polymères/usage thérapeutique , Rate/cytologie , Propriétés de surfaceRÉSUMÉ
Drug crystallization in transdermal patches is still a major challenge, confronting the formulation development of topical drug delivery systems. Encapsulation of drugs into nanoparticles is proposed here as a promising tool for regulating drug crystallization in transdermal patches. The degree of recrystallization and transdermal permeation of ibuprofen and hydrocortisone loaded in polymeric and lipid nanoparticles from matrix-type transdermal patches were investigated. Ethyl cellulose (EC4), poly (lactide-co-glycolic acid) (PLGA) and polycaprolactone (PCL) were employed for polymeric nanoparticle preparations; while medium chain triglyceride (MCT) and witepsol were used for the preparation of MCT nanoemulsion and solid lipid nanoparticles (SLNs), respectively. As control, similar patches were prepared containing the free form of the investigated model drugs. All nanoparticle-containing transdermal patches exhibited less degree of drug recrystallization after 4 weeks compared to the control groups. Among the investigated nanocarriers, transdermal patches formulated with drug-loaded lipid nanoparticles showed the lowermost degree of recrystallization. Drug encapsulation into SLNs succeeded to reduce the degree of ibuprofen and hydrocortisone recrystallization from 23.3 ± 0.9 and 21.9 ± 1.2% to 0.2 ± 0.1 and 1.8 ± 0.1%, respectively. Additionally, the decreased crystalline fraction was accompanied by a corresponding increase in the drug flux through excised pig skin, which was found to be correlated to the hydrophobicity of the different nanocarriers. In conclusion, polymeric and lipid nanoparticles proved to be effective tools for the preparation of transdermal patches with on-demand drug loadings, while lowering the recrystallization risks. Moreover, the results of this study can be a valuable guidance for the design of effective transdermal patches by controlling the crystallization of various drugs through fine tuning of the carrier hydrophobicity.
Sujet(s)
Vecteurs de médicaments/administration et posologie , Nanoparticules/administration et posologie , Animaux , Cellulose/administration et posologie , Cellulose/analogues et dérivés , Cellulose/composition chimique , Cristallisation , Vecteurs de médicaments/composition chimique , Libération de médicament , Hydrocortisone/administration et posologie , Hydrocortisone/composition chimique , Ibuprofène/administration et posologie , Ibuprofène/composition chimique , Nanoparticules/composition chimique , Polyesters/administration et posologie , Polyesters/composition chimique , Copolymère d'acide poly(lactique-co-glycolique)/administration et posologie , Copolymère d'acide poly(lactique-co-glycolique)/composition chimique , Peau/métabolisme , Absorption cutanée , Suidae , Patch transdermique , Triglycéride/administration et posologie , Triglycéride/composition chimiqueRÉSUMÉ
Particle size of nanoparticles and the respective polydispersity are key factors influencing their biopharmaceutical behavior in a large variety of therapeutic applications. Predicting these attributes would skip many preliminary studies usually required to optimize formulations. The aim was to build a mathematical model capable of predicting the particle size of polymeric nanoparticles produced by a pharmaceutical polymer of choice. Polymer properties controlling the particle size were identified as molecular weight, hydrophobicity and surface activity, and were quantified by measuring polymer viscosity, contact angle and interfacial tension, respectively. A model was built using artificial neural network including these properties as input with particle size and polydispersity index as output. The established model successfully predicted particle size of nanoparticles covering a range of 70-400nm prepared from other polymers. The percentage bias for particle prediction was 2%, 4% and 6%, for the training, validation and testing data, respectively. Polymer surface activity was found to have the highest impact on the particle size followed by viscosity and finally hydrophobicity. Results of this study successfully highlighted polymer properties affecting particle size and confirmed the usefulness of artificial neural networks in predicting the particle size and polydispersity of polymeric nanoparticles.
Sujet(s)
Nanoparticules/composition chimique , Polymères/composition chimique , Chimie pharmaceutique/méthodes , Vecteurs de médicaments/composition chimique , , Taille de particule , Polyéthylène glycols/composition chimiqueRÉSUMÉ
The use of nanoparticles for drug delivery is still restricted by their limited stability when stored in an aqueous medium. Freeze drying is the standard method for long-term storage of colloidal nanoparticles; however the method needs to be elaborated for each formulation. Spray freeze drying (SFD) is proposed here as a promising alternative for lyophilizing colloidal nanoparticles. Different types of polymeric and lipid nanoparticles were prepared and characterized. Afterwards, samples were spray freeze dried by spraying into a column of cold air with a constant concentration of different cryoprotectants, and the frozen spherules were collected for further freeze drying. Similar samples were prepared using the commonly used technique, freeze drying, as controls. Using SFD, fast-dissolving, spherical and porous nanocomposite microparticles with remarkably high flowability (CI≤10) were produced. On the contrary to similar samples prepared using the freeze drying technique, the investigated polymeric and lipid nanoparticles were completely reconstituted (Sf/Si ratio <1.5) after SFD. SFD proved to be an effective platform for improving the long-term stability of colloidal nanoparticles.
Sujet(s)
Systèmes de délivrance de médicaments , Lipides/composition chimique , Nanoparticules , Polymères/composition chimique , Chimie pharmaceutique/méthodes , Colloïdes , Stabilité de médicament , Stockage de médicament , Lyophilisation , Porosité , SolubilitéRÉSUMÉ
Lung cancer, the deadliest solid tumor among all types of cancer, remains difficult to treat. This is a result of unavoidable exposure to carcinogens, poor diagnosis, the lack of targeted drug delivery platforms and limitations associated with delivery of drug to deep lung tissues. Development of a non-invasive, patient-convenient formula for the targeted delivery of chemotherapeutics to cancer in deep lung tissue is the aim of this study. The formulation consisted of inhalable polyvinylpyrrolidone (PVP)/maltodextrin (MD)-based microparticles (MPs) encapsulating chitosan (CS) nanoparticles (NPs) loaded with either drug only or drug and magnetic nanoparticles (MNPs). Drug release from CS NPs was enhanced with the aid of MNPs by a factor of 1.7 in response to external magnetic field. Preferential toxicity by CS NPs was shown towards tumor cells (A549) in comparison to cultured fibroblasts (L929). The prepared spray freeze dried (SFD) powders for CS NPs and CS MNPs were of the same size at â¼6µm. They had a fine particle fraction (FPF≤5.2µm) of 40-42% w/w and mass median aerodynamic diameter (MMAD) of 5-6µm as determined by the Next Generation Impactor (NGI). SFD-MPs of CS MNPs possess higher MMAD due to the high density associated with encapsulated MNPs. The developed formulation demonstrates several capabilities including tissue targeting, controlled drug release, and the possible imaging and diagnostic values (due to its MNPs content) and therefore represents an improved therapeutic platform for drug delivery to cancer in deep lung tissue.
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Chitosane/composition chimique , Systèmes de délivrance de médicaments , Tumeurs du poumon/traitement médicamenteux , Poumon/effets des médicaments et des substances chimiques , Nanoparticules/composition chimique , Poudres/administration et posologie , Administration par inhalation , Chimie pharmaceutique , Chitosane/administration et posologie , Vecteurs de médicaments/composition chimique , Libération de médicament , Lyophilisation , Humains , Poumon/métabolisme , Tumeurs du poumon/métabolisme , Magnétisme , Nanoparticules/administration et posologie , Taille de particule , Poudres/composition chimique , Cellules cancéreuses en cultureRÉSUMÉ
INTRODUCTION: Respiratory infections and diseases are accompanied by or exhibit inflammation. Recent advances in nanoparticle engineering technology, together with the increased knowledge of inflammatory pathophysiology, have ignited interest in the pulmonary delivery of anti-inflammatory agents (AIAs) to achieve local treatment of pulmonary inflammatory disorders. AREAS COVERED: This review summarizes and discusses the investigated formulation approaches for the pulmonary delivery of AIAs, including: inhalation of actives as suspensions or dry powder formulations, with polymeric micro- and nano-delivery carriers, or within liposomes and lipid nanoparticles. Some recent approaches for targeting AIAs to the pulmonary endothelium have also been reviewed. The discussion focuses on finding out whether the investigated approaches were really able to achieve lung targeting and reduce the side effects associated with the systemic administration of AIAs. EXPERT OPINION: The use of the inhalation route for the pulmonary delivery of AIAs is facing several challenges. Some of the investigated formulation approaches appear to be promising in overcoming these challenges. However, in order to create products that reach patients, more therapeutically oriented studies are still needed to ensure formulation stability, in-vivo sustained release behavior, pulmonary retention, and bypassing lung clearance mechanisms.
Sujet(s)
Anti-inflammatoires/administration et posologie , Systèmes de délivrance de médicaments , Poumon/métabolisme , Administration par inhalation , Chimie pharmaceutique , Humains , Lipides/composition chimique , Liposomes , Maladies pulmonaires/traitement médicamenteux , Nanoparticules , Polymères/composition chimique , PoudresRÉSUMÉ
Formulating nanoparticles for delivery to the deep lung is complex and many techniques fail in terms of nanoparticle stability. Spray freeze drying (SFD) is suggested here for the production of inhalable nanocomposite microcarriers (NCM). Different nanostructures were prepared and characterized including polymeric and lipid nanoparticles. Nanoparticle suspensions were co-sprayed with a suitable cryoprotectant into a cooled, stainless steel spray tower, followed by freeze drying to form a dry powder while equivalent compositions were spray dried (SD) as controls. SFD-NCM possess larger specific surface areas (67-77 m(2)/g) and lower densities (0.02 g/cm(3)) than their corresponding SD-NCM. With the exception of NCM of lipid based nanocarriers, SFD produced NCM with a mass median aerodynamic diameter (MMAD) of 3.0±0.5 µm and fine particle fraction (FPF⩽5.2 µm) of 45±1.6% with aerodynamic performances similar to SD-NCM. However, SFD was superior to SD in terms of maintaining the particle size of all the investigated polymeric and lipid nanocarriers following reconstitution (S(f)/S(i) ratio for SFD≈1 versus >1.5 for SD). The SFD into cooled air proved to be an efficient technique to prepare NCM for pulmonary delivery while maintaining the stability of the nanoparticles.
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Nanoparticules/composition chimique , Poudres/composition chimique , Administration par inhalation , Chimie pharmaceutique/méthodes , Vecteurs de médicaments/composition chimique , Préparation de médicament/méthodes , Inhalateurs à poudre sèche/méthodes , Lyophilisation/méthodes , Lipides/composition chimique , Taille de particuleRÉSUMÉ
Solvent toxicity is one of the major drawbacks in the preparation of polymeric nanoparticles today. Here, polyethylene glycols (PEGs) are proposed as non-toxic solvents for the preparation of polymeric nanoparticles. Based on a preparation process similar to the solvent displacement technique, several process parameters were examined for their effects on the properties of the prepared nanoparticles by this method to achieve the optimum preparation conditions. The investigated parameters included polymer type and concentration, volume and temperature of the dispersing phase, methods of dispersing the solvent phase into the non-solvent phase, duration and speed of stirring and washing by dialysis. Ammonio methacrylate copolymer (Eudragit RL), poly-lactide-co-glycolide (PLGA), and PEG-PLGA were found to be successful polymer candidates for the preparation of nanoparticles by this method. Nanoparticles with diameters ranging from 80 to 400 nm can be obtained. The encapsulation efficiencies of bovine serum albumin, and lysozyme as model proteins were ranging from 7.3±2.2% to 69.3±1.8% depending on the strength of polymer-protein interaction. Biological assays confirmed a full lysozyme activity after the preparation process. PEG proved to be a suitable non-toxic solvent for the preparation of polymeric protein-loaded nanoparticles, maintaining the integrity of protein.