RESUMO
Fundus neovascularization diseases are a series of blinding eye diseases that seriously impair vision worldwide. Currently, the means of treating these diseases in clinical practice are continuously evolving and have rapidly revolutionized treatment opinions. However, key issues such as inadequate treatment effectiveness, high rates of recurrence, and poor patient compliance still need to be urgently addressed. Multifunctional nanomedicine can specifically respond to both endogenous and exogenous microenvironments, effectively deliver drugs to specific targets and participate in activities such as biological imaging and the detection of small molecules. Nano-in-micro (NIM) delivery systems such as metal, metal oxide and up-conversion nanoparticles (NPs), quantum dots, and carbon materials, have shown certain advantages in overcoming the presence of physiological barriers within the eyeball and are widely used in the treatment of ophthalmic diseases. Few studies, however, have evaluated the efficacy of NIM delivery systems in treating fundus neovascular diseases (FNDs). The present study describes the main clinical treatment strategies and the adverse events associated with the treatment of FNDs with NIM delivery systems and summarizes the anatomical obstacles that must be overcome. In this review, we wish to highlight the principle of intraocular microenvironment normalization, aiming to provide a more rational approach for designing new NIM delivery systems to treat specific FNDs.
Assuntos
Sistemas de Liberação de Medicamentos , Humanos , Animais , Sistemas de Liberação de Medicamentos/métodos , Neovascularização Patológica/tratamento farmacológico , Fundo de Olho , Pontos Quânticos/química , Nanopartículas Multifuncionais/química , Neovascularização Retiniana/tratamento farmacológico , Nanomedicina/métodos , Nanopartículas/químicaRESUMO
Diclofenac, a nonsteroidal anti-inflammatory drug, is commonly prescribed for managing osteoarthritis, rheumatoid arthritis, and post-surgical pain. However, oral administration of diclofenac often leads to adverse effects. This study introduces an innovative nano-in-micro approach to create diclofenac nanoparticle-loaded microneedle patches aimed at localised, sustained pain relief, circumventing the drawbacks of oral delivery. The nanoparticles were produced via wet-milling, achieving an average size of 200 nm, and then incorporated into microneedle patches. These patches showed improved skin penetration in ex vivo tests using Franz-cell setups compared to traditional diclofenac formulations. In vivo tests on rats revealed that the nanoparticle-loaded microneedle patches allowed for quick drug uptake and prolonged release, maintaining drug levels in tissues for up to 72 h. With a systemic bioavailability of 57 %, these patches prove to be an effective means of transdermal drug delivery. This study highlights the potential of this novel microneedle delivery system in enhancing the treatment of chronic pain with reduced systemic side effects.
Assuntos
Administração Cutânea , Anti-Inflamatórios não Esteroides , Diclofenaco , Sistemas de Liberação de Medicamentos , Agulhas , Diclofenaco/administração & dosagem , Diclofenaco/farmacocinética , Animais , Ratos , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacocinética , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Nanopartículas/administração & dosagem , Masculino , Pele/metabolismo , Absorção Cutânea/efeitos dos fármacos , Adesivo Transdérmico , Ratos Sprague-DawleyRESUMO
Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease that seriously threatens human life and health. Our previous study demonstrated the unique superiority of traditional Chinese medicine cryptotanshinone (CTS) combined with sustained pulmonary drug delivery for treating PF. In this study, we aimed to enhance the selectivity, targeting efficiency and sustained-release capability based on this delivery system. To this end, we developed and evaluated CTS-loaded modified liposomes-chitosan (CS) microspheres SM(CT-lipo) and liposome-exosome hybrid bionic vesicles-CS microspheres SM(LE). The prepared nano-in-micro particles system integrates the advantages of the carriers and complements each other. SM(CT-lipo) and SM(LE) achieved lung myofibroblast-specific targeting through CREKA peptide binding specifically to fibronectin (FN) and the homing effect of exosomes on parent cells, respectively, facilitating efficient delivery of anti-fibrosis drugs to lung lesions. Furthermore, compared with daily administration of conventional microspheres SM(NC) and positive control drug pirfenidone (PFD), inhaled administration of SM(CT-lipo) and SM(LE) every two days still attained similar efficacy, exhibiting excellent sustained drug release ability. In summary, our findings suggest that the developed SM(CT-lipo) and SM(LE) delivery strategies could achieve more accurate, efficient and safe therapy, providing novel insights into the treatment of chronic PF.
Assuntos
Quitosana , Exossomos , Fibronectinas , Lipossomos , Fibrose Pulmonar , Animais , Humanos , Masculino , Administração por Inalação , Antifibróticos/administração & dosagem , Antifibróticos/química , Quitosana/química , Quitosana/administração & dosagem , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Exossomos/química , Fibronectinas/administração & dosagem , Lipossomos/química , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Microesferas , Fenantrenos/administração & dosagem , Fenantrenos/química , Fenantrenos/farmacocinética , Fibrose Pulmonar/tratamento farmacológico , Piridonas , Ratos Sprague-Dawley , RatosRESUMO
Pulmonary inflammations such as chronic obstructive pulmonary disease and cystic fibrosis are widespread and can be fatal, especially when they are characterized by abnormal mucus accumulation. Inhaled corticosteroids are commonly used for lung inflammations despite their considerable side effects. By utilizing particle engineering techniques, a combined dry powder inhaler (DPI) comprising nanosized ketoprofen-embedded mannitol-coated microparticles was developed. A nanoembedded microparticle system means a novel advance in pulmonary delivery by enhancing local pulmonary deposition while avoiding clearance mechanisms. Ketoprofen, a poorly water-soluble anti-inflammatory drug, was dispersed in the stabilizer solution and then homogenized by ultraturrax. Following this, a ketoprofen-containing nanosuspension was produced by wet-media milling. Furthermore, co-spray drying was conducted with L-leucine (dispersity enhancer) and mannitol (coating and mucuactive agent). Particle size, morphology, dissolution, permeation, viscosity, in vitro and in silico deposition, cytotoxicity, and anti-inflammatory effect were investigated. The particle size of the ketoprofen-containing nanosuspension was ~230 nm. SEM images of the spray-dried powder displayed wrinkled, coated, and nearly spherical particles with a final size of ~2 µm (nano-in-micro), which is optimal for pulmonary delivery. The mannitol-containing samples decreased the viscosity of 10% mucin solution. The results of the mass median aerodynamic diameter (2.4-4.5 µm), fine particle fraction (56-71%), permeation (five-fold enhancement), and dissolution (80% release in 5 min) confirmed that the system is ideal for local inhalation. All samples showed a significant anti-inflammatory effect and decreased IL-6 on the LPS-treated U937 cell line with low cytotoxicity. Hence, developing an innovative combined DPI comprising ketoprofen and mannitol by employing a nano-in-micro approach is a potential treatment for lung inflammations.
RESUMO
Conventional oral therapy for ulcerative colitis (UC) is associated with premature release or degradation of drugs in the harsh gastrointestinal environment, resulting in reduced therapeutic effectiveness. Consequently, the present study aims to develop a dual-targeted delivery system with a nanoparticle-in-microparticle (nano-in-micro) structure. The prepared Asiatic Acid-loaded delivery system (AA/CDM-BT-ALG) has pH-sensitive properties. Cellular uptake evaluation confirms that nanoparticles exhibit targeted absorption by macrophages and Caco-2 cells through mannose (Man) receptor and biotin-mediated endocytosis, respectively. Therefore, this mechanism effectively enhances intracellular drug concentration. Additionally, the biodistribution study conducted on the gastrointestinal tract of mice indicates that the colon of the microspheres group shows higher fluorescence intensity with longer duration than the other groups. This finding indicates that the microspheres exhibit selective accumulation in areas of colon inflammation. In vivo experiments in colitis mice showed that AA/CDM-BT-ALG significantly alleviates the histopathological characteristics of the colon, reduced neutrophil, and macrophage infiltration, and decreases pro-inflammatory cytokine expression. Furthermore, the effect of AA/CDM-BT-ALG on colitis is validated to be closely related to the TLR4/MyD88/NF-κB signaling pathway. The present findings suggest that the development of a dual-targeted delivery system is accomplished effectively, with the potential to serve as a drug-controlled release system for treating UC.
Assuntos
Colite Ulcerativa , Colite , Nanopartículas , Camundongos , Humanos , Animais , Colite Ulcerativa/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Células CACO-2 , Distribuição Tecidual , Colite/tratamento farmacológico , Colo/metabolismo , Colo/patologia , Nanopartículas/química , Modelos Animais de DoençasRESUMO
Based on the biocompatibility and macrophage targeting of natural polysaccharides, combined with the physiological and pathological characteristics of the gastrointestinal tract and colonic mucosa of ulcerative colitis (UC), we prepare dexamethasone (Dex)-loaded oral colon-targeted nano-in-micro drug delivery systems coated with multilayers of chitosan (CS), hyaluronic acid (HA), and finally Eudragit S100 (ECHCD MPs) using a layer-by-layer coating technique for UC treatment through regulating the M1/M2 polarization of intestinal macrophages. HA/CS/Dex nanoparticles (HCD NPs) are ingested by macrophages via CD44 receptor-mediated endocytosis to regulate M1-to-M2 macrophage polarization and exert anti-inflammatory effects. Moreover, ECHCD MPs show better colon-targeting properties than Dex-loaded chitosan nanoparticles (CD NPs) and HCD NPs which is demonstrated by stronger mucoadhesion to inflamed colon tissues. After oral administration, ECHCD MPs exert significant anti-UC effects. Therefore, ECHCD MPs are proven to be as promising oral colon-targeting drug delivery systems for Dex and have potential application in UC treatment.
Assuntos
Quitosana , Colite Ulcerativa , Colite , Nanopartículas , Humanos , Ácido Hialurônico/farmacologia , Quitosana/farmacologia , Sistemas de Liberação de Medicamentos , Colite/tratamento farmacológico , Colite/patologia , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Macrófagos , ColoRESUMO
Intranasal delivery has gained prominence since 1990, when the olfactory mucosa was recognized as the window to the brain and the central nervous system (CNS); this has enabled the direct site specific targeting of neurological diseases for the first time. Intranasal delivery is a promising route because general limitations, such as the blood-brain barrier (BBB) are circumvented. In the treatment of multiple sclerosis (MS) or Alzheimer's disease, for example, future treatment prospects include specialized particles as delivery vehicles. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles are well known as promising delivery systems, especially in the area of nose-to-brain (N2B) delivery. Chitosan is also broadly known as a functional additive due to its ability to open tight junctions. In this study, we produced PLGA nanoparticles of different sizes and revealed for the first time their size-time-dependent uptake mechanism into the lamina propria of porcine olfactory mucosa. The intracellular uptake was observed for 80 and 175 nm within only 5 min after application to the epithelium. After 15 min, even 520 nm particles were detected, associated with nuclei. Especially the presence of only 520 nm particles in neuronal fibers is remarkable, implying transcellular and intracellular transport via the olfactory or the trigeminal nerve to the brain and the CNS. Additionally, we developed successfully specialized Nano-in-Micro particles (NiMPs) for the first time via spray drying, consisting of PLGA nanoparticles embedded into chitosan microparticles, characterized by high encapsulation efficiencies up to 51%, reproducible and uniform size distribution, as well as smooth surface. Application of NiMPs accelerated the uptake compared to purely applied PLGA nanoparticles. NiMPs were spread over the whole transverse section of the olfactory mucosa within 15 min. Faster uptake is attributed to additional paracellular transport, which was examined via tight-junction-opening. Furthermore, a separate chitosan penetration gradient of â¼150 µm caused by dissociation from PLGA nanoparticles was observed within 15 min in the lamina propria, which was demonstrated to be proportional to an immunoreactivity gradient of CD14. Due to the beneficial properties of the utilized chitosan-derivative, regarding molecular weight (150-300 kDa), degree of deacetylation (80%), and particle size (0.1-10 µm) we concluded that M2-macrophages herein initiated an anti-inflammatory reaction, which seems to already take place within 15 min following chitosan particle application. In conclusion, we demonstrated the possibility for PLGA nanoparticles, as well as for chitosan NiMPs, to take all three prominent intranasal delivery pathways to the brain and the CNS; namely transcellular, intracellular via neuronal cells, and paracellular transport.
RESUMO
The anti-tumor necrosis factor-α (anti-TNF-α) blocker, has shown great efficacy for the treatment of inflammatory bowel disease (IBD). However, systemic exposure to it can cause considerable safety problems due to reduced suppression of the systemic immune response and loss of response to the production of anti-drug antibodies. Thus, we try to devise a targeted vehicle system for oral administration of anti-TNF-α antibodies for the treatment of IBD. In the present study, we developed an oral Infliximab (IFX) loaded nano-in-microparticles, based on chitosan (CS)/carboxymethyl chitosan (CMC) and alginate (Alg), which could protect IFX from the harsh environment of the gastrointestinal tract and produce targeted drug delivery to the inflamed intestine. In vivo studies demonstrated that the IFX loaded nano-in-micro vehicle can alleviate colitis by ameliorating inflammation and maintaining the intestinal epithelial barrier.
Assuntos
Alginatos/química , Quitosana/análogos & derivados , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/administração & dosagem , Nanopartículas/química , Administração Oral , Animais , Quitosana/química , Colite/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Feminino , Células HT29 , Humanos , Inflamação/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Infliximab/química , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Inibidores do Fator de Necrose Tumoral/administração & dosagem , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Post-traumatic osteoarthritis (PTOA) associated with joint injury triggers a degenerative cycle of matrix destruction and inflammatory signaling, leading to pain and loss of function. Here, prolonged RNA interference (RNAi) of matrix metalloproteinase 13 (MMP13) is tested as a PTOA disease modifying therapy. MMP13 is upregulated in PTOA and degrades the key cartilage structural protein type II collagen. Short interfering RNA (siRNA) loaded nanoparticles (siNPs) were encapsulated in shape-defined poly(lactic-co-glycolic acid) (PLGA) based microPlates (µPLs) to formulate siNP-µPLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-µPLs against MMP13 (siMMP13-µPLs) in a mechanical load-induced mouse model of PTOA maintained potent (65-75%) MMP13 gene expression knockdown and reduced MMP13 protein production in joint tissues throughout a 28-day study. MMP13 silencing reduced PTOA articular cartilage degradation/fibrillation, meniscal deterioration, synovial hyperplasia, osteophytes, and pro-inflammatory gene expression, supporting the therapeutic potential of long-lasting siMMP13-µPL therapy for PTOA.
Assuntos
Sistemas de Liberação de Medicamentos , Articulações/lesões , Metaloproteinase 13 da Matriz/administração & dosagem , Osteoartrite , Animais , Metaloproteinase 13 da Matriz/genética , Camundongos , Nanopartículas , Osteoartrite/terapia , RNA Interferente PequenoRESUMO
Full visible spectrum photonic droplets and consequent microcapsules with nano-in-micro structure were prepared through microfluidic technique. Photo-curable resin and suspension of monodispersed soft nanogels were used as shell and core of the microcapsules, respectively. Upon UV irradiation, the droplets can be subsequently transformed into photonic microcapsules with an ultrathin polymeric shell. The shell thickness of the photonic microcapsules was found to be approximately 700 nm. Due to the ultrathin shell and soft core, the photonic microcapsules with nano-in-micro structure display dramatic changes both in shapes and photonic property under the impact of osmosis effect or temperature stimulus. Typically, the shell and core parts of nano-in-micro structure could respectively undergo a size expansion/even rupture and a size decrease/buckling under hypotonic and hypertonic condition. Correspondingly, the peak value of the reflection spectra of the microcapsules showed a redshift and blue shift, respectively. The mechanism to the structure and optical properties variation involves the osmotic pressure induced the volume-fraction change of the nanogel-based photonic dispersion and the shell buckling of the core/shell microcapsules.
RESUMO
Chitosan nano-in-microparticles (NMPs) are promising carrier systems that have gained recently more interest aiming to combine advantages of both the nano- and microsystems. They have been employed for various purposes including sustained pulmonary delivery of drugs and pulmonary delivery of peptides, proteins, or genes or as injectable scaffolds for simultaneous delivery of stem cells and supporting growth factors. Among these delivery systems, chitosan was a common ingredient due to its biocompatibility, biodegradability, and ability to sustain the release of drugs and improving their bioavailability. Here we introduce a method for the development of chitosan self-assembly nanoparticles and the incorporation of these nanoparticles into chitosan microparticles via spray drying.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , QuitosanaRESUMO
It is crucial to develop dual or multi-modal self-imaging embolic microspheres to evaluate the effects of transcatheter arterial embolization therapy of tumor. However, the preparation of such hybrid microspheres always involved in multiple steps or complicated conditions. Here, poly(vinyl alcohol) (PVA) hybrid microspheres with dual-modal T1/T2-weighted magnetic resonance imaging (MRI) have been prepared based on microfluidic technique in one step. Gd2O3 and Fe3O4 nanoparticles with a size of ~5 nm act as T1- and T2-weighted MRI contrast agents, respectively, which are simultaneously in-situ synthesized in the PVA matrix via the reaction of metal ions and alkali with PVA chains as a soft template. Meanwhile, these metallic-oxide nanoparticles act as cross-linker to gelatinize the PVA droplets to obtain nano-in-micro PVA microspheres in one step. This procedure is simple, economic and feasible. The obtained nano-in-micro PVA microspheres show good magnetothermal effect, enhanced T1- and T2-weighted MRI and embolization effect.
Assuntos
Meios de Contraste/metabolismo , Embolização Terapêutica/métodos , Neoplasias Hepáticas Experimentais/terapia , Imageamento por Ressonância Magnética/métodos , Nanopartículas de Magnetita/química , Microesferas , Álcool de Polivinil/química , Animais , Neoplasias Hepáticas Experimentais/metabolismo , Neoplasias Hepáticas Experimentais/patologia , CoelhosRESUMO
The preparation of a nano-in-micro delivery system (NiMDS) under mild conditions without using toxic organic solvents and expensive equipment still faces challenges. In this study, we introduced the co-axial air flow method to prepare NiMDS for the oral delivery of conjugated linoleic acid (CLA). The chitosan nanoparticles were prepared using the stearic-acid-modified chitosan through self-aggregation. Then, the chitosan nanoparticles were incorporated into alginate microparticles by the co-axial air flow method. The obtained chitosan nanoparticles and NiMDS were spherical in shape with the average sizes of 221â»243 nm and 130â»160 µm, respectively. Compared with alginate microparticles, the hybrid particles were of fewer fragments, were bigger in size, had a higher mechanical strength, and showed a controlled release in the phosphate buffer solution (pH 1.2 or 7.4). The release kinetics study showed that encapsulating the chitosan nanoparticles into the alginate microparticles inhibited the dissolution of alginate microparticles at the initial stage. These results revealed the potential of NiMDS as an ideal oral carrier for the sustained release of CLA in the gastrointestinal environment.
Assuntos
Ácidos Linoleicos Conjugados/administração & dosagem , Ácidos Linoleicos Conjugados/química , Nanopartículas/administração & dosagem , Nanopartículas/química , Administração Oral , Alginatos/química , Células CACO-2 , Linhagem Celular Tumoral , Quitosana/química , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Tamanho da Partícula , SolubilidadeRESUMO
Functionalized gold nanoparticles (AuNPs) have been widely investigated as promising multifunctional nanosystems for the theragnosis of lung cancer, the most common and prominent cause of cancer death worldwide. Nevertheless, nanoparticles are not in appropriate sizes for an accurate deep lung delivery and the lack of locally and effective delivery of therapeutic biomolecules to the deep lungs is, in fact, the major cause of low therapeutic outcome. Herein we incorporate, for the first time, AuNPs into respirable microparticles. AuNPs were functionalized with biocompatible oligo(2-oxazoline)-based optically stable fluorescent coatings, and conjugated with a laminin peptide (YIGSR) for targeted lung cancer delivery. These POxylated AuNPs were then incorporated into a chitosan matrix by a clean process, supercritical CO2-assisted spray drying (SASD), yielding nano-in-micro clean ultrafine dry powder formulations. The engineered formulations present the adequate morphology and flowability to reach the deep lung, with aerodynamic sizes ranging 3.2-3.8µm, and excellent fine particle fraction (FPF) (FPF of 47% for CHT-bearing targeted AuNPs). The optimal biodegradation and release profiles enabled a sustained and controlled release of the embedded nanoparticles, with enhanced cellular uptake, opening new prospects for future lung theragnosis.