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In order to ensure prolonged pharmacokinetic profile along with local tolerability at the injection site, tricaprylin-based drug crystalline suspension (TS) was designed and its local distribution, pharmacokinetics, and inflammatory response, were evaluated with conventional aqueous suspension (AS). As model drug particles, entecavir 3-palmitate (EV-P), an ester lipidic prodrug for entecavir (EV), was employed. The EV-P-loaded TS was prepared by ultra-sonication method. Prepared TS and conventional AS exhibited comparable morphology (rod or rectangular), median diameter (2.7 and 2.6 µm), crystallinity (melting point of 160-165°C), and in vitro dissolution profile. However, in vivo performances of drug microparticles were markedly different, depending on delivery vehicle. At AS-injected site, drug aggregates of up to 500 µm were formed upon intramuscular injection, and were surrounded with inflammatory cells and fibroblastic bands. In contrast, no distinct particle aggregation and adjacent granulation was observed at TS-injected site, with >4 weeks remaining of the oily vehicle in micro-computed tomographic observation. Surprisingly, TS exhibited markedly alleviated local inflammation compared to AS, endowing markedly lessened necrosis, fibrosis thickness, inflammatory area, and macrophage infiltration. The higher initial systemic exposure was observed with TS compared to AS, but TS provided prolonged delivery of EV for 3 weeks. Therefore, we suggest that the novel TS system can be a promising tool in designing parenteral long-acting delivery, with improved local tolerability.
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Locust bean gum (LBG), a polysaccharide-based natural polymer, is being widely researched as an appropriate additive for various products, including food, gluten-free formulations, medicines, paper, textiles, oil well drilling, cosmetics, and medical uses. Drug delivery vehicles, packaging, batteries, and catalytic supports are all popular applications for biopolymer-based materials. This review discusses sustainable food packaging and drug delivery applications for LBG. Given the benefits of LBG polysaccharide as a source of dietary fiber, it is also being investigated as a potential treatment for many health disorders, including colorectal cancer, diabetes, and gastrointestinal difficulties. The flexibility of LBG polysaccharide allows it to form hydrogen bonds with water molecules, a crucial characteristic of biomaterials, and the film-forming properties of LBG are critical for food packaging applications. The extraction process of LBG plays an important role in properties such as viscosity and gel-forming properties. Moreover, there are multiple factors such as temperature, pressure, pH, etc. The LBG-based functional composite film is effective in improving the shelf life as well as monitoring the freshness of fruits, meat and other processed food. The LBG-based hydrogel is excellent carrier of drugs and can be used for slow and sustainable release of active components present in drugs. Thus, the primary goal of this review was to conduct a comprehensive evaluation of the literature with a focus on the composition, properties, processing, food packaging, and medicine delivery applications of LBG polysaccharides. Thus, we investigated the chemical composition, extraction, and characteristics of LBG polysaccharides that underlie their applications in the food packaging and medicine delivery fields.
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Sistemas de Liberação de Medicamentos , Embalagem de Alimentos , Galactanos , Mananas , Gomas Vegetais , Polissacarídeos , Gomas Vegetais/química , Galactanos/química , Mananas/química , Embalagem de Alimentos/métodos , Polissacarídeos/química , Humanos , Portadores de Fármacos/químicaRESUMO
Alzheimer's disease (AD) is a neurodegenerative disorder initiated by amyloid-beta (Aß) accumulation, leading to impaired cognitive function. Several delivery approaches have been improved for AD management. Among them, human serum albumin (HSA) is broadly employed for drug delivery and targeting the Aß in AD owing to its biocompatibility, Aß inhibitory effect, and nanoform, which showed blood-brain barrier (BBB) crossing ability via glycoprotein 60 (gp60) receptor and secreted protein acidic and rich in cysteine (SPARC) protein to transfer the drug molecules in the brain. Thus far, there is no previous review focusing on HSA and its drug delivery system in AD. Hence, the reviewed article aimed to critically compile the HSA therapeutic as well as drug delivery role in AD management. It also delivers information on how HSA-incorporated nanoparticles with surfaced embedded ligands such as TAT, GM1, and so on, not only improve BBB permeability but also increase neuron cell targetability in AD brain. Additionally, Aß and tau pathology, including various metabolic markers likely BACE1 and BACE2, etc., are discussed. Besides, the molecular interaction of HSA with Aß and its distinctive forms are critically reviewed that HSA can segregate Zn(II) and Cu(II) metal ions from Aß owing to high affinity. Furthermore, the BBB drug delivery challenges in AD are addressed. Finally, the clinical formulation of HSA for the management of AD is critically discussed on how the HSA inhibits Aß oligomer and fibril, while glycated HSA participates in amyloid plaque formation, i.e., ß-structure sheet formation. This review report provides theoretical background on HSA-based AD drug delivery and makes suggestions for future prospect-related work.
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Doença de Alzheimer , Barreira Hematoencefálica , Sistemas de Liberação de Medicamentos , Humanos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Albumina Sérica Humana/administração & dosagem , Animais , Nanopartículas/administração & dosagem , Peptídeos beta-Amiloides/metabolismoRESUMO
FoxO1, a member of the Forkhead transcription factor family subgroup O (FoxO), is expressed in a range of cell types and is crucial for various pathophysiological processes, such as apoptosis and inflammation. While FoxO1's roles in multiple diseases have been recognized, the target has remained largely unexplored due to the absence of cost-effective and efficient inhibitors. Therefore, there is a need for natural FoxO1 inhibitors with minimal adverse effects. In this study, docking, MMGBSA, and ADMET analyses were performed to identify natural compounds that exhibit strong binding affinity to FoxO1. The top candidates were then subjected to molecular dynamics (MD) simulations. A natural product library was screened for interaction with FoxO1 (PDB ID- 3CO6) using the Glide module of the Schrödinger suite. In silico ADMET profiling was conducted using SwissADME and pkCSM web servers. Binding free energies of the selected compounds were assessed with the Prime-MMGBSA module, while the dynamics of the top hits were analyzed using the Desmond module of the Schrödinger suite. Several natural products demonstrated high docking scores with FoxO1, indicating their potential as FoxO1 inhibitors. Specifically, the docking scores of neochlorogenic acid and fraxin were both below -6.0. These compounds also exhibit favorable drug-like properties, and a 25 ns MD study revealed a stable interaction between fraxin and FoxO1. Our findings highlight the potential of various natural products, particularly fraxin, as effective FoxO1 inhibitors with strong binding affinity, dynamic stability, and suitable ADMET profiles.
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Tamarind seed polysaccharide (TSP) is a biocompatible, non-ionic polymer with antioxidant properties. Its uses include drug delivery, food industry, and wastewater treatment. TSP has various hydroxy functional groups, one of the most favorable sites for graft copolymerization of different monomers. Hence, various chemical methods for TSP modification were developed to satisfy increasing industrial demand. Of particular interest in scientific community are the methods of graft copolymerization because of their ability to alter the physicochemical properties of TSP, including pH sensitivity and the swelling index, leading to improvements in the adsorption efficiency of hazardous heavy metals and dyes from wastewater effluents. Moreover, in recent years, TSP has been used for controlled drug delivery applications due to its unique advantages of high viscosity, broad pH tolerance, non-carcinogenicity, mucoadhesive properties, biocompatibility, and high drug entrapment capacity. In light of the plethora of literature on the topic, a comprehensive review of TSP-based graft copolymers and unmodified and modified TSP important applications is necessary. Therefore, this review comprehensively highlights several synthetic strategies for TSP-grafted copolymers and discusses unmodified and modified TSP potential applications, including cutting-edge pharmaceutical, environmental applications, etc. In brief, its many advantages make TSP-based polysaccharide a promising material for applications in various industries.
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Tamarindus , Tamarindus/química , Polissacarídeos/química , Preparações Farmacêuticas , Sistemas de Liberação de Medicamentos , Viscosidade , Sementes/químicaRESUMO
Activation of NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) has been associated with multiple chronic pathologies, including diabetes, atherosclerosis, and rheumatoid arthritis. Moreover, histone deacetylases (HDACs), specifically HDAC6 is required for the NLRP3 inflammasome to assemble and activate. Thus, NLRP3 serves as an attractive target for the development of novel therapeutic approaches. Several companies are now attempting to develop specific modulators of the NLRP3 inflammasome, but only a handful of small molecules of NLRP3 inflammasome inhibitors, such as MCC950 and Tranilast, are currently available for clinical use. However, their use is limited due to severe side effects and short half-lives. Thus, the repurposing of FDA-approved drugs with NLRP3 inhibitory activity is needed. The present study was aimed at repurposing preexisting drugs that might act as safe and effective NLRP3 inhibitors. A library of 2,697 FDA-approved drugs was screened for binding with NLRP3 (PDB: 7ALV) using Glide (Schrödinger). The top seven FDA-approved drugs with potential binding affinities were selected based on docking scores and subjected to ADMET profiling using pkCSM and SwissADME. The binding of the ADMET-favorable FDA-approved drugs to NLRP3 was validated using MMGBSA (Prime) and Molecular Dynamics (Desmond) in the Schrödinger suite. ADMET profiling revealed that of the seven best docking drugs, empagliflozin and citicoline had good drug-likeness properties. Moreover, MMGBSA analysis and molecular dynamics demonstrated that empagliflozin and citicoline exhibited stable ligand-NLRP3 interactions in the presence of solvents. This study sheds light on the ability of various FDA-approved drugs to act as NLRP3 inhibitors.Communicated by Ramaswamy H. Sarma.
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Biofilms developed by microorganisms cause an extremely severe clinical problem that leads to drug failure. Bioactive polymeric hydrogels display potential for controlling the formation of microorganism-based biofilms, but their rapid biodegradability in these biofilm sites is still a major challenge. To overcome this, chitosan (CS), a natural functional biomaterial, has been used because of its effective penetrability in the cell wall of microorganisms; however, its fast biodegradability has restricted its further use. Hence, in this study, to improve the stability of CS and increase its penetration retention inside a biofilm, grafted CS was prepared and then crosslinked with sodium alginate (SA) to synthesize CS-poly(MA-co-AA)SA hydrogel via a free radical grafting method, therefore enhancing its antibiofilm efficiency against biofilms. The prepared hydrogel demonstrated excellent effectiveness against (≥90 % inhibition) biofilms of Candida albicans. Additionally, in vitro and in vivo safety assays established that the prepared hydrogel can be used in a biofilm microenvironment and might reduce drug resistance burden owing to its long-term antibiofilm effect and improved CS stability at the biofilm site. Furthermore, in vitro wound healing outcomes of hydrogel indicated its potential application for chronic wound treatment. This research opens a new advanced strategy for biofilm-associated infection treatment, including wound treatment.
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Quitosana , Fluconazol , Fluconazol/farmacologia , Quitosana/farmacologia , Candida albicans , Alginatos/farmacologia , Hidrogéis/farmacologia , Biofilmes , Movimento CelularRESUMO
Mechanical constraints imposed on the Pd-H system can induce significant strain upon hydrogenation-induced expansion, potentially leading to changes in the thermodynamic behavior, such as the phase-transition pressure. However, the investigation of the constraint effect is often tricky due to the lack of simple experimental techniques for measuring hydrogenation-induced expansion. In this study, a capacitive-based measurement system is developed to monitor hydrogenation-induced areal expansion, which allows us to control and evaluate the magnitude of the substrate constraint. By using the measurement technique, the influence of substrate constraint intensity on the thermodynamic behavior of the Pd-H system is investigated. Through experiments with different constraint intensities, it is found that the diffefrence in the constraint intensity minimally affects the phase-transition pressure when the Pd-H system allows the release of constraint stress through plastic deformation. These experiments can improve the understanding of the substrate constraint behaviours of Pd-H systems allowing plastic deformation while demonstrating the potential of capacitive-based measurement systems to study the mechanical-thermodynamic coupling of M-H systems.
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Despite the superior clinical efficacy of the re-esterified triglyceride (rTG) form compared to the ethylester form, few studies have been conducted on improving the bioavailability of the rTG form of omega-3 oil. The aim of study was to evaluate the effect of self emulsifying formulation on the improvement of bioavailability of rTG form of omega-3 oil. To develop a re-esterified triglyceride (rTG) soft capsule, an rTG-loaded self-emulsifying delivery system (SEDS) was designed using coconut oil, polysorbate 80, and lecithin. Candidate formulations were designed from a phase-diagram study and optimal SEDS formulations containing 85% of high omega-3 (ω-3) oils were screened from the evaluation of droplet size distribution, measurement of oil floating area and emulsion turbidity. The selected, optimized rTG SEDS formulation was filled into a soft capsule (NOVASEDS) and applied to a sequence-randomized, double-blind, single-dose, and two-way crossover clinical study (n = 44), and the the bioavailability of NOVASEDS was compared with that of a 'raw' rTG capsule (rTG OMEGA3) as control. The droplet size (D50) formed from the candidate formulations was approximately 30-45 µm, and the optimal formulation showed a unimodal particle distribution with the smallest oil floating area and small changes in turbidity after 24 h. Cmax and AUC from 0 to 24 h for NOVASEDS, calculated from docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and as the sum of DHA and EPA, were significantly higher (P < 0.05) than corresponding values for rTG OMEGA3. In conclusion, NOVASEDS formulated by SEDS technology enabled the manufacture of a high rTG payload soft capsule with improved bioavailability in human subjects.
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The simultaneous drug delivery efficiency of a co-loaded single-carrier system of docetaxel (DTX)- and tariquidar (TRQ)-loaded nanostructured lipid carrier (NLC) functionalized with PEG and RIPL peptide (PRN) (D^T-PRN) was compared with that of a physically mixed dual-carrier system of DTX-loaded PRN (D-PRN) and TRQ-loaded PRN (T-PRN) to overcome DTX mono-administration-induced multidrug resistance. NLC samples were prepared using the solvent emulsification evaporation technique and showed homogeneous spherical morphology, with nano-sized dispersion (<220 nm) and zeta potential values of -15 to -7 mV. DTX and/or TRQ was successfully encapsulated in NLC samples (>95% encapsulation efficiency and 73-78 µg/mg drug loading). In vitro cytotoxicity was concentration-dependent; D^T-PRN exhibited the highest MDR reversal efficiency, with the lowest combination index value, and increased the cytotoxicity and apoptosis in MCF7/ADR cells by inducing cell-cycle arrest in the G2/M phase. A competitive cellular uptake assay using fluorescent probes showed that, compared to the dual nanocarrier system, the single nanocarrier system exhibited better intracellular delivery efficiency of multiple probes to target cells. In the MCF7/ADR-xenografted mouse models, simultaneous DTX and TRQ delivery using D^T-PRN significantly suppressed tumor growth as compared to other treatments. A single co-loaded system for PRN-based co-delivery of DTX/TRQ (1:1, w/w) constitutes a promising therapeutic strategy for drug-resistant breast cancer cells.
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Epidermal growth factor (EGF) has been used in wound management and regenerative medicine since the late 1980s. It has been widely utilized for a long time and still is because of its excellent tolerability and efficacy. EGF has many applications in tissue engineering, cancer therapy, lung diseases, gastric ulcers, and wound healing. Nevertheless, its in vivo and during storage stability is a primary concern. This review focuses on the topical use of EGF, especially in chronic wound healing, the emerging use of biomaterials to deliver it, and future research possibilities. To successfully deliver EGF to wounds, a delivery system that is proteolytically resistant and stable over the long term is required. Biomaterials are an area of interest for the development of such systems. These systems may be used in non-healing wounds such as diabetic foot ulcers, pressure ulcers, and burns. In these pathologies, EGF can reduce the risk of amputation of the lower extremities, as it accelerates the wound healing process. Furthermore, appropriate delivery system would also stabilize and control the EGF release profile in a wound. Several in vitro and in vivo studies have already proven the efficacy of such systems in the above-mentioned types of wounds. Moreover, several formulations such as ointments and intralesional injections are already available on the market. However, these products are still problematic in terms of inadequate diffusion of EGF, low bioavailability storage conditions, and shelf-life. This review discusses the nano formulations comprising biomaterials infused with EGF which could be a promising delivery system for chronic wound healing in the future.
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Pé Diabético , Veteranos , Humanos , Fator de Crescimento Epidérmico/farmacologia , Fator de Crescimento Epidérmico/uso terapêutico , Cicatrização , Sistemas de Liberação de Medicamentos , Pé Diabético/tratamento farmacológicoRESUMO
To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.
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Diabetes Mellitus , Insulina , Ratos , Animais , Humanos , Ratos Sprague-Dawley , Emulsões/química , Solubilidade , Sistemas de Liberação de Medicamentos/métodos , Administração Oral , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Disponibilidade BiológicaRESUMO
The lipophilicity of a peptide drug can be considerably increased by hydrophobic ion pairing with amphiphilic counterions for successful incorporation into lipid-based formulations. Herein, to enhance the oral absorption of insulin (INS), a self-microemulsifying drug delivery system (SMEDDS) formulation was developed. Prior to optimization, INS was complexed with sodium n-octadecyl sulfate (SOS) to increase the loading into the SMEDDS. The INS-SOS complex was characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and its dissociation behavior. The SMEDDS was optimized using a D-optimal mixture design with three independent variables including Capmul MCM (X1, 9.31%), Labrasol (X2, 49.77%), and Tetraglycol (X3, 40.92%) and three response variables including droplet size (Y1, 115.2 nm), INS stability (Y2, 46.75%), and INS leakage (Y3, 17.67%). The desirability function was 0.766, indicating excellent agreement between the predicted and experimental values. The stability of INS-SOS against gastrointestinal enzymes was noticeably improved in the SMEDDS, and the majority of INS remained in oil droplets during release. Following oral administration in diabetic rats, the optimized SMEDDS resulted in pharmacological availabilities of 3.23% (50 IU/kg) and 2.13% (100 IU/kg). Thus, the optimized SMEDDS is a good candidate for the practical development of oral delivery of peptide drugs such as INS.
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Diabetes Mellitus Experimental , Insulina , Administração Oral , Animais , Disponibilidade Biológica , Diabetes Mellitus Experimental/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Ratos , SolubilidadeRESUMO
Background: Montelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer's disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency. Purpose: This study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration. Methods: To decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats. Results: Microscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 µm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 µm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks. Conclusion: The MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer's disease with extended dose intervals.
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Doença de Alzheimer , Nanopartículas , Acetatos , Animais , Ciclopropanos , Nanopartículas/química , Tamanho da Partícula , Quinolinas , Ratos , Solubilidade , Sulfetos , SuspensõesRESUMO
Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q10, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q10 solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q10 within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q10 suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q10 suspension. A Coenzyme Q10 brain distribution study revealed a higher Coenzyme Q10 distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q10 suspension. Coenzyme Q10-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q10.
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Sistemas de Liberação de Medicamentos , Ubiquinona , Administração Oral , Animais , Disponibilidade Biológica , Encéfalo , Emulsões , Excipientes , Ratos , Solubilidade , TensoativosRESUMO
Despite the multiple ongoing and novel initiatives for developing brain-targeted drug delivery systems, insurmountable obstacles remain. A perfect drug delivery device that can bypass the brain-blood barrier and boost therapeutic efficacy is urgently needed for clinical applications. Exosomes hold unrivaled benefits as a drug delivery vehicle for treating brain diseases due to their endogenous and innate attributes. Unique properties, such as the ability to penetrate physical barriers, biocompatibility, innate targeting features, ability to leverage natural intracellular trafficking pathways, favored tumor homing, and stability, make exosomes suitable for brain-targeted drug delivery. Herein, we provide an overview of recent exosome-based drug delivery nanoplatforms and discuss how these inherent vesicles can be used to deliver therapeutic agents to the brain to cure neurodegenerative diseases, brain tumors, and other brain disorders. Moreover, we review the current roadblocks associated with exosomes and other brain-targeted drug delivery systems and discuss future directions for achieving successful therapy outcomes.
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Encefalopatias , Exossomos , Neoplasias , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Encefalopatias/tratamento farmacológico , Encefalopatias/metabolismo , Sistemas de Liberação de Medicamentos , Exossomos/metabolismo , Humanos , Neoplasias/tratamento farmacológicoRESUMO
DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation via interaction with EZH2 and is involved in the canonical Wnt signaling pathway. Additionally, interaction between UC.145 and another long non-coding RNA adjacent to DKK1, PRKG1-AS1, induced a synergistic effect on Wnt signaling. The regulation of these three genes was closely associated with patient overall survival. Inactivation of UC.145 induced apoptosis and inhibited the growth and migratory, invasive, and colony-forming abilities of gastric cancer cells. The study findings provide insights into Wnt signaling in gastric cancer and support UC.145 as a potential novel predictive biomarker for the disease.
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A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.
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Nanopartículas , Administração Oral , Animais , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Emulsões , Tamanho da Partícula , Pirimidinonas , Ratos , Solubilidade , Tetra-HidroisoquinolinasRESUMO
INTRODUCTION: The buccal route has been considered an attractive alternative delivery route for injectable formulations. Cell-penetrating peptides (CPPs) are gaining increased attention for their cellular uptake and tissue permeation effects. This study was aimed to evaluate the in vitro and ex vivo permeation-enhancing effect of penetratin-conjugated liposomes for salmon calcitonin (sCT) in TR146 human buccal cells and porcine buccal tissues. METHODS: Penetratin was conjugated to phospholipids through a maleimide-thiol reaction. Liposomes were prepared and sCT was encapsulated using a thin-film hydration method. Physical properties such as particle size, zeta potential, encapsulation efficiency, and morphological images via transmission electron microscopy were obtained. Cellular uptake studies were conducted using flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). A cell permeation study was performed using a Transwell® assay, and permeation through porcine buccal tissue was evaluated. The amount of sCT permeated was quantified using an ELISA kit and was optically observed using CLSM. RESULTS: The particle size of penetratin-conjugated liposomes was approximately 123.0 nm, their zeta potential was +29.6 mV, and their calcitonin encapsulation efficiency was 18.0%. In the cellular uptake study using FACS and CLSM, stronger fluorescence was observed in penetratin-conjugated liposomes compared with the solution containing free sCT and control liposomes. Likewise, the amount of sCT permeated from penetratin-conjugated liposomes was higher than that from the free sCT solution and control liposomes by 5.8-fold across TR146 cells and 91.5-fold across porcine buccal tissues. CONCLUSION: Penetratin-conjugated liposomes are considered a good drug delivery strategy for sCT via the buccal route.
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Peptídeos Penetradores de Células , Lipossomos , Animais , Calcitonina , Peptídeos Penetradores de Células/farmacologia , Sistemas de Liberação de Medicamentos/métodos , Humanos , Lipossomos/química , Mucosa Bucal , Absorção pela Mucosa Oral , SuínosRESUMO
Improving the aqueous solubility of poorly soluble compounds have been a major issue in the pharmaceutical industry. In the present study, binary amorphous solid dispersions (SDs) of Coenzyme Q10 (CoQ10), a biopharmaceutics classification system (BCS) II compound and Soluplus® were prepared to enhance the solubility and pharmacokinetic properties compared to crystalline CoQ10. SDs were prepared with different ratios of CoQ10 and Soluplus® (1:3, 1:5, and 1:7) using spray drying technology, and the physicochemical properties of the SDs were evaluated. X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy suggested the conversion of the crystalline form of CoQ10 to a binary amorphous system in the SDs. Fourier transform infrared spectroscopy revealed no potential interactions between CoQ10 and Soluplus®. The solubility of the optimal SD formulation (SD 1:7) was approximately 9000-fold higher than that of crystalline CoQ10, and the increment was Soluplus® concentration dependent. As a result, optimized SD 1:7 also showed significantly enhanced dissolution rate where maximum drug release was observed within 30 min in two different dissolution media. Moreover, in contrast to crystalline CoQ10, CoQ10 SDs showed improved pharmacokinetic parameters. Thus, the SD 1:7 formulation is expected to improve biopharmaceutical properties and therapeutic efficacy of CoQ10.