RESUMO
Overexpression of P-glycoprotein (P-gp) on cancer cells is a major hurdle to effectively treat tumors with multidrug resistance (MDR). The current study aimed to explore anticancer drug and P-gp inhibitor delivery as a promising strategy to efficiently treat colorectal cancer with MDR. To this end, a multidrug-loaded all-in-one nanosponge (ANS) was developed to simultaneously deliver doxorubicin (DOX), paclitaxel (PTX), and the P-gp inhibitor tetrandrine (TET), referred to as DOX/PTX/TET@ANS, without chemical conjugation. ANS with high loading content and efficiency facilitated a pH-dependent and controlled release with different profiles. Compared to free drugs and DOX/PTX@ANS, DOX/PTX/TET@ANS exhibited more effective anticancer effects on P-gp-overexpressing colorectal cancer cells and solid tumor mouse xenografts, without major toxicity. Notably, ANS composed of pluronic shell induced in vitro P-gp inhibition compared to TET, implying a synergistic anticancer effect. These findings suggest that ANS can encapsulate multiple drugs to efficiently deliver chemotherapy, particularly in MDR tumors.
Assuntos
Neoplasias , Poloxâmero , Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Animais , Linhagem Celular Tumoral , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Humanos , Camundongos , Poloxâmero/farmacologiaRESUMO
Atopic dermatitis (AD) is a chronic cutaneous disease with a complex underlying mechanism, and it cannot be completely cured. Thus, most treatment strategies for AD aim at relieving the symptoms. Although corticosteroids are topically applied to alleviate AD, adverse side effects frequently lead to the withdrawal of AD therapy. Tacrolimus (TAC), a calcineurin inhibitor, has been used to treat AD, but its high molecular weight and insolubility in water hinder its skin permeability. Herein, we developed and optimized TAC-loaded chitosan-based nanoparticles (TAC@CNPs) to improve the skin permeability of TAC by breaking the tight junctions in the skin. The prepared nanoparticles were highly loadable and efficient and exhibited appropriate characteristics for percutaneous drug delivery. TAC@CNP was stable for 4 weeks under physiological conditions. CNP released TAC in a controlled manner, with enhanced skin penetration observed. In vitro experiments showed that CNP was non-toxic to keratinocyte (HaCaT) cells, and TAC@CNP dispersed in an aqueous solution was as anti-proliferative as TAC solubilized in a good organic solvent. Importantly, an in vivo AD mouse model revealed that topical TAC@CNP containing ~1/10 of the dose of TAC found in commercially used Protopic® Ointment exhibited similar anti-inflammatory activity to that of the commercial product. TAC@CNP represents a potential therapeutic strategy for the management of AD.
Assuntos
Quitosana , Dermatite Atópica , Nanopartículas , Tacrolimo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Tacrolimo/química , Tacrolimo/farmacologia , Tacrolimo/administração & dosagem , Tacrolimo/farmacocinética , Tacrolimo/uso terapêutico , Quitosana/química , Animais , Nanopartículas/química , Camundongos , Humanos , Portadores de Fármacos/química , Pele/efeitos dos fármacos , Pele/patologia , Pele/metabolismo , Administração Tópica , Absorção Cutânea/efeitos dos fármacos , Liberação Controlada de Fármacos , Modelos Animais de Doenças , Células HaCaTRESUMO
Existing anticancer therapeutics exhibit short half-lives, non-specificity, and severe side effects. To address this, active-targeting nanoparticles have been developed; however, the complex fabrication procedures, scale-up, and low reproducibility delay FDA approval, particularly for functionalized nanoparticles. We developed levan nanoparticles via simple one-pot nanoprecipitation for specific anticancer drug delivery. Levan is a plant polysaccharide which has a binding affinity to CD44 receptors and amphiphilicity. The nanoparticles are self-assembled and enable active-targeting without chemical modifications. The paclitaxel-loaded levan nanoparticles (PTX@LevNP) demonstrated a sustained PTX release and long-term stability. The LevNP can bind CD44 receptors on cancer cells, and PTX@LevNP showed enhanced anticancer activity in CD44-positive cells (SCC7 cells). In SCC7 tumor-bearing mice, the accumulation of LevNP in tumor tissue was 3.7 times higher than that of the free-dye, resulting in improved anticancer efficacy of PTX@LevNP. This new strategy using levan can produce nanoparticles for effective cancer treatment without complex fabrication procedures.
Assuntos
Nanopartículas , Neoplasias , Animais , Camundongos , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos/métodos , Frutanos/farmacologia , Neoplasias/tratamento farmacológico , Paclitaxel/farmacologia , Reprodutibilidade dos TestesRESUMO
Retinyl palmitate (RP) is a retinol ester with strong antioxidant and anti-inflammatory properties as an antiwrinkle agent. However, it has poor aqueous solubility and easily degrades into inactive forms for topical applications. Therefore, we developed chitosan-coated nanocapsules (ChiNCs) to encapsulate RP using a simple nanoprecipitation method for protection against physiological conditions and to enable deep skin penetration. The as-prepared RP-loaded nanocapsules (RP@ChiNCs) loaded with approximately 5 wt.% RP exhibited a hydrodynamic diameter of 86 nm and surface charge of 24 mV. They had adequate stability to maintain their physicochemical properties after lyophilization in a biological buffer. Notably, ChiNCs provided RP with remarkable protection against degradation for 4 weeks at 37 °C. Thus, RP@ChiNCs exhibited good antioxidant activity in situ for sufficiently long periods without considerable changes in their efficacy. Furthermore, ChiNCs enhanced the skin penetration of lipophilic RP based on the inherent nature of chitosan. RP@ChiNCs exhibited good in vitro antioxidant and anti-inflammatory effects without causing any cytotoxicity in dermal fibroblasts. Accordingly, they promoted cell proliferation in a wound-scratch test and enhanced collagen synthesis. These results suggest that RP@ChiNCs are promising candidates for cosmetic and biomedical applications.
RESUMO
Ferrocene-based nanoparticles have garnered interest as reactive oxygen species (ROS)-responsive nanocarriers of anticancer drugs and imaging agents. However, their biomedical applications remain limited due to their poor physiological stability. PEGylation of nanocarriers improves their stability and biocompatibility. In this study, we aimed to develop novel PEG-ferrocene nanoparticles (PFNPs) with enhanced stability and ROS responsiveness for the delivery of paclitaxel (PTX) and imaging agents. PEGylation improved the stability of ferrocene nanoparticles, inhibiting their ROS-responsive destruction. Several PEG-ferrocene polymers containing different molar ratios of methacrylic acid and poly (ethylene glycol) methyl ether methacrylate was designed for optimization. ROS-responsive polymers with optimal monomer ratios were self-assembled into PFNPs with enhanced stability. The PFNPs distended, effectively releasing encapsulated PTX and imaging agents within 8 h in the presence of ROS. Furthermore, they remained stable, with no changes in their hydrodynamic diameters or polydispersity indexes after storage in an aqueous solution and biological buffer. The accumulation of PFNPs in a tumor model in vivo was 15-fold higher than a free dye. PTX-loaded PFNPs showed a substantial tumor-suppression effect, reducing tumor size to approximately 18% of that in the corresponding control group. These findings suggest a promising application of ROS-responsive PFNPs in tumor treatment as biocompatible nanocarriers of anticancer drugs and imaging agents.
RESUMO
Osteoarthritis (OA) is a degenerative joint disorder associated with inflammation, functional disability, and high socioeconomic costs. The development of effective therapies against inflammatory OA has been limited owing to its complex and multifactorial nature. The efficacy of Prussian blue nanozymes coated with Pluronic (PPBzymes), US Food and Drug Administration-approved components, and their mechanisms of action have been described in this study, and PPBzymes have been characterized as a new OA therapeutic. Spherical PPBzymes were developed via nucleation and stabilization of Prussian blue inside Pluronic micelles. A uniformly distributed diameter of approximately 204 nm was obtained, which was maintained after storage in an aqueous solution and biological buffer. This indicates that PPBzymes are stable and could have biomedical applications. In vitro data revealed that PPBzymes promote cartilage generation and reduce cartilage degradation. Moreover, intra-articular injections with PPBzymes into mouse joints revealed their long-term stability and effective uptake into the cartilage matrix. Furthermore, intra-articular PPBzymes injections attenuated cartilage degradation without exhibiting cytotoxicity toward the synovial membrane, lungs, and liver. Notably, based on proteome microarray data, PPBzymes specifically block the JNK phosphorylation, which modulates inflammatory OA pathogenesis. These findings indicate that PPBzymes might represent a biocompatible and effective nanotherapeutic for obstructing JNK phosphorylation.
Assuntos
Cartilagem Articular , Osteoartrite , Camundongos , Animais , Fosforilação , Poloxâmero/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/uso terapêutico , Osteoartrite/patologia , Cartilagem Articular/metabolismo , Injeções Intra-ArticularesRESUMO
Prussian blue (PB) is a metal cluster nanoparticle (NP) of cyanide-bridged iron(II)-iron(III) and exhibits a characteristic blue color. Its peroxidase-, catalase-, and superoxide-dismutase-like activities effectively remove excess reactive oxygen species that induce inflammation and tumorigenesis. However, the dispersion of PB NPs is not sufficiently stable for their application in the biomedical field. In this study, we developed Pluronic-stabilized Prussian blue nanoparticles (PB/Plu NPs) using a series of Pluronic triblock copolymers as a template material for PB NPs. Considering the hydrophilic-lipophilic balance (HLB) values of the Pluronic series, including F68, F127, L35, P123, and L81, the diameters of the PB/Plu NPs decreased from 294 to 112 nm with decreasing HLB values. The smallest PB NP stabilized with Pluronic P123 (PB/PP123 NP) showed the strongest antioxidant and anti-inflammatory activities and wound-healing efficacy because of its large surface area. These results indicated that the spatial distribution of PB NPs in the micelles of Pluronic greatly improved the stability and reactive oxygen species scavenging activity of these NPs. Therefore, PB/Plu NPs using U.S.-FDA-approved Pluronic polymers show potential as biocompatible materials for various biomedical applications, including the treatment of inflammatory diseases in the clinic.
RESUMO
Chronic inflammatory wounds pose therapeutic challenges in the biomedical field. Polymeric nanofibrous matrices provide extracellular-matrix-like structures to facilitate wound healing; however, wound infection and the subsequent accumulation of reactive oxygen species (ROS) delay healing. Therefore, we herein developed electrospun nanofibers (NFs), composed of chitosan-stabilized Prussian blue (PBChi) nanoparticles (NPs) and poly(vinyl alcohol) (PVA), with ROS scavenging activity to impart antioxidant and wound healing properties. The PBChi NPs were prepared using chitosan with different molecular weights, and their weight ratio with respect to PVA was optimized to yield PBChi-NP-coated PVA NFs with well-defined NF structures. In situ and in vitro antioxidant activity assays showed that the PBChi/PVA NFs could effectively remove ROS. Particularly, PBChi/PVA NFs with a lower chitosan molecular weight exhibited greater antioxidant activity. The hydroxyl radical scavenging activity of PBChi10k/PVA NFs was 60.4 %, approximately two-fold higher than that of PBChi100k/PVA NFs. Further, at the concentration of 10 µg/mL, they could significantly lower the in vitro ROS level by up to 50.7 %. The NFs caused no significant reduction in cell viability, owing to the excellent biocompatibility of PVA with PBChi NPs. Treatment using PBChi/PVA NFs led to faster cell proliferation in in vitro scratch wounds, reducing their size from 202 to 162 µm. The PBChi/PVA NFs possess notable antioxidant and cell proliferation properties as ROS-scavenging wound dressings.
Assuntos
Quitosana , Nanofibras , Nanopartículas , Antibacterianos/química , Antioxidantes/química , Antioxidantes/farmacologia , Quitosana/química , Ferrocianetos , Radical Hidroxila , Nanofibras/química , Nanopartículas/química , Álcool de Polivinil/química , Espécies Reativas de Oxigênio , CicatrizaçãoRESUMO
Osteoarthritis (OA) is a degenerative joint disorder associated with inflammation, functional disability, and high socioeconomic costs. The development of effective therapies against inflammatory OA has been limited owing to its complex and multifactorial nature. The efficacy of Prussian blue nanozymes coated with Pluronic (PPBzymes), US Food and Drug Administration-approved components, and their mechanisms of action have been described in this study, and PPBzymes have been characterized as a new OA therapeutic. Spherical PPBzymes were developed via nucleation and stabilization of Prussian blue inside Pluronic micelles. A uniformly distributed diameter of approximately 204 nm was obtained, which was maintained after storage in an aqueous solution and biological buffer. This indicates that PPBzymes are stable and could have biomedical applications. In vitro data revealed that PPBzymes promote cartilage generation and reduce cartilage degradation. Moreover, intra-articular injections with PPBzymes into mouse joints revealed their long-term stability and effective uptake into the cartilage matrix. Furthermore, intra-articular PPBzymes injections attenuated cartilage degradation without exhibiting cytotoxicity toward the synovial membrane, lungs, and liver. Notably, based on proteome microarray data, PPBzymes specifically block the JNK phosphorylation, which modulates inflammatory OA pathogenesis. These findings indicate that PPBzymes might represent a biocompatible and effective nanotherapeutic for obstructing JNK phosphorylation.
Assuntos
Proteínas Quinases JNK Ativadas por Mitógeno , Osteoartrite , Estados Unidos , Animais , Camundongos , Fosforilação , Poloxâmero , Osteoartrite/tratamento farmacológicoRESUMO
Cancer, which is a leading cause of death, contributes significantly to reducing life expectancy worldwide. Even though paclitaxel (PTX) is known as one of the main anticancer drugs, it has several limitations, including low solubility in aqueous solutions, a limited dosage range, an insufficient release amount, and patient resistance. To overcome these limitations, we suggest the development of PTX-loaded thermosponge nanoparticles (PTX@TNP), which result in improved anticancer effects, via a simple nanoprecipitation method, which allows the preparation of PTX@TNPs with hydrophobic interactions without any chemical conjugation. Further, to improve the drug content and yield of the prepared complex, the co-organic solvent ratio was optimized. Thus, it was observed that the drug release rate increased as the drug capacity of PTX@TNPs increased. Furthermore, increasing PTX loading led to considerable anticancer activity against multidrug resistance (MDR)-related colorectal cancer cells (HCT 15), implying a synergistic anticancer effect. These results suggest that the solubilization of high drug amounts and the controlled release of poorly water-soluble PTX using TNPs could significantly improve its anticancer therapy, particularly in the treatment of MDR-p-glycoprotein-overexpressing cancers.
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Illite is a clay mineral that shows antioxidant and antibacterial activities because of the abundance of important clay elements in its structure. However, illite has low bioactivity due to its low solubility and electron-donating ability in aqueous solutions. Therefore, we aimed to develop polyvinylpyrrolidone (PVP)-stabilized illite microparticles (P-lite MPs) via polymer adsorption on illite surfaces. An increasing amount of PVP was used to coat a fixed amount of illite to prepare P-lite MPs of different hydrodynamic diameters in the range of 4-9 µm. These sizes were maintained for 2 weeks during storage in a biological buffer without any noticeable changes. The stabilization of illite microparticles using a hydrophilic PVP polymer improved their aqueous dispersity and free radical-scavenging activity. Since the large surface area of microparticles provides several sites for interactions, the smallest P-lite MP exhibited the highest antioxidant and antibacterial activities. More importantly, the MPs showed effective free radical-scavenging activity in vitro without any cytotoxicity. Therefore, P-lite MPs with improved bioavailability may represent a suitable bioactive material for various industrial and biomedical applications.
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Transepidermal drug delivery achieves high drug concentrations at the action site and ensures continuous drug delivery and better patient compliance with fewer adverse effects. However, drug delivery through topical application is still limited in terms of drug penetration. Chitosan is a promising enhancer to overcome this constraint, as it can enhance drug diffusion by opening the tight junctions of the stratum corneum. Therefore, here, we developed a novel chitosan nanosponge (CNS) with an optimal ratio and molecular weight of chitosan to improve drug penetration through skin. To prepare the CNS, two types of chitosan (3 and 10 kDa) were each conjugated with poloxamer 407 using para-nitrophenyl chloroformate, and the products were mixed with poloxamer 407 at ratios of 5:5, 8:2, and 10:0. The resulting mixtures were molded to produce flexible soft nanosponges by simple nanoprecipitation. The CNSs were highly stable in biological buffer for four weeks and showed no toxicity in human dermal fibroblasts. The CNSs increased drug permeability through human cadaver skin in a Franz-type diffusion cell, with substantially higher permeability with 3 kDa chitosan at a ratio of 8:2. This suggests the applicability of the novel CNS as a promising carrier for efficient transepidermal drug delivery.
RESUMO
BACKGROUND: Astaxanthin (ASTA), a carotenoid, is a strong antioxidant. However, its application in functional foods, pharmaceuticals, and cosmetics remains limited due to its low aqueous solubility and stability. Several different encapsulating materials have been used to improve the stability and bioavailability of ASTA; however, the currently investigated nano-carriers for ASTA require additional improvements with regard to their loading capacity and stability. METHODS: In this study, we developed lecithin nano-liposol (Lec NS) as a novel carrier of ASTA using a simple emulsion evaporation method. The physicochemical characteristics including hydrodynamic diameter, polydispersity index, surface charge and morphology were analyzed by DLS and TEM. The antioxidant activity of the ASTA-loaded Lec NS (ASTA@Lec NS) was evaluated using a DPPH radical scavenging assay and in vitro antioxidant assay. The study of in vitro wound healing efficacy was carried out to observe the beneficial effect of antioxidant activity of ASTA@Lec NS on cell migration. RESULTS: ASTA@Lec NS showed improved stability and efficacy owing to improved aqueous solubility of ASTA inside Lec NS. Both in situ and in vitro antioxidant activities of ASTA@Lec NS were higher than that of bare ASTA and Lec NS. It also exhibited strong wound healing efficacy by regulation of ROS level in in vitro cell model. CONCLUSION: This study revealed that the encapsulation of ASTA into Lec NS using a wet phase transfer enhanced its physiological stability and bioavailability for effective scavenging of reactive oxygen species.
Assuntos
Antioxidantes/farmacologia , Lecitinas/química , Nanopartículas/química , Cicatrização/efeitos dos fármacos , Animais , Disponibilidade Biológica , Morte Celular/efeitos dos fármacos , Lipossomos , Camundongos , Células NIH 3T3 , Nanopartículas/ultraestrutura , Solubilidade , Xantofilas/farmacologiaRESUMO
Aim: Prussian blue nanoparticles (PB NPs) have been reported as excellent antioxidant agents owing to their ability to scavenge reactive oxygen species. However, their poor stability in vivo limits their use in biomedical applications. Materials & methods: In this study, we developed chitosan-templated PB NPs using water-soluble chitosan samples with molecular weights ranging from 3 to 100 kDa, which stabilized the PB NPs and improved their antioxidant activity. Results & conclusion: The chitosan-templated PB NPs coordinated with the optimal chitosan molecular weight had uniform sphere-like particles, improved stability and effective scavenging activity of in vitro reactive oxygen species generation in murine fibroblast cells stimulated by oxidative stress agents without any cytotoxicity, implying that they could be promising antioxidant agents.
Assuntos
Antioxidantes/farmacologia , Quitosana/farmacologia , Ferrocianetos/farmacologia , Nanopartículas/química , Animais , Antioxidantes/química , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Quitosana/química , Ferrocianetos/química , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Peso Molecular , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/químicaRESUMO
Dengue fever is one of the most important mosquito-borne viral infections in large parts of tropical and subtropical countries and is a significant public health concern and socioeconomic burden. There is an urgent need to develop antivirals that can effectively reduce dengue virus (DENV) replication and decrease viral load. Niclosamide, an antiparasitic drug approved for human use, has been recently identified as an effective antiviral agent against a number of pH-dependent viruses, including flaviviruses. Here, we reveal that neutralization of low-pH intracellular compartments by niclosamide affects multiple steps of the DENV infectious cycle. Specifically, niclosamide-induced endosomal neutralization not only prevents viral RNA replication but also affects the maturation of DENV particles, rendering them non-infectious. We found that niclosamide-induced endosomal neutralization prevented E glycoprotein conformational changes on the virion surface of flaviviruses, resulting in the release of non-infectious immature virus particles with uncleaved pr peptide from host cells. Collectively, our findings support the potential application of niclosamide as an antiviral agent against flavivirus infection and highlight a previously uncharacterized mechanism of action of the drug.