RESUMEN
Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and ß-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease ß-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.
Asunto(s)
Alcaloides , Enfermedad de Alzheimer , Ciclodextrinas , Polifenoles , Sesquiterpenos , Animales , Ratas , Enfermedad de Alzheimer/tratamiento farmacológico , Acetilcolinesterasa , Peróxido de Hidrógeno , Encéfalo , Mucosa Nasal , Péptidos beta-Amiloides , EscopolaminaRESUMEN
Some cancer cell membrane (CCM)-derived nanovesicles show strong homing effects and are used for targeted cancer therapy. By co-constructing the B16F10 cell membrane with a PEGylated phospholipid membrane, a new nanocarrier with a composite nanocrown structure was developed, which can evade immune recognition and actively target homologous melanoma. The nanocrowns have an encapsulation efficiency of more than 90% for paclitaxel and showed no significant difference (p > 0.05) from the PEGylated phospholipid membrane vesicles. Compared with the hyaluronic acid-modified PEGylated phospholipid membrane vesicles, the biomimetic nanocrowns enhanced the escape of nanovesicles from reticuloendothelial cells in vitro and extended the circulation time in vivo; moreover, the nanocrowns showed superior melanoma-targeted drug delivery capability and improved anticancer effects of paclitaxel as demonstrated by the inhibition of B16F10 cell proliferation and induction of apoptosis by interfering with microtubule formation. In contrast, the modification of hyaluronic acid did not increase the targeting capacity or antitumor effects of the nanocrowns, confirming that the superior targeting capacity was mediated by the exposed homologous CCMs rather than by hyaluronic acid. Our results demonstrate the potential of using biomimetic nanocrowns for active melanoma-targeted therapy.
Asunto(s)
Melanoma , Nanopartículas , Línea Celular Tumoral , Membrana Celular , Humanos , Ácido Hialurónico/química , Melanoma/tratamiento farmacológico , Nanopartículas/química , Paclitaxel/uso terapéutico , Fosfolípidos , PolietilenglicolesRESUMEN
We designed cholesterol- and phospholipid-free multilamellar niosomes (MLNs) structured by glyceryl monooleate (GMO) and poloxamer 407 (F127), and evaluated their capacity for transdermal drug delivery. The optimized MLNs had a mean size of 97.88 ± 63.25 nm and an encapsulation efficiency of 82.68% ± 2.14%. The MLNs exhibited a remarkable sustained cargo release, and improved the permeation of the stratum corneum. Compared with the tincture, lower transdermal flux but higher skin deposition of aconitine in vitro were achieved in the MLN group (p < 0.05). Additionally, both water-soluble rhodamine B- and liposoluble coumarin 6-labeled MLNs were found to penetrate deeply into the skin through the hair follicles and could be internalized by fibroblasts Notably, the MLNs possessed greater wettability, and the study focused on delivery to deeper hair follicles and up to the outer hair sheath, which showed advantages for treating diseases of hair follicles, and was potentially superior to the hydrophobic PLGA nanoparticles (diameter: 637.87 ± 22.77 nm) which mainly accumulated in superficial hair follicles. Hair follicles were therefore demonstrated to be an important way to enhance skin permeability, and MLNs are a promising alternative for topical and transdermal drug delivery.
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Liposomas , Nanopartículas , Administración Cutánea , Animales , Colesterol/metabolismo , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Folículo Piloso , Liposomas/química , Nanopartículas/química , Fosfolípidos/química , Ratas , Ratas Sprague-Dawley , Piel/metabolismo , Absorción CutáneaRESUMEN
The greatest limitation in the development of transdermal drug delivery systems is that only a few drugs can permeate the skin due to the barrier function of the stratum corneum. Active and passive methods are generally available for improving the ability of drug transdermal delivery. However, nanoparticles, as a passive approach, exhibit capacity-constrained permeation enhancement. Thus, microneedle-mediated nanoparticles possess enormous potential and broad prospects. Microneedles promote the penetration of macromolecules by creating microchannels on the skin surface. In this review, the prevailing subknowledge on microneedles (mechanism, classification, and applications of microneedles combined with nanoparticles) is discussed to provide a guideline for readers and a basic reference for further in-depth studies of this novel drug delivery system.
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Agujas , Absorción Cutánea , Administración Cutánea , Sistemas de Liberación de Medicamentos , Microinyecciones , Piel/metabolismoRESUMEN
Due to the lack of a delivery system that actively targets hypertrophic scar fibroblasts (HSFs), it is difficult to concentrate the effects of drugs on hypertrophic scars (HSs). We recently discovered that the HSF membrane has a homologous targeting effect and developed an active targeted drug delivery system for the local treatment of HSs. A diphenyl carbonate cross-linked cyclodextrin metal organic framework (CDF) containing more than 26% (w/w) quercetin (QUE) was coated with a HSF membrane (QUE@HSF/CDF) and then dispersed in Bletilla striata polysaccharide (BSP)-fabricated dissolvable microneedles (BSP-MNs-QUE@HSF/CDF) for local administration. This biomimetic nanodrug delivery system improved efficacy on HSs by regulating Wnt/ß-catenin and JAK2/STAT3 pathways and reducing the expression of collagens I and III in HS, and this performance was superior to those of systems without HSF functionalization or the assistance of microneedles. Additionally, we found that BSP has synergistic effects and the microneedles have higher mechanical strength and better physical stability than microneedles made of hyaluronic acid. This currently designed drug delivery strategy integrating biomimetic nanoparticles and dissolvable microneedles is promising for applications in the fields of skin disease treatment and cosmetics.
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Cicatriz Hipertrófica , Ciclodextrinas , Estructuras Metalorgánicas , Biomimética , Cicatriz Hipertrófica/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Humanos , Estructuras Metalorgánicas/uso terapéutico , Microinyecciones , AgujasRESUMEN
To overcome the poor water solubility of total flavones of Arisaematis rhizoma, microemulsions (MEs) can be used as a carrier for transdermal administration to promote their solubilization and skin permeability. Here, we investigated the physical compatibility of MEs in hydrogels and their skin permeation-enhancing effects. Transparency of microemulsion-based hydrogels (MBGs) was analyzed to evaluate ME compatibility with different hydrogel matrices. Transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy were used to explore the microstructures of MBGs and ME-hydrogel combinations. Uniform and transparent MBG was obtained by adding 1% sodium hyaluronate (SH) to the optimized ME. MBG prepared with SH as a matrix expressed pseudoplastic-fluid and shear-thinning characteristics, making it easy to apply in clinical settings. No new FTIR peak occurred in the MBG compared with ME and hydrogel matrix, indicating a physical combination of ME and the polymer network gel. Nanoscale droplets of ME migrated in the gel network, and the migration capacity and in vitro transdermal permeation flux negatively correlated with SH concentration in the gel system. In conclusion, in MBGs, ME can keep nanoscale droplets migrating in the hydrogel network, thereby enhancing transdermal drug delivery.
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Medicamentos Herbarios Chinos/administración & dosificación , Medicamentos Herbarios Chinos/farmacocinética , Hidrogeles/química , Absorción Cutánea/efectos de los fármacos , Administración Cutánea , Química Farmacéutica , Portadores de Fármacos/química , Liberación de Fármacos , Estabilidad de Medicamentos , Emulsiones/química , Microscopía Electrónica de Transmisión , Nanopartículas/química , SolubilidadRESUMEN
There is a lack of actively targeting drug delivery carriers for the topical treatment of epidermal diseases, which results in drug waste and an increased incidence of toxic side effects in the clinic. We recently discovered that epidermal cells (HaCaT cells) have homologous targeting functions and developed HaCaT cell membrane-coated pH-sensitive micelles for therapeutic active targeting of skin disease. We encapsulated shikonin in these biomimetic nanocarriers and found that the nanocarriers accumulated mainly in the active epidermis when delivered with karaya gum-fabricated water-soluble microneedles. The nanocarriers were internalized by the target cells, resulting in swelling of histidine fragments with protonation and subsequent triggering of drug release, which increased the therapeutic efficacy of shikonin against imiquimod-induced psoriatic epidermal hyperplasia. This emerging biomimetic delivery strategy is a new approach for improving the treatment of skin diseases and is also very promising for use in the field of cosmetics. Additionally, we found abnormally high protein expression of Na+/K+-ATPase in diseased skin; thus, this protein may be a biomarker of psoriasis.
Asunto(s)
Queratinocitos , Psoriasis , Administración Cutánea , Portadores de Fármacos/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Imiquimod/uso terapéutico , Agujas , Psoriasis/tratamiento farmacológico , PielRESUMEN
Melittin is a promising antitumor substance; however, it is a nonspecific cytolytic peptide, which limits its clinical application. In this study, melittin liposomes (Mel-Lip) and hyaluronic acid (HA)-modified Mel-Lip (Mel-HA-Lip) were designed to reduce the toxicity and increase the anti-tumor effects of melittin. The optimal preparation procedure was evaluated using a uniform design based on the single factor method, and the concentration of HA was determined based on the cellular uptake of coumarin 6 labeled HA-Lip. Liposomes and HA-modified liposomes were evaluated in vitro by assessing cytotoxicity, cellular uptake, and release behavior. Liposomes prepared in the optimum formulation improved stability, with a particle size of 132.7 ± 1.55 nm, zeta potential of -11.5 ± 1.51 mV, entrapment efficiency of 86.25 ± 1.28%, and drug-loading efficiency of 3.91 ± 0.49%. Cellular uptake tests revealed that the uptake of nanoparticles significantly increased with HA modification, suggesting that HA modification enhanced the internalization of liposomes within cells, which was consistent with the results of the cytotoxicity analysis. Furthermore, in vitro release experiments showed that Mel-HA-Lip possessed a stronger sustained-release effect compared with Mel-Lip. The results of this experiment provide insight into the potential tumor-targeting effects of melittin.
RESUMEN
BACKGROUND: A red blood cell membrane (RBCm)-derived drug delivery system allows prolonged circulation of an antitumor treatment and overcomes the issue of accelerated blood clearance induced by PEGylation. However, RBCm-derived drug delivery systems are limited by low drug-loading capacities and the lack of tumor-targeting ability. Thus, new designs of RBCm-based delivery systems are needed. RESULTS: Herein, we designed hyaluronic acid (HA)-hybridized RBCm (HA&RBCm)-coated lipid multichambered nanoparticles (HA&RBCm-LCNPs) to remedy the limitations of traditional RBCm drug delivery systems. The inner core co-assembled with phospholipid-regulated glycerol dioleate/water system in HA&RBCm-LCNPs met the required level of blood compatibility for intravenous administration. These newly designed nanocarriers had a honeycomb structure with abundant spaces that efficiently encapsulated paclitaxel and IR780 for photochemotherapy. The HA&RBCm coating allowed the nanocarriers to overcome the reticuloendothelial system barrier and enhanced the nanocarriers specificity to A549 cells with high levels of CD44. These properties enhanced the combinatorial antitumor effects of paclitaxel and IR780 associated with microtubule destruction and the mitochondrial apoptotic pathway. CONCLUSIONS: The multifunctional HA&RBCm-LCNPs we designed expanded the functionality of RBCm and resulted in a vehicle for safe and efficient antitumor treatment.