Drug Delivery and Translational Research最新文献

Psoriasis is a prevalent chronic disease affecting 2-3% of the global population. Cyclosporine A (CyA) has been widely used with great promise in the treatment of moderate to severe psoriasis despite various side effects associated with its systemic administration. Topical administration of CyA circumvents systemic side effects; however, the poor water solubility and large molecular weight of CyA pose challenges for dermal delivery. In this study, choline-based ionic liquids (ILs) were used to enhance the dermal delivery of CyA for the potential treatment of psoriasis. All four ILs tested significantly improved the solubility of CyA, which was greater than that of the control group with dimethyl sulfoxide (DMSO) as a solubilizer (20%, w/w). The saturated solubility of CyA in two of the ILs, choline geranate ([Ch][Ge]) and choline ricinoleate ([Ch][Ra]), reached more than 90 mg/mL, and the solubilization capability of the ILs except [Ch][Ci] was resistant to water dilution. The negligible change in CyA content determined by high-performance liquid chromatography and the secondary structure detected by circular dichroism spectroscopy confirmed the stability of CyA in the ILs. At 4 h in the in vitro penetration test, the amount of CyA retained in the skin in the IL groups was slightly greater than that in the control group (20% DMSO). The water content of the ILs significantly affected their penetration ability. When the water content increased from 10 to 70%, the dermal delivery of CyA first increased, peaked at a water content of 30%, and then decreased. The dermal delivery ability of [Ch][Ge] and [Ch][Ra] with a water content of 70% was still comparable to that of 20% DMSO. Moreover, CyA-loaded ILs (0.5%, w/w) significantly relieved the symptoms of psoriasis in an imiquimod (IMQ)-induced mouse model, and the levels of inflammatory factors, including tumor necrosis factor α, interleukin 22 and interleukin 17, in the affected area were reduced by 71.7%, 75.6%, and 89.3%, respectively. The IL tested, choline sorbate ([Ch][So]), showed low cytotoxicity to human immortalized epidermal cells (HaCaT). After 7 days of consecutive application, [Ch][So] did not cause significant irritation. In conclusion, ILs demonstrate promising potential for the dermal delivery of CyA for the treatment of psoriasis.

Methotrexate successful therapy encounters various challenges in chemotherapy, such as poor oral bioavailability, low specificity, side effects and the development of drug resistances. In this study, it is proposed a dual-targeted nanocarrier comprising magnetite/chitosan nanoparticles for an efficient Methotrexate delivery. The formation of the particles was confirmed through morphological analysis using electron microscopy and elemental mappings via energy dispersive X-ray spectroscopy. These nanoparticles exhibited a size of ≈ 270 nm, a zeta potential of ≈ 24 mV, and magnetic responsiveness, as demonstrated by hysteresis cycle analysis and visual observations under a magnetic field. In addition, these particles displayed high stability, as evidenced by size and surface electric charge measurements, during storage at both 4 ºC and 25 ºC for at least 30 days. Electrophoretic properties were examined in relation to pH and ionic strength, confirming these core/shell nanostructure. The nanoparticles demonstrated a pH-responsive drug release as observed by a sustained Methotrexate release over the next 90 h under pH ≈ 7.4, while complete release occurred within 3 h under acidic conditions (pH ≈ 5.5). In the biocompatibility assessment, the magnetite/chitosan particles showed excellent hemocompatibility ex vivo and no cytotoxic effects on normal MCF-10 A and cancer MCF-7 cells. Furthermore, the Methotrexate-loaded nanoparticles significantly enhanced the antitumor activity reducing the half-maximal inhibitory concentration by ≈ 2.7-fold less compared to the free chemotherapeutic.

Multifunctional therapies have emerged as innovative strategies in cancer treatment. In this research article, we proposed a nanostructured lipid carrier (NLC) designed for the topical treatment of cutaneous melanoma, which simultaneously delivers 5-FU and Bcl-2 siRNA. The characterized nanoparticles exhibited a diameter of 259 ± 9 nm and a polydispersion index of 0.2, indicating a uniform size distribution. The NLCs were primarily localized in the epidermis, effectively minimizing the systemic release of 5-FU across skin layers. The ex vivo skin model revealed the formation of a protective lipid film, decreasing the desquamation process of the stratum corneum which can be associated to an effect of increasing permeation. In vitro assays demonstrated that A375 melanoma cells exhibited a higher sensitivity to the treatment compared to non-cancerous cells, reflecting the expected difference in their metabolic rates. The uptake of NLC by A375 cells reached approximately 90% within 4 h. The efficacy of Bcl-2 knockdown was thoroughly assessed using ELISA, Western blot, and qRT-PCR analyses, revealing a significant knockdown and synergistic action of the NLC formulation containing 5-FU and Bcl-2 siRNA (at low concentration --100 pM). Notably, the silencing of Bcl-2 mRNA also impacted other members of the Bcl-2 protein family, including Mcl-1, Bcl-xl, BAX, and BAK. The observed modulation of these proteins strongly indicated the activation of the apoptosis pathway, suggesting a successful inhibition of melanoma growth and prevention of its in vitro spread.

During the development of hepatocellular carcinoma (HCC), hepatic stellate cells undergo activation and transform into cancer-associated fibroblasts (CAFs) due to the influence of tumor cells. The interaction between CAFs and tumor cells can compromise the effectiveness of chemotherapy drugs and promote tumor proliferation, invasion, and metastasis. This study explores the potential of glycyrrhetinic acid (GA)-modified liposomes (lip-GA) as a strategy for co-delivery of berberine (Ber) and doxorubicin (Dox) to treat HCC. The characterizations of liposomes, including particle size, zeta potential, polydispersity index, stability and in vitro drug release, were investigated. The study evaluated the anti-proliferation and anti-migration effects of Dox&Ber@lip-GA on the Huh-7 + LX-2 cell model were through MTT and wound-healing assays. Additionally, the in vivo drug distribution and anti-tumor efficacy were investigated using the H22 + NIH-3T3-bearing mouse model. The results indicated that Dox&Ber@lip-GA exhibited a nanoscale particle size, accumulated specifically in the tumor region, and was efficiently taken up by tumor cells. Compared to other groups, Dox&Ber@lip-GA demonstrated higher cytotoxicity and lower migration rates. Additionally, it significantly reduced the deposition of extracellular matrix (ECM) and inhibited tumor angiogenesis, thereby suppressing tumor growth. In conclusion, Dox&Ber@lip-GA exhibited superior anti-tumor effects both in vitro and in vivo, highlighting its potential as an effective therapeutic strategy for combating HCC.

Major depression is a prevalent disorder characterized by sadness, lack of interest or pleasure, interrupted sleep or food, and impaired concentration. Mirtazapine (MTZ), a tetracyclic antidepressant drug, is commonly used to treat moderate to severe depression. MTZ is classified as a BCS class II drug that has shown bioavailability of 50% due to extensive first-pass metabolism. The aim of this research is to develop a delivery platform with enhanced solubility and oral bioavailability of MTZ through formulating polymeric micelles modeled in a rapid release tablet. Mirtazapine loaded polymeric micelles (MTZ-PMs) were formulated to enhance the solubility. Solutol^® HS 15 and Brij 58 were used as combined surfactants in a ratio of (20:1) to MTZ in addition to Transcutol^® P as a penetration enhancer. The following in vitro tests were performed: particle size, PDI, zeta potential, solubility factor, stability index, and transmission electron microscopes. Afterward, MTZ-PMs were converted to dry free flowable powder through loading on the adsorptive surface of Aerosil 200; then, the powder mixture was directly compressed (MTZ-PMs-RRT) into 13 mm tablets. MTZ-PMs-RRT was further investigated using in vitro evaluation tests of the tablets, namely, weight variation, thickness, diameter, hardness, friability, disintegration time, drug content, and in vitro dissolution test, which complied with the pharmacopeial limits. The pharmacokinetic parameters of MTZ-PMs-RRT compared to Remeron^® tablet were further investigated in rabbits. The results showed enhanced solubility of MTZ with improved percentage relative bioavailability to 153%. The formulation of MTZ in the form of MTZ-PMs-RRT successfully improved the solubility, stability, and bioavailability of MTZ using a simple and scalable manufacturing process.

In the present work, we have designed a one-pot green protocol in which anti-cancer drugs (curcumin and doxorubicin) can be directly loaded on the surface of gold nanoparticles during their formation. We have further demonstrated that low-intensity pulsed ultrasound (LIPUS) can be used to effectively induce the release of anti-cancer drugs from the surface of gold nanoparticles in an ex vivo tissue model. With this protocol, gold nanoparticles can be easily loaded with different types of anticancer drugs, irrespective of their affinity towards water, and even hydrophobic molecules, like curcumin, can be attached onto the gold nanoparticles in an aqueous medium. The method is very simple and straightforward and does not require stirring or mechanical shaking. The drug molecules interact with the gold seeds formed during the reduction and growth process and modulate the final morphology into a spherical shape. A black-colored colloidal solution of gold nanowire networks is formed in the absence of these anti-cancer drug molecules in the reaction mixture. We used hyperspectral-enhanced dark field microscopy to examine the uptake of gold nanoparticles by breast cancer cells. Upon exposure to LIPUS, the release of the anti-cancer drug from the particle surface can be quantified by fluorescence measurements. This release of drug molecules along with trisodium citrate from the surface of gold nanoparticles by ultrasound resulted in their destabilization and subsequent aggregation, which could be visually observed through the change in the color of colloidal sol. Cancer cell viability was studied by MTT assay to examine the efficacy of this nanoparticle-based drug delivery system. Ultraviolet-visible spectroscopy, dynamic light scattering (DLS), and transmission electron microscope (TEM) analysis were used to characterize the nanoparticles and quantify anti-cancer drug release.

This study aimed to formulate diacerein (DCN)-loaded flexosomes for enhanced efficacy against osteoarthritis. A 2³ D-optimal design was employed, investigating the impact of surfactant type (A), surfactant concentration (%w/v) (B), and oleylamine amount (mg) (C). Flexosomes were formulated using a rotary evaporator, and Design-Expert^® software was utilized to statistically analyze entrapment efficiency (EE%), zeta potential (ZP), poly-dispersity index (PDI), and particle size (PS) to determine the optimum formula. The selection criteria prioritized increased ZP (as absolute value) and EE%, coupled with decreased PDI and PS. Rigorous physicochemical, in vivo, and ex vivo tests were conducted to validate the safety, stability, and activity of the optimal formula. Physicochemical assessments encompassed pH measurement, transmission electron microscopy, differential scanning calorimetry, release profiles, storage effects, and Fourier transform infrared spectroscopy. In vivo tests included permeation studies, histopathology, anti-inflammatory activity, and skin irritancy, while ex vivo tests focused on permeation parameters and skin deposition. The optimum formula demonstrated high desirability (0.931), along with favorable EE% (90.93%), ZP (- 40.4 mV), particle size (188.55 nm), and sustained behavior. Notably, improved in vivo permeation (132 µm), skin deposition (193.43 µg/cm²), and antinociceptive activity (66%) compared to DCN suspension (48 µm, 66.31 µg/cm², and 26%, respectively) were observed. The optimal formula also exhibited excellent safety and storage characteristics. In conclusion, DCN-loaded flexosomes exhibit significant potential for effectively managing osteoarthritis.

Methicillin-resistant Staphylococcus aureus (MRSA) has become a leading causative pathogen of nosocomial pneumonia with an alarming in-hospital mortality rate of 30%. Last resort antibiotic, vancomycin, has been increasingly used to treat MRSA infections, but the rapid emergence of vancomycin-resistant strains urges the development of alternative treatment strategies against MRSA-associated pneumonia. The bacteriolytic enzyme, lysostaphin, targeting the cell wall peptidoglycan of S. aureus, has been considered as a promising alternative for MRSA infections. Its proteinaceous nature is likely benefit from direct delivery to the lungs, but the challenges for successful pulmonary delivery of lysostaphin lying on a suitable inhalation device and a formulation with sufficient storage stability. In this study, the applicability of a vibrating mesh nebulizer (Aerogen Solo^®) and a soft mist inhaler (Respimat^®) was investigated. Both devices were capable of aerosolizing lysostaphin solution into inhalable droplets and caused minimum antibacterial activity loss. In addition, lysostaphin stabilized with phosphate-buffered saline and 0.1% Tween 80 was proved to have acceptable stability for at least 12 months when stored at 4 °C. These promising data encourage further clinical development of lysostaphin for management of MRSA-associated lung infections.

The aim of this study was to design surfactants based on histidine (His) for hydrophobic ion-pairing and evaluate their safety and efficacy. Lauryl, palmitoyl and oleyl alcohol, as well as 2-hexyl-1-decanol were converted into surfactants with histidine as head-group via esterification. The synthesized His-surfactants were characterized regarding pK_a, critical micellar concentration (CMC), biodegradability, toxicity on Caco-2 cells, and ability to provide endosomal escape. Furthermore, the suitability of these agents to be employed as counterions in hydrophobic ion pairing was evaluated. Chemical structures were confirmed by ¹H-NMR, FT-IR, and MS. The synthesized surfactants showed pK_a values ranging from 4.9 to 6.0 and CMC values in the range of 0.3 to 7.0 mM. Their biodegradability was proven by enzymatic cleavage within 24 h. Below the CMC, His-surfactants did not show cytotoxic effects on Caco-2 cells (cell viability > 80%). All His-surfactants showed the ability to provide endosomal escape in a pH-dependent manner in the range of 5.2 to 6.8. Complexes formed between His-surfactants and heparin or plasmid DNA (pDNA) via hydrophobic ion pairing showed at least 100-fold higher lipophilicity than the correspondent model drugs. According to these results, His-surfactants might be a promising safe tool for delivering hydrophilic macromolecular drugs and nucleic acids.

In recent years, the continuous development of innovative nanopharmaceuticals is expanding their biomedical and clinical applications. Nanomedicines are being revolutionized to circumvent the limitations of unbound therapeutic agents as well as overcome barriers posed by biological interfaces at the cellular, organ, system, and microenvironment levels. In many ways, the use of nanoconfigured delivery systems has eased challenges associated with patient differences, and in our opinion, this forms the foundation for their potential usefulness in developing innovative medicines and diagnostics for special patient populations. Here, we present a comprehensive review of nanomedicines specifically designed and evaluated for disease management in the pediatric population. Typically, the pediatric population has distinguishing needs relative to those of adults majorly because of their constantly growing bodies and age-related physiological changes, which often need specialized drug formulation interventions to provide desirable therapeutic effects and outcomes. Besides, child-centric drug carriers have unique delivery routes, dosing flexibility, organoleptic properties (e.g., taste, flavor), and caregiver requirements that are often not met by traditional formulations and can impact adherence to therapy. Engineering pediatric medicines as nanoconfigured structures can potentially resolve these limitations stemming from traditional drug carriers because of their unique capabilities. Consequently, researchers from different specialties relentlessly and creatively investigate the usefulness of nanomedicines for pediatric disease management as extensively captured in this compilation. Some examples of nanomedicines covered include nanoparticles, liposomes, and nanomicelles for cancer; solid lipid and lipid-based nanostructured carriers for hypertension; self-nanoemulsifying lipid-based systems and niosomes for infections; and nanocapsules for asthma pharmacotherapy.