Current Drug Delivery - Online First

Both bufalin (BF) and quercetin (QUE) have demonstrated significant antitumor potential. However, they suffer from poor solubility and low bioavailability, which largely limit their clinical application. In order to increase the antitumor activity of BF and QUE by synergistic effect, BF and QUE co-loaded nanosuspension (BF-QUE NS) was developed.

The MTT method was used to determine the viability of HepG2 cells after treatment with BF and QUE at different mass ratios, and the optimal combination ratio was screened. BF-QUE NS was prepared by the anti-solvent precipitation method, and the single factors affecting its preparation were investigated to optimize the formulation and preparation process of the best combined NS. BF-QUE NS was characterized by observing morphology, measuring particle size and zeta potential, X-ray diffraction, differential scanning calorimetry, and drug release in vitro. Cytotoxicity was detected using the MTT method; the uptake of BF-QUE NS by HepG2 cells was observed by laser confocal microscopy and flow cytometry; apoptosis of HepG2 cells was detected by flow cytometry. BF-QUE NS was systematically characterized, and H22 tumor-bearing mice were further used to investigate the targeting distribution, antitumor effect.

The optimal synergistic ratio of BF to QUE was 3:2. The mass ratio of BF and QUE in BF-QUE NS was 1.47:1. The optimized BF-QUE NS exhibited an average particle size of 238.4 ± 2.1 nm, polydispersity index of 0.250 ± 0.004, zeta potential of -22.2 ± 0.3 mV, and presented good short-term physical stability. In vitro and in vivo experiments demonstrated that BF-QUE NS exhibited significant liver tumor-targeting efficacy, achieving an inhibition rate of 72.59% in H22 tumor-bearing mice, along with high safety profiles.

BF-QUE NS provides a practical solution to the delivery challenges of poorly soluble anti-cancer drugs.

The prepared BF-QUE NS enhanced the drug solubility and promoted the targeted accumulation in tumors, thereby strengthening the synergistic anti-tumor effect of BF and QUE. BF-QUE NS shows potential for clinical application as an anti-liver tumor drug.

Burn wounds are painful injuries that demand immediate and effective management. Conventional wound care solutions often have limitations, such as discomfort during application or removal and potential damage to healing tissue. Therefore, developing novel wound dressings that support biological processes and promote wound healing is highly beneficial. Electrospun nanofibers have emerged as a promising platform for the development of biomedical wound dressings due to their unique structural and functional properties. This study evaluates the burn wound healing potential of electrospun nanofibers composed of aloe polysaccharides, sodium alginate, and Polyvinyl Alcohol (PVA), impregnated with Silver Nanoparticles (AgNPs).

AgNPs were synthesized using a green approach, employing Aloe vera as a reducing agent. Characterization of AgNPs was performed using UV-vis spectroscopy, FTIR, zeta potential analysis, and TEM. Aloe polysaccharides were extracted using ultrasonication and characterized via FTIR, XRD, and DSC. The extracted polysaccharides were then blended with PVA and sodium alginate to fabricate electrospun nanofiber sheets, into which the synthesized AgNPs were incorporated and analyzed for antibacterial, angiogenesis, and in vivo studies.

AgNPs exhibited spherical morphology with sizes ranging from 20 to 27 nm under TEM. Electrospun nanofiber sheet displayed a uniform structure with an average fiber diameter of 129 nm, as confirmed by SEM analysis. A sustained release of silver ions (78.98 ± 0.61% over 48 hours) was observed. The nanofibers exhibited strong antibacterial activity against Escherichia coli and Staphylococcus aureus, promoted angiogenesis, and significantly enhanced wound healing in a burn wound model.

AgNPs impregnated nanofiber sheet exhibited superior wound healing, angiogenesis, and antibacterial properties ideal for wound healing applications. The nanofiber sheets mimicked the extracellular matrix and supported angiogenesis. Enhanced wound closure in vivo studies confirmed the therapeutic potential of the nanofibers.

AgNPs-impregnated nanofiber sheets offer antibacterial activity and support angiogenesis, suggesting their potential as a multifunctional wound dressing for effective burn treatment.

Methicillin-Resistant Staphylococcus Aureus (MRSA) is a major cause of purulent Skin and Soft-Tissue Infections (SSTIs), posing significant global health and economic challenges. This study aims to optimize a drug delivery system, specifically Tigecycline-loaded transfersomes, to address the limitations of current treatments, including bacterial resistance, systemic side effects, and poor drug penetration, thereby offering a safer and more effective alternative for MRSA-related SSTIs.

A novel Tigecycline transfersomal formulation was developed using the thin film hydration method. The study investigated the effects of varying drug-to-lipid ratios, lipid-to-edge activator ratios, and different hydration media on the characteristics of the Tigecycline-loaded transfersomes. The formulation’s morphology, release profile, and antibacterial activity against clinical MRSA strains were also evaluated.

The Tigecycline-loaded transfersomes were successfully prepared with particle sizes ranging from 92.3 to 290.8 nm, zeta potential values from -16.22 to -48.7 mV, and encapsulation efficiencies ranging from 54.8% to 84.39%. The formulation prepared using distilled water as the hydration medium, a lipid-to-edge activator ratio of 80:20, and a drug-to-lipid ratio of 3:8 was selected for further assessment due to its optimal characteristics. The selected transfersomes were spherical with an average diameter of 131 nm. The formulation exhibited a controlled drug release profile and demonstrated a twofold increase in antibacterial activity against MRSA compared to non-liposomal Tigecycline.

The results highlighted the significant role of formulation parameters in tailoring transferosomal characteristics and enhancing therapeutic performance. The study builds on existing research by introducing Tigecycline—a broad-spectrum antibiotic—into transfersomal systems for the first time. However, further in vivo validation is necessary.

Tigecycline-loaded transfersomes demonstrated improved drug delivery and antibacterial efficacy against MRSA. This novel formulation shows promise as an effective topical therapy for antibiotic-resistant SSTIs.

One of the least invasive, recognized potential routes for both local and systemic drug delivery and the most patient-friendly methods of administering therapeutic agents is transdermal drug delivery. It minimizes gastrointestinal side effects, prevents hepatic first-pass metabolism, lowers dosage frequency, and boosts patient compliance.

This review aims to examine the nanostructured systems for transdermal drug delivery, focusing on their types, design, development and mechanism in enhancing drug permeation through the skin.

This review article synthesized findings from recent studies on nanostructured systems used in transdermal drug delivery systems. With a particular focus on offering a comprehensive understanding of transdermal drug delivery methods and augmentation strategies, the author examines current trends and potential uses of transdermal technologies.

Nanostructured systems have shown increased drug penetration, improved bioavailability and controlled release profiles.

Nanostructured systems offer a versatile and effective approach to overcoming the limitations of traditional transdermal drug delivery methods. Future research should focus on optimizing these systems for clinical applications, ensuring safety and regulatory compliance.

Difficulty in wound healing is a significant worldwide clinical challenge with serious health consequences and even life-threatening consequences. We designed an acrylic hydrogel loaded with metformin and investigated its mechanism of action in promoting wound repair.

In this study, we obtained self-assembled metformin hydrogels (SAMHs) delivery system using acrylic acid (AA) as matrix and ammonium persulfate (APS) as initiator, and evaluated the appearance, water vapor transmission rate, swelling properties, mechanical properties, and bioactivities of the SAMHs, and finally assessed the potential of the SAMHs for the treatment of chronic wounds in a diabetic rat wound model.

SAMHs were colorless and transparent in appearance, with a water vapor transmission rate of 3530 g·m^-2·day^-1, a dissolution rate of 504%, a Young's modulus of 34 Kpa, and an elongation at break of 595.7%.The drug loading capacity of SAMHs was 0.8±0.04 mg·g^-1 and the cumulative release amounted to 71.67±2.03%. In vivo experiments showed that on day 14, the SAMHs group achieved a wound healing rate of 96.74%, with complete epithelialization, a collagen fiber content of 75.10%, elevated VEGF expression, and a TNF-α level of 162.62 pg·mL⁻¹, all of which exhibited significant differences compared to the control group.

SAMHs exhibit excellent performance in several aspects, achieving slow drug release and promoting wound repair. In addition, SAMHs are simple and low-cost to prepare, which is expected to bring more cost-effective treatment options for diabetic patients. However, antimicrobial properties and clinical trial data are lacking in this study, and their applicability in complex wounds requires further validation.

The hydrogel we prepared has excellent properties, is suitable for use in chronic wounds and promotes wound healing in diabetic rats and is an effective therapeutic strategy for chronic wounds.

Renal fibrosis is recognized as the final common pathway of chronic kidney disease (CKD) progression, ultimately leading to end-stage renal failure and defined by excessive accumulation of extracellular matrix (ECM) by renal myofibroblasts in the interstitium. To establish an effective drug delivery system targeting fibrotic lesions, we developed nanoparticles modified with short-chain peptides that bind type IV collagen (Col IV), a distinct ECM component remodeled in fibrosis.

Col IV-targeting nanoparticles were intravenously administered to a unilateral ureteral obstruction (UUO) rat model of renal fibrosis. The distribution of these nanoparticles to the renal interstitium was examined via fluorescence-based ex vivo imaging and analysis of frozen kidney tissue sections. Additionally, we assessed cellular uptake in renal fibroblasts (NRK-49F), with or without transforming growth factor-beta 1 (TGF-β1) stimulation, using flow cytometry.

Both Col IV-targeting and non-targeting nanoparticles exhibited increased distribution in the fibrotic renal interstitium compared to healthy tissue. Moreover, the Col IV-targeting nanoparticles localized more extensively in the fibrotic interstitium than their non-targeting counterparts. In vitro, Col IV-targeting nanoparticles also showed significantly higher accumulation in NRK-49F cells, irrespective of TGF-β1 stimulation, compared to non-targeting nanoparticles.

In a UUO-induced renal fibrosis model, these nanoparticles efficiently migrated to the fibrotic renal interstitium, and in vitro experiments using NRK-49F cells demonstrated enhanced uptake by renal fibroblasts and myofibroblasts, central mediators of ECM deposition in fibrotic progression.

We successfully fabricated and evaluated Col IV-targeting nanoparticles, which may serve as an effective drug delivery platform for antifibrotic therapies, potentially mitigating CKD progression.

The interaction of the kidneys with nanoparticles is a fundamental issue that accelerates the proper design of efficient and safe nanotherapeutics. The present study aimed to establish the kidney toxicity and the biodistribution profile of novel gold and silver nanocluster formulations.

Gold and silver nanoclusters were synthesized in an albumin template to probe their kidney-nano interaction. The interaction was performed on healthy animals to unveil the toxicity of nanoclusters on kidney tissue.

Albumin-based gold nanoclusters (BSA-AuNCs) and albumin-based silver nanoclusters (BSA-AgNCs), exhibited comparable core size (2.2±1.3 nm and 2.5±1.6 nm, respectively) and hydrodynamic diameter (11.3±2.1 nm for BSA-AuNC and 10.7±1.9 nm for BSA-AgNC) indicating similarity in their core and overall sizes. Zeta potential measurements demonstrated a comparable surface charge between BSA- AuNC (18.1±3.2 mV) and BSA- AgNC (20.1±3.6 mV), which closely resembled the surface charge of albumin in water (20.7±3.5 mV). Upon administration to rats via intravenous route, ICP-OES measurements showed a significant silver and gold nanocluster accumulation in various vital organs with unequal distribution patterns. BSA-AgNC exhibited higher concentrations in the liver and spleen, while BSA-AuNC showed predominant accumulation in the liver and kidneys. However, the administered BSA-AgNC induced more renal damage than BSA- AuNCs.

The identified renal toxicity linked to BSA-AgNCs, despite their lower kidney accumulation than BSA-AuNCs, illuminates the intricate interplay between nanoparticle biodistribution and toxicity. This underscores the significance of considering the core metal type in nanoparticle design and evaluation. Further investigation is needed to clarify the underlying molecular mechanisms of the observed biodistribution and toxicity.

The primary aim of this study was to develop an effective treatment strategy for periodontal diseases that maximizes therapeutic effects while minimizing systemic adverse effects. Specifically, the study focused on creating a xerogel-based localized drug delivery system for the slow release of doxycycline hyclate (DH) to treat periodontal disease.

Xerogels were prepared using the solvent casting method, with the solvent being evaporated slowly at ambient conditions. The prepared DH xerogels underwent comprehensive characterization to assess their in-silico compatibility, pharmacokinetics, and physicochemical properties. The properties studied included drying time and rate, thickness, moisture content, swelling index, organoleptic properties, scanning electron microscopy, FTIR spectroscopy, differential scanning calorimetry, drug release and kinetics, and antibacterial activity.

In-silico studies demonstrated compatibility between the ingredients, indicating minimal adverse effects on the body. The analysis revealed hydrogen bonding between the drug and polymers, changing the drug's crystallization characteristics to an amorphous form. The release profiles of DH from the xerogels indicated a slow release, ranging from 29.42% to 66.30% over 10 hours, following the Hopfenberg model.

The findings of this study suggest that the formulated xerogels are well-suited for periodontal applications. The slow-release profile of DH from the xerogels offers a promising approach for localized treatment of periodontal disease, reducing the risk of systemic adverse effects. This data is valuable for dental practitioners and pharmaceutical formulators, providing a new avenue for enhancing periodontal disease treatment.

Influenza, a seasonal infectious disease, has consistently posed a formidable challenge to global health in recent years. Favipiravir, an RNA-dependent RNA polymerase inhibitor, serves as an anti-influenza medication, currently administered solely in oral form for clinical use. However, achieving an effective therapeutic outcome often necessitates high oral doses, which can be accompanied by adverse effects and suboptimal patient adherence.

To enhance favipiravir delivery efficiency and potentially mitigate dosage-related side effects, this study aimed to formulate favipiravir as a dry powder for pulmonary inhalation, facilitating direct targeting of lung tissue.

Employing L-leucine as a carrier, favipiravir was prepared as an inhalable dry powder through the spray-drying technique. A 3x3 full-factorial design approach was adopted to optimize the formulation. The optimized spray-dried powder underwent comprehensive characterization, including assessments of its morphology, crystallinity, flowability, and aerodynamic particle size distribution. The therapeutic efficacy of the powder was evaluated in a mouse model infected with the H1N1 influenza virus.

The formulated powder demonstrated good aerosol properties, rendering it suitable for inhalation delivery. Its therapeutic efficacy was demonstrated in the mouse model, where it exhibited marked protective effects against the virus in vivo after 5 days of treatment. Notably, the inhalation dose required (15 mg/kg/day) was significantly lower than the oral gavage dose (150 mg/kg/day), indicating that substantially reduced doses, when administered via inhalation, were sufficient to confer protection against mortality in mice.

The findings underscore the potential of inhalation therapy using spray-dried favipiravir powder as an effective and efficient treatment option for influenza, offering the promise of reduced dosing requirements and associated adverse effects.

Overcoming the poor aqueous solubility of small-molecule drugs is a major challenge in developing clinical pharmaceuticals. Felodipine (FLDP), an L-type calcium calcium channel blocker, is a poorly water-soluble drug.

The study aimed to explore the potential applications of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (Soluplus) stabilized amorphous dispersions for augmenting the oral delivery of poorly water-soluble drugs.

Soluplus-stabilized amorphous FLDP (FLDP-SSAs) was prepared using a two-phase mixing method. The samples were analyzed for their microscopic and macroscopic behavior using polarized light microscopy (PLM), differential scanning calorimetry (DSC), molecular simulation, and in vitro dissolution studies. Subsequently, the pharmacokinetics of FLDP-SSAs were evaluated.

The maximum drug-to-Soluplus mass ratio of FLDP-SSAs was 50:50, with a drug concentration of 8.0 mg/mL. They exhibited an amorphous nature, as confirmed by PLM and DSC. FLDP-SSAs generated nanoparticles with a particle size of approximately 50 nm during in vitro dissolution. Compared to FLDP oral solution, FLDP-SSAs exhibited higher solubility due to their amorphous nature and the generation of nanoparticles. The area under the curve (AUC) for oral FLDP-SSAs was 16.7-fold larger than that of the FLDP suspension.

FLDP-SSAs could stabilize FLDP in an amorphous state and serve as drug carriers to enhance oral absorption.

Poly(methyl vinyl ether co-maleic acid) (PMVE/MA) hydrogel microneedles (HMN) are investigated for transdermal delivery of macromolecular drugs owing to their biocompatibility and super-swelling properties. However, the drug delivery efficacy reduces with increasing molecular weight due to the entrapment within the HMN matrices. Furthermore, integrating external drug reservoirs extends the drug diffusion path and reduces the efficiency of drug permeation.

A direct drug loading approach in the HMN matrix was introduced in this work following a pH modification step. The effect of pH modification on the physicochemical properties of HMN was studied. Then, bovine serum albumin (BSA), a model protein, was loaded into the pH-modified HMN, and the morphological changes in HMN and protein stability were also assessed. Finally, the efficacy of BSA-loaded HMN in the transdermal delivery was evaluated ex vivo.

A significant increase in swelling was recorded following the pH modification of HMN (p < 0.001). The structure of pH-modified hydrogel was highly porous, and ATR-FTIR spectra indicated a shift in the carboxylic peak. The secondary structure of BSA loaded in the pH-modified HMN was also preserved. The BSA-loaded HMN mediated a sustained ex-vivo drug release with a cumulative release of 64.70% (3.88 mg) in 24 h.

Hence, the model drug-incorporated PMVE/MA HMN system shows potential for sustainable transdermal delivery of proteins.

Assessing the cytotoxicity of gold nanoparticles (GNPs) has gained importance due to their development in the biomedical field.

In this study, we systematically synthesized gold nanorods (GNRs), gold nanobipyramids (GNBPs), and gold nanocups (GNCs) using a seed-mediated method, with an average length of 32.53 ± 4.67 nm, 72.90 ± 7.54 nm and 118.01 ± 11.02 nm, respectively.

Furthermore, using the cell counting kit-8 (CCK-8) assay, we assessed the cellular cytotoxicity of three different types of GNPs with various different surface coatings, such as organic cetyltrimethylammonium bromide (CTAB) and polyethylene glycol (PEG). The results showed that the cytotoxic behavior of GNPs was shape-dependent in the concentration range of 3.125 -100 μg/mL. The types of GNPs and their surface coating had a significant impact on how the GNPs behaved in cells. Compared to PEG-coated GNPs, which do not induce cell injury, CTAB-coated GNPs show more noticeable cytotoxicity.

Furthermore, compared to GNCs, the toxicity of GNRs and GNBPs against GES-1 cells, RAW 264.7 cells and LX-2 cells was greater. Our research provides an important new understanding of the effects of surface modification on the biocompatibility and the shape of GNPs in the biomedical field.