Eosinophilic esophagitis (EoE) is a chronic inflammatory condition primarily managed with topical corticosteroids such as budesonide. While commercial treatments exist, clinical outcomes are frequently hindered by inadequate drug retention on the esophageal mucosa. To enhance targeted delivery and mucosal retention, this study presents a mucoadhesive oral formulation consisting of a suspension of budesonide-embedded short cellulose acetate (CA-B) fibers. The fibers (mean diameter 0.2 μm and length 138 μm) were suspended in a 0.5% (w/v) aqueous alginate solution to optimize mucoadhesion. Rheological characterization revealed a critical fiber concentration threshold of 0.1% (w/v) for CA-B network formation, above which the suspension transitions into a highly structured, viscoplastic system with pronounced solid-like behavior. Upon administration, the short CA-B fibers mechanically interlock and conform to the mucosal surface, enabling sustained drug release and subsequent tissue diffusion. Formulation efficacy was validated through ex vivo mucoadhesion assays utilizing a porcine esophageal model. In vitro release kinetics followed a first-order model predicting a maximum cumulative budesonide release of 74%. Furthermore, transport modeling determined the optimal inter-fiber distance to achieve a sustained, localized therapeutic dose of budesonide at the mucosal surface. This suspendable short-fiber platform provides a robust strategy for enhancing mucosal retention in EoE, with broad applicability for targeted drug delivery across mucosal barriers.
Porous silicates have been investigated as drug carriers to promote the solubility and in vitro dissolution of poorly water-soluble drugs, owing to their potential to adsorb drug molecules in the amorphous form within their structural cavities. This study aimed to evaluate the efficiency of bentonite (BT), Aeroperl 300 Pharma (AP), and Florite PS-200 (FR) as water-insoluble silicate drug carriers, and the polymer polyvinylpyrrolidone-vinyl acetate (PVPVA) in improving the dissolution of ritonavir (RTV). The effect of phosphatidylcholine (PC) as a water-insoluble excipient on drug dissolution was also investigated. Multiple linear regression analysis of the dissolution data was performed to identify the factors influencing dissolution, complemented by mechanistic simulations of the best-performing carrier. The in vitro dissolution rank order of carriers with a 30% drug load (DL) based on % dissolved300min was AP = FR > PVPVA = BT in the absence of PC, and AP > FR > PVPVA > BT with PC. The extent of dissolution for all formulations increased in the presence of PC, with the AP and FR formulations exceeding that of marketed formulations. High drug load did not significantly affect the dissolution profile of silicate formulations, but it reduced dissolution from PVPVA solid dispersion. In silico results showed that silicate pore size governed RTV release, with open pores forming fewer hydrogen bonds, allowing more facile RTV release. The significant improvement in RTV dissolution with AP and FR supports the use of these carriers for poorly soluble drugs as alternatives to traditional polymers, especially for formulations with high drug loads.
Tocopheryl polyethylene glycol 1000 succinate (TPGS-1000) is a nonionic surfactant commonly used in pharmaceutical formulation as solubilizer, emulsifier and permeation enhancer. The aim of this study was to assess the impact of TPGS-1000 incorporation on liposomal formulation characteristics, and its applicability in ophthalmic nanoformulations. To this end, liposomal formulations containing a fixed concentration of soybean phosphatidylcholine (SPC, 100 mM) with increasing concentration of TPGS-1000 (0, 0.5 and 12.5 mM) were developed by the thin lipid film hydration method, followed by extrusion. Their characterization included measurements of pH, osmolality, mean diameter, polydispersity index, zeta potential, concentration of liposomes, and morphological observation by transmission electron microscopy. In vitro cytotoxicity of SPC, TPGS-1000 and liposomal formulations was assessed on corneal epithelial cells (HCE-T) and retinal epithelial cells (ARPE-19). As an inhibitor of mitochondrial respiratory complex II, TPGS-1000 ability to induce oxidative stress was evaluated in vitro on ARPE-19 cells. The quality of the liposomal formulations improved with TPGS-1000 content, which reduced and homogenized the liposomes size, and increased the formulations translucency. However, TPGS-1000 had a dose-dependent in vitro cytotoxicity on corneal and retinal cells. The in vitro cytotoxicity of the liposomal formulations increased with TPGS-1000 content. In the presence of an antioxidant agent, the cytotoxic effect of TPGS-1000 on ARPE-19 cells was significantly decreased. Low doses of TPGS-1000 or its combination with an antioxidant should therefore be considered in ophthalmic nanoformulations, especially those targeting the posterior segment of the eye, to prevent ocular damages due to the pro-oxidant effect of TPGS-1000.
Wounds pose a significant challenge to both healthcare and the economy, as current therapies often fail to address the complex biology of healing. Exosomes derived from fetal tissue, enriched with regenerative microRNAs and proteins, have demonstrated strong potential in promoting wound repair. Melatonin is an indoleamine with multiple effects, including antioxidant and immunomodulatory activities. It has been shown to promote tissue regeneration; however, it degrades rapidly and has low bioavailability. This study investigates the potential of melatonin-loaded fetal tissue-derived exosomes (MEL@EXO) combined with a pH-responsive, biocompatible hydrogel composed of chitosan, polyvinylpyrrolidone (PVP), hyaluronic acid (HA), and glycerin to accelerate full-thickness wound healing. Fetal tissue-derived exosomes were isolated from Wistar rat fetal tissues using differential centrifugation and PEG-induced extraction. Melatonin was encapsulated by electroporation. Exosomes had the expected size, globular shape, stability, and high melatonin-loading efficiency. The hydrogel was prepared by gradually adding PVP to chitosan dissolved in citric acid under constant stirring, followed by the incorporation of HA and glycerin. The hydrogel showed a pH-responsive sol-gel transition and porous architecture, enabling sustained exosome release. Cytotoxicity evaluation on Human Dermal Fibroblast (HDF cell line) confirmed that the MEL@EXO hydrogel and its components exhibited no cytotoxic effects. Furthermore, the hemolysis test revealed no significant hemolysis, confirming the biocompatibility of the composite. In vivo, MEL@EXO hydrogel accelerated wound closure compared to the control and single-component groups. Histological studies revealed that wounds treated with MEL@EXO were undergoing re-epithelialization, thick collagen deposition, and angiogenesis. These findings support the potential of the MEL@EXO hydrogel as a robust and versatile platform for full-thickness wound healing.
BACKGROUND:The use of automated injectors for the administration of radiopharmaceuticals limits staff exposure and optimises the dose administered to patients, but many of these devices are only validated for a limited number of radiopharmaceuticals. The objectives of this study were to investigate the physicochemical phenomena occurring during the manipulation of fluorinated radiopharmaceuticals when in contact with injector tubings and to quantify and qualify the interactions between the radiopharmaceuticals and the tubing materials. RESULTS:For six of the radiopharmaceuticals tested, the measured doses reached 97.64 ± 0.24% of the programmed dose. These results indicate an absence of sorption phenomena and validate their use on the injector. In contrast, the three most lipophilic molecules caused the injector to malfunction, resulting in significant residual activity in the tubing of up to 67%. These results were confirmed by activimeter measurements and positron emission tomography images. RESULTS:from electronic microscopy results showed an alteration of the inner surface of the tubings that came into contact with lipophilic radiopharmaceuticals; however, this modification did not drastically alter the surface Zeta potential. Infrared spectroscopy confirmed the composition of the tubings as being plasticized polyvinyl chloride (PVCp), and plasticizer identification and quantification showed the presence of di-(2-ethylhexyl) adipate (reaching 37.5%) and di-(2-ethylhexyl) phthalate (more than 20%). A clear improvement was observed when co-extruded polyethylene / PVPp tubings were used. CONCLUSIONS:Unlike lipophilic radiopharmaceuticals, which exhibit sorption behaviour dependent on the presence of plasticizers, the tested hydrophilic radiopharmaceuticals demonstrated minimal interaction with PVCp tubing and can be reliably administered using the automated injector.
Oxidative stress induced by inhaled oxidants, particularly cigarette smoke, contributes to the development of several acute and chronic respiratory diseases through oxidative damage and epigenetic alterations. Curcumin (CUR), a well-characterized natural polyphenol with potent antioxidant and anti-inflammatory properties, is considered a promising agent for modulating oxidative stress-related signaling pathways and epigenetic mechanisms; however, its poor aqueous solubility and bioavailability limit its clinical application. Therefore, in the present study, PEGylated curcumin (PEG-CUR) was investigated as a modified CUR formulation for subsequent incorporation into a dissolving microneedle-based intranasal delivery system. Exposure to cigarette smoke resulted in significant alterations in the expression of oxidative stress-related genes (SEPP1, NCF2, SFTPD, CCL5, and PTGS1) in nasal epithelial cells. However, pretreatment with curcumin (CUR) and polyethylene glycol-curcumin (PEG-CUR) mitigated these gene expression changes. Both treatments also reduced global DNA methylation, with PEG-CUR showing a more pronounced effect than CUR. Following the demonstration of the beneficial effects of PEG-CUR, we developed PEG-CUR-loaded dissolving microneedle patches (PEG-CUR-DMNPs) as a localized intranasal delivery platform designed to facilitate PEG-CUR delivery through rapid dissolution of the microneedle tips. The mechanical robustness and penetration capability of the patches were initially evaluated using Parafilm® and ex vivo rat dorsal skin models. To further confirm their appropriateness for intranasal use, PEG-CUR-DMNPs were subsequently tested on ex vivo sheep nasal mucosa to evaluate microneedle penetration and dissolution kinetics. Overall, these results indicate that PEG-CUR-DMNPs represent a promising approach for localized intranasal drug delivery targeting oxidative stress-related respiratory diseases.
Nanoemulsions are increasingly explored to enhance dermal drug delivery due to their nano-size. Microfluidic processing for nanoemulsion generation has attracted much attention but requires extensive optimisation. This study leverages 3D printed microfluidic chips for size reduction of a premixed emulsion as a scalable approach to fabricate cationic oil‑in‑water nanoemulsions loaded with ibuprofen (2%w/w) for dermal delivery. Phase inversion composition (PIC) and homogenisation were used as benchmark methods. Nanoemulsions comprising ethyl oleate, Tween® 80 and cetyltrimethylammonium bromide were optimised using the PIC (∼33 nm) and subsequently used to prepare premixed emulsions (∼84 nm). Microfluidisation effectively reduced the droplet size of premixed coarse emulsions (∼57-67 nm), achieving size reduction comparable to that obtained using conventional homogenisation (∼62 nm). Varying the microchannel geometry in microfluidic chips and flow rate did not significantly affect the nanoemulsion properties. Nanoemulsions prepared by homogenisation remained <200 nm for 3 months at 40°C and 12 months at 25°C, but they were less stable than those prepared via PIC and microfluidisation. Nanoemulsions produced via PIC exhibited higher skin permeation of ibuprofen (∼14 µg) as compared with microfluidisation (∼10 µg) and homogenisation (∼7 µg). Microchannel processing improved nanoemulsion stability and skin delivery over homogenisation, offering scalable, energy-efficient continuous manufacturing, although PIC remained superior overall.
Chronic wounds infected by Candida albicans impose a significant clinical burden, yet topical amphotericin B (AMB) delivery is constrained by low aqueous solubility. Wet-spun poly(vinyl alcohol) (PVA)/chitosan fibres loaded with an AMB/hydroxypropyl-γ-cyclodextrin (HP-γ-CD) inclusion complex were developed as a sustained-release antifungal wound dressing. Phase solubility analysis confirmed inclusion complex formation with an apparent stability constant of 36.1 × 103 M⁻1 in distilled water (AL-type profile, R2 = 0.9984), characterised by Fourier-transform infrared spectroscopy (FTIR), 1H NMR, and scanning electron microscopy (SEM). IC-SE-1 achieved ∼ 354-fold and ∼ 136-fold solubility enhancement in distilled water and phosphate-buffered saline (PBS, pH 7.4), respectively, while fully retaining antifungal activity (MIC = 1 µg/mL; p = 0.112 vs. pure AMB). The complex was incorporated into fibres at four PVA:chitosan ratios and crosslinked with tripolyphosphate and glutaraldehyde. Formulation P6C4 (PVA 60%:chitosan 40%) demonstrated the most favourable overall performance, with the highest water-holding capacity (346.51 ± 4.10%), swelling (463.40 ± 11.12%), tensile strength (18.47 ± 2.18 MPa), and elongation (431.57 ± 52.22%). Woven fibres maintained inhibition zones against C. albicans from day 2 to day 7, with AMB release exceeding the MIC throughout, while haemolysis remained below 5% (ASTM F756-08). HP-γ-CD complexation enables sustained above-MIC AMB delivery from a dual-crosslinked biopolymeric dressing, providing in vitro proof-of-concept for Candida-infected chronic wounds, pending cytotoxicity and in vivo validation.
Drug release and permeation play crucial roles in the therapeutic efficacy of cataplasms. However, due to the lack of research on the mechanisms underlying drug release and permeation, achieving optimal release and permeation characteristics through trial-and-error methods is inefficient. Therefore, we aimed to investigate the mechanisms of drug release and permeation in emulsion-type cataplasms from a structural perspective.Cataplasms with varied crosslinking densities, drug loadings, and drug types were prepared; drug release and permeation studies were performed using Franz diffusion cells, while the microstructural evolution of both the cataplasms and the skin was characterized via scanning electron microscopy, differential scanning calorimetry, Fourier-transform infrared spectroscopy, and histology.It was revealed that drug release essentially occurred as the drug escaped from structural constraints through the swelling of the crosslinked network. Drug permeation was demonstrated to be governed by four synergistic mechanisms: (1) the physical contact established by the intimate adhesion between cataplasms and the skin; (2) the influence of drug release amount on drug permeation behavior; (3) stratum corneum hydration induced by water-mediated keratin swelling; (4) disruption of the stratum corneum lipid structure resulting from L-menthol. In addition, this study revealed that the acidity and basicity of the drug itself constituted a key determinant of drug permeation. Overall, the present work is expected to provide a scientific basis for the rational design of cataplasms, improve research and development efficiency, and further promote advances in this field.
While pharmacodynamic and pharmacokinetic drug-drug interactions are well established, physicochemical interactions between co-administered oral drug products and their impact on drug absorption remain poorly understood. This study combined biorelevant in vitro testing and physiologically based pharmacokinetic (PBPK) modeling to investigate such interactions between three commercially available drug products SPORANOX (itraconazole), ACTOS (pioglitazone) and GEVILON (gemfibrozil). The in vitro experiments revealed contradictory effects. The apparent solubility of itraconazole was improved in the presence of gemfibrozil, and certain cellulose-based polymers present in ACTOS and GEVILON inhibited precipitation of itraconazole after release from the amorphous solid dispersion. However, in release experiments, Tween 80 present in the GEVILON formulation led to lower itraconazole concentrations due to destabilization of supersaturation. PBPK modeling suggested that this effect could be one of the main reasons for the decreased bioavailability of itraconazole in the presence of the other drug products, as observed in prior clinical studies. This work highlights the potential relevance of physicochemical interactions between different drug products for the efficacy and safety of oral pharmacotherapy. The staged approach presented herein enables early detection of such interactions so that formulation strategies can be applied to mitigate them.
Metastatic breast cancer remains a major therapeutic challenge due to the limited efficacy of current treatments against both primary tumors and distant metastases. Here, we developed an arginine-based click-crosslinked nanoplatform for the co-delivery of camptothecin (CPT) and STAT3 siRNA (siSTAT3). The nanoplatform was constructed using a dibenzocyclooctyne-functionalized arginine derivative, where guanidinium-phosphate interactions enabled efficient siRNA loading and copper-free click crosslinking improved structural stability. Hyaluronic acid modification further enhanced tumor cell uptake through CD44 recognition. HDCPT@siSTAT3 achieved efficient intracellular delivery, lysosomal escape, and intracellular release of CPT and siSTAT3. In 4T1 breast cancer cells, HDCPT@siSTAT3 reduced STAT3 expression by approximately 50%, promoted apoptosis, and inhibited migration. In 4T1 breast tumor models, HDCPT@siSTAT3 suppressed tumor growth with minimal systemic toxicity. Moreover, the treatment significantly decreased lung metastatic burden in a 4T1-Luc metastasis model. The integration of arginine-based interactions, covalent cross-linking, and active targeting may provide a useful strategy for combined chemo-gene therapy in metastatic breast cancer.
The Stimulator of Interferon Genes (STING) pathway is a promising target for vaccine adjuvants and cancer immunotherapy, but the clinical application of the endogenous STING agonist 2',3'-cGAMP is hindered by poor membrane permeability, enzymatic degradation, and rapid renal clearance. To address these barriers, we developed a liposome formulation of cGAMP (cGAMP-Lipo) for intramuscular administration. The optimized cGAMP-Lipo exhibited high encapsulation efficiency (≥90 %), a uniform size of 70-80 nm, and enhanced STING activation in THP-1 cells with a 37-fold lower EC50 (45.85 nM) compared to free cGAMP. In vivo, cGAMP-Lipo significantly boosted antigen-specific immune responses, increasing anti-RBD IgG titers by up to 18-fold relative to the aluminum adjuvant and promoting Th1-skewed immunity (IgG2c/IgG1 ratio = 29.6) with a high proportion of effector CD8⁺ T cells. In a B16-OVA melanoma model, cGAMP-Lipo achieved substantial tumor growth inhibition and enhanced CD8⁺ T cell infiltration. Pharmacokinetic studies revealed that cGAMP-Lipo formed a sustained depot at the injection site, extending the local half-life from 0.50 h to 7.09 h and increasing local exposure by 43-fold. Moreover, the manufacturing process was successfully scaled up to 1 L with consistent batch-to-batch reproducibility. Collectively, this work establishes cGAMP-Lipo as a potent, durable, and scalable STING agonist adjuvant platform with strong potential for clinical translation in both infectious disease vaccination and cancer immunotherapy.
Effective treatment of aggressive breast tumors remains challenging due to poor drug selectivity, systemic toxicity, and limited therapeutic synergy. Here, a thermo/pH‑responsive magnetic Janus nanogel was employed as a smart platform for on‑demand co‑delivery of 5‑fluorouracil (5‑Fu) and quercetin (Qu) combined with magnetic hyperthermia. Drug release behavior under acidic and hyperthermic conditions was investigated, followed by evaluation of cellular uptake and cytotoxicity in 4T1 breast cancer cells. Therapeutic efficacy was further assessed in BALB/c mice bearing orthotopic 4T1 tumors under alternating magnetic field (AMF)-induced hyperthermia. Tumor growth, histopathological alterations, hepatotoxicity, and the expression of apoptosis‑related genes (Bax, Bcl‑2, p53, caspase‑3, caspase‑8, and caspase‑9) were analyzed. The Janus nanogel exhibited dual-stimuli-responsive release of 5-Fu and Qu and showed enhanced in vitro cytotoxicity in the nanoformulated co-delivery system. In vivo, treatment with drug‑loaded nanogels combined with AMF produced pronounced tumor regression (p < 0.01) and extensive apoptotic cell death. Gene expression analysis indicated activation of both intrinsic and extrinsic apoptotic pathways, reflected by upregulation of Bax, p53, and caspases together with an increased Bax/Bcl‑2 ratio. No significant hepatotoxicity was observed. The integration of dual‑drug chemotherapy with magnetic hyperthermia using a thermo/pH‑responsive Janus nanogel provides a synergistic and safe therapeutic strategy for aggressive breast cancer. These findings highlight the potential of stimuli‑responsive nanocarriers for advanced combination cancer therapy.
We present a unified framework for dissolution profile modeling and formulation optimization to identify formulation settings that reproduce a target dissolution profile. In generic drug development, the reference formulation is often unavailable or proprietary, making the underlying release behavior difficult to verify in advance. The proposed framework integrates parametric dissolution models and functional data analysis using functional principal component analysis (FPCA) within a candidate-based formulation-space exploration workflow. Curve similarity is quantified using the integrated squared difference, with the regulatory similarity factor f2 used as an additional evaluation metric. The framework was evaluated using two extended-release dissolution datasets exhibiting different release behaviors. Results demonstrated that model performance depends on the relationship between the modeling approach and the underlying dissolution characteristics. The parametric approach achieved strong performance when the dissolution behavior was well represented by the assumed model structure, whereas FPCA provided a flexible alternative when the underlying release behavior was not adequately described by a predefined model. The proposed framework enables systematic identification of candidate formulations and provides a flexible strategy for dissolution-guided inverse formulation design under uncertain release behavior.
Inflammatory skin diseases, such as psoriasis, lead to significant humanistic and economic burdens, mainly psychosocial impacts due to the relapsing papulosquamous characteristic of the disease. Due to the extensive skin lesions, topical therapies remain the main form of treatment. However, their effectiveness is limited by poor skin penetration. In addition, single-target mechanisms limit the simultaneous modulation of inflammatory and oxidative pathways involved in the pathogenesis of psoriasis and other skin diseases. To overcome these limitations, we developed hybrid lipid-polymeric nanoparticles (HLPNs) for the co-delivery of coenzyme Q10 (CoQ10), an endogenous antioxidant with anti-inflammatory properties, and small interfering RNA (siRNA) targeting TNFα, a central pro-inflammatory cytokine. HLPNs exhibited particles of 150-250 nm with low polydispersity (0.08-0.16), and high CoQ10 encapsulation efficiency (>85%). The presence of poly(allylamine hydrochloride) reversed the zeta potential (-27 to + 20 mV), enabling high siRNA binding efficiency and RNase protection. Structural analysis (ATR-FTIR, DSC, PXRD) confirmed successful CoQ10 incorporation into the lipid matrix and its amorphous conversion. HLPNs enhanced CoQ10 penetration into the stratum corneum (2-4.5-fold) and viable epidermis/dermis (4.7-7.5-fold) compared to solution, while confocal microscopy demonstrated improved siRNA skin delivery. In cell culture, HLPN-siRNA complexes promoted robust siRNA uptake in keratinocytes and macrophages. Therapeutic efficacy was validated in LPS-stimulated RAW264.7 macrophages, where HLPN_CoQ10-siTNFα significantly suppressed TNFα (3-6.5-fold), IL-6 (2-2.7-fold), and IL-1β (1.3-3-fold) secretion, while preserving CoQ10's antioxidant capacity and reducing reactive oxygen species (1.3-1.5-fold). Collectively, these findings show that the dual lipid-polymeric nature of HLPNs enables combinatorial delivery of antioxidant and RNAi therapies, offering a promising strategy for complex inflammatory skin disorders.
Despite the fact that acetylsalicylic acid (ASA) remains clinically important for inflammatory conditions, conventional oral administration is hampered by gastrointestinal adverse effects and variable systemic exposure. Whilst polymeric microneedles (MNs) enable transdermal delivery as an alternative to oral delivery through bypassing the stratum corneum; how drug solid-state behaviour affects the release kinetics of sustained-release MN systems has yet to be thoroughly elucidated. Herein, ASA-loaded poly (lactic-co-glycolic acid) (PLGA) MNs were developed to examine how retained but altered ASA crystallinity within the PLGA matrices contributes to release across in vitro, ex vivo and in silico models. 10*10 arrays of pyramidal PLGA MNs with a needle length of 600 µm were produced via micromoulding. Parent ASA stability studies showed near-quantitative recovery following fabrication-like exposure (98.0 ± 3.11%). Because the MNs were not only able to penetrate Parafilm M® and dermatomed porcine skin under a 32 N application force, but also withstand whole-patch compression at the exact same insertion force, the fabricated MN patches were deemed mechanically robust enough for application-relevant insertion into the skin under tested conditions. Whilst PXRD showed that ASA loaded into PLGA MNs retained crystalline features, albeit attenuated, DSC demonstrated that ASA-PLGA MNs exhibited a broadened, lower-temperature ASA-associated endotherm. As such, it was inferred that ASA solid-state behaviour had been altered within the polymer matrix. In contrast to apparent ex vivo release, which reached near completion by 168 h, in vitro ASA release was slower and incomplete, with drug release plateauing at approximately 60% by 504 h. These differences suggest that retained but altered ASA crystallinity may contribute to sustained release by limiting the rate at which ASA dissolves and diffuses from the PLGA matrix under static in vitro conditions. However, when MNs are in constant contact ex vivo, hydration of the PLGA matrix, in consort with tissue-associated diffusion and partitioning may promote continued removal of dissolved ASA from the polymer-skin interface, thereby accelerating apparent release. Taken together, this work identifies ASA solid-state behaviour as one formulation variable that interacts with the release environment to shape release from PLGA MNs. Furthermore, an exploratory in silico model simulating a potential ASA pharmacokinetic profile based on empirically obtained release profiles sets the foundation for future in vivo investigation.
Reduced brain cholesterol synthesis is an early dysfunction that plays a major role in Huntington's disease (HD) pathogenesis. Because the blood-brain barrier (BBB) prevents cholesterol uptake from the circulation, surface-modified, biodegradable, and biocompatible nanoparticles (NPs) that enhance BBB crossing have emerged as promising tools for delivering cholesterol to the brain in HD mouse models. In these models, such NPs have been shown to rescue cognitive, motor, and neuropathological defects. Here, we describe a new formulation of nanoparticles primarily composed of cholesterol and surface-engineered with a short carbon chain fatty acid (BUT) or its variant glucose (Glu) -conjugated (BUT-Glu) to enhance BBB penetration, referred to as BUT-chol-NPs and BUT-Glu-chol-NPs. We characterized key technological and pharmaceutical properties of these NPs and assessed their ability to cross the BBB and reach different brain regions and cell types following systemic administration in wild-type mice. Both BUT-chol-NPs and BUT-Glu-chol-NPs may represent new delivery systems for supplying cholesterol to the HD brain or to treat other neurological disorders in which cholesterol metabolism is impaired.
Global disease patterns are being rapidly reshaped by environmental changes such as rising temperatures, pollution, and more frequent natural disasters. Notable effects include a rise in skin infections, such as cellulitis, as well as upper respiratory and urinary tract infections. Cellulitis, an acute bacterial infection predominantly caused by S. aureus and Streptococcus species, is clinically challenging due to recurrence, primarily because of antimicrobial resistance and limitations of standard systemic therapies. Oral antibiotics like ofloxacin, though effective, are associated with significant suboptimal drug localization, systemic adverse effects and necessitate reliable and more targeted therapeutic approaches. This study reports the development and optimization of a pH-sensitive nanoparticle-loaded in situ gel for the local management of cellulitis. As the encapsulating polymer, Eudragit® S100 was used to load Ofloxacin via the nanoprecipitation method and optimized through Design of Experiments, achieving high entrapment efficiency of ∼96% and a nano size of 85-110 nm. These nanoparticles were incorporated into a Carbopol-HPMC-based in situ gel containing lidocaine to provide immediate pain-relieving action. The system exhibited pH-triggered sol-gel transition, enhanced viscosity under simulated wound conditions, and sustained drug release following controlled kinetics. In vitro and ex vivo studies demonstrated prolonged drug release post permeation, effective antimicrobial activity driven by MIC and MBC tests, and improved retention. In vivo evaluation in S. aureus-infected rat models confirmed reduced lesion severity, absence of skin irritation, inflammation and accelerated healing. Overall, this dual-delivery platform renders a promising scheme for concurrent pain management and sustained antimicrobial therapy, potentially improving patient compliance by altering therapeutic outcomes in cellulitis treatment.
Onychomycosis is a prevalent and therapeutically challenging fungal infection, largely due to the highly keratinised nail plate that severely restricts drug penetration. Voriconazole (VCZ) is a broad-spectrum antifungal agent; however, its poor aqueous solubility and limited permeability hinder its use in topical and localised delivery. Rather than relying on transungual drug transport, minimally invasive hollow microneedles (MNs) offer an alternative strategy by enabling direct administration of liquid formulations into the periungual and subungual soft tissues surrounding the nail unit. In this study, a choline-geranic acid (CAGE) ionic liquid (IL)-based submicron ionic liquid-in-water (IL/W) emulsion (1:9 v/v CAGE:2% w/v poloxamer 188 aqueous phase) was developed as an antifungal delivery platform with particular relevance to nail fungal infections. CAGE ILs with different choline-to-geranic acid molar ratios were synthesised and structurally confirmed. VCZ solubility increased markedly with increasing geranic acid content, reaching 13.27 ± 0.09 mg/g in CAGE 1:4 compared with negligible solubility in aqueous media. A CAGE-based emulsion exhibited a mean droplet size of 582.50 ± 9.97 nm, a low polydispersity index (0.263 ± 0.015), and a zeta potential of -8.80 ± 2.98 mV, and demonstrated good droplet size stability at 25 °C and 37 °C. Syringeability testing showed low break-loose forces (< 1.5 N) for all formulations, while the CAGE 1:4 emulsion required a significantly lower glide force (1.15 ± 0.07 N) compared with neat CAGE 1:4 (14.57 ± 0.24 N), supporting its suitability for hollow MNs assisted delivery. Ex vivo studies using neonatal porcine skin as a proof-of-concept soft tissue model demonstrated efficient formulation delivery following hollow MN-assisted administration. VCZ delivery was markedly enhanced by the combined use of the selected CAGE composition and hollow MNs. VCZ-loaded CAGE 1:4 delivered via hollow MNs achieved 80.66 ± 12.58 µg permeation at 24 h (87.23 ± 13.60% of the administered dose), while the CAGE-based emulsion maintained high permeation efficiency (74.47 ± 14.40% of dose) at a reduced VCZ loading. Cytocompatibility assessment using human skin-derived primary fibroblasts showed cell viability above 80% at concentrations ≤ 100 µg/mL. In vitro disk diffusion assessment against Candida albicans showed that CAGE-containing formulations produced clear zones of inhibition, whereas VCZ-alone discs did not produce an observable inhibition zone under these diffusion-limited assay conditions. This study demonstrates that the integration of CAGE IL, emulsion formulation, and hollow MNs-assisted delivery provides an effective strategy to enhance antifungal drug solubility, injectability, and delivery performance, offering a promising proof-of-concept periungual/subungual delivery platform for antifungal therapy of nail fungal infections.
