Search Results (1,274)

Lipid nanoparticle (LNP)-based delivery systems are promising tools for advancing RNA-based therapies. However, there are underlying challenges for the oral delivery of LNPs. In this study, we optimized an LNP formulation, which we encapsulated in a pH-sensitive Eudragit^® S 100 (Eu) coating. LNPs were prepared using the DLin-MC3-DMA ionizable lipid, cholesterol, DMG-PEG, and DSPC at a molar ratio of 50:38.5:10:1.5. LNPs were coated with 1% Eu solution via nanoprecipitation using 0.25% acetic acid to get Eu-coated LNPs (Eu-LNPs). Particle characteristics of LNPs were determined by using dynamic light scattering (DLS). Ribogreen and agarose gel retardation assays were used to evaluate nucleic acid entrapment and stability. LNPs and Eu-LNPs were ~120 nm and 4.5 μm in size, respectively. Eu-LNPs decrease to an average size of ~191 ± 22.9 nm at a pH of 8. Phosphate buffer (PB)-treated and untreated Eu-LNPs and uncoated LNPs were transfected in HEK-293 cells. PB-treated Eu-LNPs showed significant transfection capability compared to their non-PB-treated counterparts. Eu-LNPs protected their nucleic acid payloads in the presence of a simulated gastric fluid (SGF) with pepsin and maintained transfection capacity following SGF or simulated intestinal fluid. Hence, Eu coating is a potentially promising approach for the oral administration of LNPs. Full article

Cutaneous and oral mucosal adverse events (AEs) are among the most common non-hematologic toxicities observed during breast cancer treatment. These complications arise across various therapeutic modalities including chemotherapy, targeted therapy, hormonal therapy, radiotherapy, and immunotherapy. Although often underrecognized compared with systemic side effects, dermatologic and mucosal toxicities can severely impact the patients’ quality of life, leading to psychosocial distress, pain, and reduced treatment adherence. In severe cases, these toxicities may necessitate dose reductions, treatment delays, or discontinuation, thereby compromising oncologic outcomes. The growing use of precision medicine and novel targeted agents has broadened the spectrum of AEs, with some therapies linked to distinct dermatologic syndromes and mucosal complications such as mucositis, xerostomia, and lichenoid reactions. Early detection, accurate classification, and timely multidisciplinary management are essential for mitigating these effects. This review provides a comprehensive synthesis of current knowledge on cutaneous and oral mucosal toxicities associated with modern breast cancer therapies. Particular attention is given to clinical presentation, underlying pathophysiology, incidence, and evidence-based prevention and management strategies. We also explore emerging approaches, including nanoparticle-based delivery systems and personalized interventions, which may reduce toxicity without compromising therapeutic efficacy. By emphasizing the integration of dermatologic and mucosal care, this review aims to support clinicians in preserving treatment adherence and enhancing the overall therapeutic experience in breast cancer patients. The novelty of this review lies in its dual focus on cutaneous and oral complications across all major therapeutic classes, including recent biologic and immunotherapeutic agents, and its emphasis on multidisciplinary, patient-centered strategies. Full article

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Quinoa protein isolate (QPI) and sodium alginate (SA) have excellent biocompatibility and functional properties, making them promising candidates for food-grade delivery systems. In this study, we developed, for the first time, a QPI/SA complex-stabilized Pickering emulsion for curcumin encapsulation. The coacervation behavior of QPI and SA was investigated from pH 1.6 to 7.5, and the structural and interfacial characteristics of the complexes were analyzed using zeta potential measurements, Fourier-transform infrared spectroscopy, scanning electron microscopy, and contact angle analysis. The results showed that the formation of QPI/SA complexes was primarily driven by electrostatic interactions, hydrogen bonding, and hydrophobic interactions, with enhanced amphiphilicity observed under optimal conditions (QPI/SA = 5:1, pH 5). The QPI/SA-stabilized Pickering emulsions demonstrated excellent emulsification performance and storage stability, maintaining an emulsification index above 90% after 7 d when prepared with 60% oil phase. In vitro digestion studies revealed stage-specific curcumin release, with sustained release in simulated gastric fluid (21.13%) and enhanced release in intestinal fluid (88.21%). Cytotoxicity assays using HeLa cells confirmed the biocompatibility of QPI/SA complexes (≤500 μg/mL), while curcumin-loaded emulsions exhibited dose-dependent anticancer activity. These findings suggest that QPI/SA holds significant potential for applications in functional foods and oral delivery systems. Full article

Oral delivery of hydrophobic compounds remains challenging due to their poor aqueous solubility and the potential toxicity associated with conventional surfactant-based emulsions. To address these issues, we present a surfactant-free encapsulation strategy using electrosprayed alginate hydrogel beads for the stable and controlled delivery of hydrophobic oils. Hydrophobic compounds were dispersed in high-viscosity alginate solutions without surfactants via ultrasonication, forming kinetically stable oil-in-water dispersions. These mixtures were electrosprayed into calcium chloride baths, yielding monodisperse hydrogel beads. Higher alginate concentrations improved droplet sphericity and suppressed phase separation by enhancing matrix viscosity. The resulting beads exhibited stimuli-responsive degradation and controlled release behavior in response to physiological ionic strength. Dense alginate networks delayed ion exchange and prolonged structural integrity, while elevated external ionic conditions triggered rapid disintegration and immediate payload release. This simple and scalable system offers a biocompatible platform for the oral delivery of lipophilic active compounds without the need for surfactants or complex fabrication steps. Full article

Background/Objectives: The incorporation of bioactive molecules into mesoporous carriers is a promising strategy to improve stability, solubility, and therapeutic efficacy. In this study, we report for the first time the encapsulation of the synthetic chalcone 4-Cl into KIT-6 mesoporous silica and evaluate its cytotoxicity, toxicological profile, and pharmacological activities (antinociceptive, anti-inflammatory, and anxiolytic) using an in vivo zebrafish (Danio rerio) model. Methods: Zebrafish were orally dosed with 4-Cl, 4-Cl/KIT-6, or KIT-6 (4, 20, 40 mg/kg) and mortality was recorded for 96 h. For analgesia, zebrafish pretreated with 4-Cl, 4-Cl/KIT-6, KIT-6, or morphine received a tail stimulus (0.1% formalin). Locomotor activity (quadrant crossings) was monitored for 30 min to assess analgesia (neurogenic: 0–5 min; inflammatory: 15–30 min). For inflammation, abdominal edema and weight gain were assessed 4 h after intraperitoneal carrageenan (1.5%). Zebrafish (n = 6/group) received 4-Cl, 4-Cl/KIT-6, or KIT-6 (4, 20, 40 mg/kg, p.o.). Controls received ibuprofen (100 mg/kg, p.o.) or 3% DMSO. Weight was measured hourly for 4 h post-carrageenan (difference between baseline and hourly weights). Results: Physicochemical characterizations confirmed successful encapsulation without compromising the ordered structure of KIT-6, as evidenced by a significant reduction in surface area and pore volume, indicating efficient drug incorporation. In vivo assays demonstrated that the 4-Cl/KIT-6 formulation maintained the pharmacological activities of the free chalcone, reduced toxicity, and, notably, revealed a significant anxiolytic effect for the first time. Conclusions: These findings highlight KIT-6 as a promising platform for chalcone delivery systems and provide a solid basis for future preclinical investigations. Full article

Peroxisome proliferator-activated receptor alpha (PPARα) is a key regulator of lipid metabolism, making its agonists valuable therapeutic targets for various diseases, including chronic peripheral neuropathy. Existing PPARα agonists face limitations such as poor selectivity, sub-optimal bioavailability, and safety concerns. We previously demonstrated that A190, a novel, potent, and selective PPARα agonist, effectively alleviates chemotherapy-induced peripheral neuropathy and CFA-induced inflammatory pain as a non-opioid therapeutic agent. However, A190 alone has solubility and permeability issues that limits its oral delivery. To overcome this challenge, in this study, four new-generation ester prodrugs of A190; A190-PD-9 (methyl ester), A190-PD-14 (ethyl ester), A190-PD-154 (isopropyl ester), and A190-PD-60 (cyclic carbonate) were synthesized and evaluated for their enzymatic bioconversion and chemical stability. The lead candidate, A190-PD-60, was further formulated as a microemulsion (A190-PD-60-ME) and optimized via Box–Behnken design. A190-PD-60-ME featured nano-sized droplets (~120 nm), low polydispersity (PDI < 0.3), and high drug loading (>90%) with significant improvement in artificial membrane permeability. Crucially, pharmacokinetic evaluation in rats demonstrated that A190-PD-60-ME reached a 16.6-fold higher Cmax (439 ng/mL) and a 5.9-fold increase in relative oral bioavailability compared with an A190-PD-60 dispersion. These findings support the combined prodrug-microemulsion approach as a promising strategy to overcome oral bioavailability challenges and advance PPARα-targeted therapies. Full article

Curcumin is widely recognized for its various pharmacological properties, including antioxidant, anti-inflammatory, and anti-tumor activities. Nevertheless, the development of curcumin as a therapeutic agent is impeded by its limited oral bioavailability, which stems from its chemical instability, poor aqueous solubility, and rapid degradation. This study aimed to develop granule formulations incorporating poly(N-isopropylacrylamide)-grafted hyaluronic acid or HA-g-pNIPAM to enhance dissolution and protect curcumin from degradation. Three formulations were developed: F10 (HA-g-pNIPAM physically mixed with curcumin), F10 Encap (curcumin encapsulated within HA-g-pNIPAM), and F11 (curcumin granules without HA-g-pNIPAM). The stability results showed that F10 Encap effectively maintained curcumin content throughout the study period, retaining approximately 94% of its initial concentration by day 30, compared to 70% from F11 (p < 0.05) at 30 °C and 75% relative humidity. All dried curcumin granules exhibited excellent flowability, as determined by the angle of repose measurements. All three formulations exhibited a consistent particle size distribution across replicates, with a peak in the 150–180 μm size range. The sustained release observed for F10 Encap and F10 after the initial burst suggested that the HA-g-pNIPAM provided a controlled release mechanism, ensuring continuous curcumin dissolution over 240 min in gastric and intestinal conditions. These findings suggested that HA-g-pNIPAM improved dissolution and stability of curcumin. Full article

Background: Salivary pH plays a critical role in oral health by influencing enamel demineralization, buffering capacity, and the ecology of oral microbiota. Essential oils such as Origanum vulgare (oregano) possess well-documented antimicrobial properties that may reduce acidogenic bacterial activity. However, the effects of edible delivery systems like jellies on salivary pH modulation and their potential interactions with hormonal states remain poorly understood. Methods: This study evaluated the in vitro antimicrobial activity of an oregano-oil-based jelly formulation against standard bacterial (Staphylococcus aureus, Streptococcus pyogenes, and Escherichia coli) and fungal (Candida albicans) strains using the Kirby–Bauer disc diffusion method. Additionally, a human trial (n = 91) measured salivary pH before and after administration of the oregano-oil jelly. Participants were characterized by age, smoking status, menopausal status, and presence of menstruation. Multiple linear regression was used to identify predictors of final salivary pH. Results: The oregano-oil jelly demonstrated strong in vitro antimicrobial activity, with inhibition zones up to 8 mm for E. coli and C. albicans. In vivo, mean unstimulated salivary pH increased from 6.94 to 7.07 overall, indicating a mild alkalinizing effect. However, menstruating participants showed a significant decrease in final pH (from 7.03 to 6.78). Multiple regression identified menstruation as a significant negative predictor (β = −0.377, p < 0.001) and initial pH as a positive predictor (β = +0.275, p = 0.002). Menopausal status was not a significant predictor, likely due to the small sample size. Conclusions: Oregano-oil jellies may represent a promising natural approach to support oral health by increasing salivary pH and providing strong antimicrobial activity. However, physiological states such as menstruation can significantly modulate this response, underscoring the importance of personalized or phase-aware oral care strategies. Further studies with larger, diverse cohorts and controlled hormonal assessments are needed to validate these findings and optimize product formulations. Full article

Background/Objectives: Parenteral nutrition (PN) supports patients unable to receive nutrients via the gastrointestinal tract, but it lacks the health-promoting natural bioactive compounds found in a typical oral diet. This study aimed to develop a human serum albumin-based intravenous delivery system for lutein (an antioxidant carotenoid with vision-supportive and hepatoprotective properties) as a PN additive. Methods: An albumin–lutein nanosuspension (AlbLuteN) was synthesized using a modified nanoparticle albumin-bound (nab^TM) technology and characterized physicochemically. The nanoformulation was added to four commercial PN admixtures to assess the supplementation safety throughout the maximum infusion period. Visual inspection and measurements of fat globules larger than 5 µm (PFAT5) and the mean hydrodynamic diameter (Z-average), zeta potential, pH, osmolality, and lutein content were performed to detect potential interactions and evaluate the physicochemical stability. Results: AlbLuteN consisted of uniform particles (Z-average of 133.5 ± 2.8 nm) with a zeta potential of −28.1 ± 1.8 mV, lutein content of 4.76 ± 0.39%, and entrapment efficiency of 84.4 ± 6.3%. Differential scanning calorimetry confirmed the amorphous state of lutein in the nanosuspension. AlbLuteN was successfully incorporated into PN admixtures, without visible phase separation or significant changes in physicochemical parameters. The PFAT5 and Z-average values remained within pharmacopeial limits over 24 h. No substantial shifts in zeta potential, pH, or osmolality were observed. The lutein content remained stable, with losses below 3%. Conclusions: AlbLuteN can be safely added to representative PN admixtures without compromising their stability. This approach offers a novel strategy for intravenous lutein delivery and may contribute to improving the nutritional profile of PN. Full article

Background: Fowl typhoid (FT), a septicemic infection caused by Salmonella Gallinarum (SG), and H9N2 avian influenza are two economically important diseases that significantly affect the global poultry industry. Methods: We exploited the live attenuated Salmonella Gallinarum (SG) mutant JOL3062 (SG: ∆lon ∆pagL ∆asd) as a delivery system for H9N2 antigens to induce an immunoprotective response against both H9N2 and FT. To enhance immune protection against H9N2, a prokaryotic and eukaryotic dual expression plasmid, pJHL270, was employed. The hemagglutinin (HA) consensus sequence from South Korean avian influenza A virus (AIV) was cloned under the Ptrc promoter for prokaryotic expression, and the B cell epitope of neuraminidase (NA) linked with matrix protein 2 (M2e) was placed for eukaryotic expression. In vitro and in vivo expressions of the H9N2 antigens were validated by qRT-PCR and Western blot, respectively. Results: Oral immunization with JOL3121 induced a significant increase in SG and H9N2-specific serum IgY and cloacal swab IgA antibodies, confirming humoral and mucosal immune responses. Furthermore, FACS analysis showed increased CD4+ and CD8+ T cell populations. On day 28 post-immunization, there was a substantial rise in the hemagglutination inhibition titer in the immunized birds, demonstrating neutralization capabilities of immunization. Both IFN-γ and IL-4 demonstrated a significant increase, indicating a balance of Th1 and Th2 responses. Intranasal challenge with the H9N2 Y280 strain resulted in minimal to no clinical signs with significantly lower lung viral titer in the JOL3121 group. Upon SG wildtype challenge, the immunized birds in the JOL3121 group yielded 20% mortality, while 80% mortality was recorded in the PBS control group. Additionally, bacterial load in the spleen and liver was significantly lower in the immunized birds. Conclusions: The current vaccine model, designed with a host-specific pathogen, SG, delivers a robust immune boost that could enhance dual protection against FT and H9N2 infection, both being significant diseases in poultry, as well as ensure public health. Full article

Donepezil (DPZ) is an Alzheimer’s disease (AD) drug that promotes cholinergic neurotransmission and exhibits excellent acetylcholinesterase (AChE) selectivity. The current oral formulations of DPZ demonstrate decreased bioavailability, attributed to limited drug permeability across the blood–brain barrier (BBB). In order to overcome these limitations, various dosage forms aimed at delivering DPZ have been explored. This discussion will focus on the nose-to-brain (N2B) delivery system, which represents the most promising approach for brain drug delivery. Intranasal (IN) drug delivery is a suitable system for directly delivering drugs to the brain, as it bypasses the BBB and avoids the first-pass effect, thereby targeting the central nervous system (CNS). Currently developed formulations include lipid-based, solid particle-based, solution-based, gel-based, and film-based types, and a systematic review of the N2B research related to these formulations has been conducted. According to the in vivo results, the brain drug concentration 15 min after IN administration was more than twice as high those from other routes of administration, and the direct delivery ratio of the N2B system improved to 80.32%. The research findings collectively suggest low toxicity and high therapeutic efficacy for AD. This review examines drug formulations and delivery methods optimized for the N2B delivery of DPZ, focusing on technologies that enhance mucosal residence time and bioavailability while discussing recent advancements in the field. Full article

Background: Sodium–glucose cotransporter 2 (SGLT2) inhibitors have transformed type 2 diabetes mellitus (T2DM) management by promoting glucosuria, lowering glycated hemoglobin (HbA1c), blood pressure, and weight; however, their use is limited by genitourinary infections and ketoacidosis. Phytocannabinoids—bioactive compounds from Cannabis sativa—exhibit multi-target pharmacology, including interactions with cannabinoid receptors, Peroxisome Proliferator-Activated Receptors (PPARs), Transient Receptor Potential (TRP) channels, and potentially SGLT2. Objective: To evaluate the potential of phytocannabinoids as novel modulators of renal glucose reabsorption via SGLT2 and to compare their efficacy, safety, and pharmacological profiles with synthetic SGLT2 inhibitors. Methods: We performed a narrative review encompassing the following: (1) the molecular and physiological roles of SGLT2; (2) chemical classification, natural sources, and pharmacokinetics/pharmacodynamics of major phytocannabinoids (Δ⁹-Tetrahydrocannabinol or Δ⁹-THC, Cannabidiol or CBD, Cannabigerol or CBG, Cannabichromene or CBC, Tetrahydrocannabivarin or THCV, and β-caryophyllene); (3) in silico docking and drug-likeness assessments; (4) in vitro assays of receptor binding, TRP channel modulation, and glucose transport; (5) in vivo rodent models evaluating glycemic control, weight change, and organ protection; (6) pilot clinical studies of THCV and case reports of CBD/BCP; (7) comparative analysis with established synthetic inhibitors. Results: In silico studies identify high-affinity binding of several phytocannabinoids within the SGLT2 substrate pocket. In vitro, CBG and THCV modulate SGLT2-related pathways indirectly via TRP channels and CB receptors; direct IC₅₀ values for SGLT2 remain to be determined. In vivo, THCV and CBD demonstrate glucose-lowering, insulin-sensitizing, weight-reducing, anti-inflammatory, and organ-protective effects. Pilot clinical data (n = 62) show that THCV decreases fasting glucose, enhances β-cell function, and lacks psychoactive side effects. Compared to synthetic inhibitors, phytocannabinoids offer pleiotropic benefits but face challenges of low oral bioavailability, polypharmacology, inter-individual variability, and limited large-scale trials. Discussion: While preclinical and early clinical data highlight phytocannabinoids’ potential in SGLT2 modulation and broader metabolic improvement, their translation is impeded by significant challenges. These include low oral bioavailability, inconsistent pharmacokinetic profiles, and the absence of standardized formulations, necessitating advanced delivery system development. Furthermore, the inherent polypharmacology of these compounds, while beneficial, demands comprehensive safety assessments for potential off-target effects and drug interactions. The scarcity of large-scale, well-controlled clinical trials and the need for clear regulatory frameworks remain critical hurdles. Addressing these aspects is paramount to fully realize the therapeutic utility of phytocannabinoids as a comprehensive approach to T2DM management. Conclusion: Phytocannabinoids represent promising multi-target agents for T2DM through potential SGLT2 modulation and complementary metabolic effects. Future work should focus on pharmacokinetic optimization, precise quantification of SGLT2 inhibition, and robust clinical trials to establish efficacy and safety profiles relative to synthetic inhibitors. Full article

Background/Objectives: Hot-melt extrusion (HME) has gained prominence for the manufacture of sustained-release oral dosage forms, yet the application of wax-based matrices and their resilience to alcohol-induced dose dumping (AIDD) remains underexplored. This study aimed to develop and characterise wax-based sustained-release felodipine formulations, with a particular focus on excipient functionality and robustness against AIDD. Methods: Felodipine sustained-release formulations were prepared via HME using Syncrowax HGLC as a thermally processable wax matrix. Microcrystalline cellulose (MCC) and lactose monohydrate were incorporated as functional fillers and processing aids. The influence of wax content and filler type on mechanical properties, wettability, and drug release behaviour was systematically evaluated. Ethanol susceptibility testing was conducted under simulated co-ingestion conditions (4%, 20%, and 40% v/v ethanol) to assess AIDD risk. Results: MCC-containing tablets demonstrated superior sustained-release characteristics over 24 h, showing better wettability and disintegration. In contrast, tablets formulated with lactose monohydrate remained structurally intact during dissolution, overly restricting drug release. This limitation was effectively addressed through granulation, where reduced particle size significantly improved surface accessibility, with 0.5–1 mm granules achieving a satisfactory release profile. Ethanol susceptibility testing revealed divergent behaviours between the two filler systems. Unexpectedly, MCC-containing tablets showed suppressed drug release in ethanolic media, likely resulting from inhibitory effect of ethanol on filler swelling and disintegration. Conversely, formulations containing lactose monohydrate retained their release performance in up to 20% v/v ethanol, with only high concentrations (40% v/v) compromising matrix drug-retaining functionality and leading to remarkably increased drug release. Conclusions: This study highlights the pivotal role of excipient type and constitutional ratios in engineering wax-based sustained-release formulations. It further contributes to the understanding of AIDD risk through in vitro assessment and offers a rational design strategy for robust, alcohol-resistant oral delivery systems for felodipine. Full article

Background/Objectives: Despite advancements in surgery, esophagectomy remains one of the most challenging and complex gastrointestinal surgical procedures, burdened by significant perioperative morbidity and mortality rates, as well as high financial costs. Recognizing the need for standardized care provided by a multidisciplinary healthcare team, the EUropean PErioperative MEdical Networking (EUPEMEN) initiative developed a dedicated protocol for perioperative care of patients undergoing esophagectomy, aiming to enhance recovery, reduce morbidity, and homogenize care delivery across European healthcare systems. Methods: Developed through a multidisciplinary European collaboration of five partners, the protocol incorporates expert consensus and the latest scientific evidence. It addresses the entire perioperative pathway, from preoperative preparation to hospital discharge and postoperative recovery, emphasizing patient-centered care, risk mitigation, and early functional restoration. Results: The implementation of the EUPEMEN esophagectomy protocol is expected to improve patient outcomes through a day-by-day structured prehabilitation plan, meticulous intraoperative management, and proactive postoperative rehabilitation. The approach promotes reduced postoperative complications, earlier return to oral intake, and shorter hospital stays, while supporting multidisciplinary coordination. Conclusions: The EUPEMEN protocol for esophagectomy provides a comprehensive guideline framework for optimizing perioperative care in esophageal surgery. In addition, it serves as a practical guide for healthcare professionals committed to advancing surgical recovery and standardizing clinical practice across diverse care environments across Europe. Full article