Search Results (336)

Objectives: Rhizoma Coptidis alkaloids (RCAs) have been proven highly promising in diabetes therapy. However, poor solubility, low bioavailability, and a lack of an effective delivery strategy are major hurdles to improving clinical outcomes. Herein, mPEG-PLGA nanoparticles were employed to deliver RCA orally to enhance anti-diabetic effects. Methods: The RCA-loaded nanoparticles (RCA NPs) were prepared using the emulsion solvent diffusion method. The physicochemical properties of RCA NPs were characterized by morphology, particle size, zeta potential, polydispersity index, drug loading, and drug release. Pharmacokinetic and tissue distribution were determined by UPLC-MS/MS. The hypoglycemic effect was evaluated in a type 2 diabetes mouse model. To illustrate potential mechanisms of action, the expression of PI3K/Akt signaling pathway-related genes and their proteins was detected by RT-PCR and Western blot, respectively. Results: The prepared RCA NPs were spherical in structure, with a particle size of approximately 145 nm and a sustained drug release profile (approximately 50% within 24 h). Compared with RCAs, RCA NP bioavailability increased approximately 2.2-fold, and the hypoglycemic, hypolipidemic, hepatoprotective, anti-inflammatory effects were significantly improved. The better outcome might be due to upregulation of expression and phosphorylation levels within the IRS1/PI3K/AKT/GLUT4 signal pathway in liver tissues. Conclusions: RCA NPs hold great potential for further clinical translation. Full article

Objective: The therapeutic efficacy of the classic antibiotic combination trimethoprim/sulfamethoxazole (TMP/SMZ) is often limited by the significant pharmacokinetic mismatch. In this study, a polyethylene glycol-polylactic-co-glycolic acid (PEG-PLGA) nanodelivery system was employed to improve the pharmacokinetic matching of TMP and SMZ. The investigation also evaluated the enhanced in vivo antibacterial efficacy of this formulation. Methods: Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry (UPLC-MS/MS) was employed to systematically characterize the absorption, distribution, and excretion profiles of PEG-PLGA-loaded TMP nanoparticles (NPs) in rats. In vitro antibacterial activity was assessed against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vivo efficacy and biosafety of the TMP NPs/SMZ regimen were evaluated using a murine E. coli infection model via survival monitoring, biochemical assays, and histopathology. Results: Pharmacokinetic analysis revealed that TMP NPs achieved a relative bioavailability of 193.05% and extended the elimination half-life by 3.37-fold compared to free TMP. Tissue distribution showed significantly increased drug accumulation in the liver, spleen, and kidneys, with renal clearance as the primary excretion pathway (73.89%). In vitro, the nano-formulation reduced the minimum inhibitory concentration (MIC) by 2-4-fold and shortened the bactericidal duration from 12 to 8 h. In vivo, the TMP NPs/SMZ combination significantly improved survival rates, accelerated recovery, and alleviated infection-induced organ damage without systemic toxicity. Conclusions: This nanotechnology-based strategy effectively aligns the pharmacokinetics of TMP and SMZ, prolongs their synergistic window, and enhances biosafety, offering a viable approach to revitalize classic antibiotic combinations. Full article

Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer’s disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood–brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)—designated as TGN/RAP12-RBC-NPs@Ltn—which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes—pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)—in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD. Full article

Objectives: In response to the challenge that Staphylococcus aureus (S. aureus) vaccines fail to induce durable protective immunity, this study aims to develop a novel antigen-adjuvant co-design strategy. Specifically, we rationally combined the immunodominant toxin antigen LukS-PV with the immunologically subdominant adhesin antigen ClfA, co-delivered via the PLGA-PEG nanoadjuvant system, to elicit synergistic, durable, and balanced humoral and cellular immune responses. Methods: Firstly, recombinant antigens LukS-PV and ClfA were individually covalently conjugated to PLGA-PEG 25% nanoparticles (25% NPs) using EDC/NHS chemical coupling to construct a combined nanovaccine, followed by systemic safety verification in a mouse model. Subsequently, specific antibody titers were detected by ELISA, and the secretion levels of IL-4, IFN-γ, and IL-17A were measured by ELISPOT assay to comprehensively evaluate the humoral and cellular immune responses induced by the vaccine. Finally, the protective efficacy of the vaccine was assessed through acute and long-term (up to 180 days) lethal challenge experiments, thereby verifying the effectiveness of this co-design strategy based on rational antigen selection. Results: The combined vaccine group (25% NPs-rClfA + 25% NPs-rLukS-PV) not only elicited high levels of specific antibodies but, more importantly, induced robust cellular immune responses dominated by Th1 and Th17 cells. Challenge experiments confirmed that the protective efficacy of the combined vaccine was significantly superior to that of any single-antigen vaccine and provided complete protection for up to 180 days. Crucially, the same antigen combination formulated with a traditional aluminum adjuvant failed to confer this durable protection, underscoring the essential role of adjuvant synergy. Conclusions: This study demonstrates that rational combination of immunodominant and subdominant antigens with a compatible nanoadjuvant induces synergistic and durable immunity against S. aureus. This co-design strategy addresses key limitations of previous vaccines and provides a promising foundation for future clinical development. Full article

Background/Objective: Osimertinib (OSI) is a third-generation tyrosine kinase inhibitor approved for non-small cell lung cancer (NSCLC) therapy. OSI is administered orally; this route limits the amount of OSI reaching the tumor in the lungs and is associated with serious systemic toxicity. This study aimed to develop a dry powder inhalable formulation to provide tumor-targeted delivery and minimize systemic toxicity. To the best of our knowledge, this is the first study to prepare and evaluate a dry powder inhalation formulation of OSI. Methods: Chitosan-coated PLGA nanoparticles (PLGA-C NPs) encapsulating OSI were prepared using a single emulsion-solvent evaporation technique. PLGA-C NPs were assembled into respirable nanocomposite microparticles (NCMPs) via spray drying with L-leucine as a carrier. PLGA-C NPs were characterized for particle size, zeta-potential, encapsulation efficiency, and in vitro efficacy in A-549 cell line. NCMPs were evaluated for solid-state properties, aerosolization performance, stability and in vitro release. Results: PLGA-C NPs exhibited a particle size of 145.18 ± 3.0 nm, high encapsulation efficiency and a positive zeta potential. In vitro studies demonstrated a 3.6-fold reduction in IC50 compared to free OSI, superior antimigratory effects and enhanced cell cycle arrest. Solid-state characterization of NCMPs demonstrated drug encapsulation in the polymer without chemical interaction. NCMPs exhibited excellent aerosolization (mass median aerodynamic diameter of 1.09 ± 0.23 μm, fine particle fraction of 73.48 ± 8.6%) and sustained drug release (61.76 ± 3.9% at 24 h). Stability studies confirmed the physicochemical stability integrity. Conclusions: These findings suggest that this novel dry powder inhalable OSI formulation may improve therapeutic outcomes while reducing systemic toxicity. Full article

Background: While intravenous administration of nanoparticles (NPs) is effective for targeting the lungs and liver, directing them to other organs and tissues remains challenging. Methods: Here, we report alternative administration routes that improve organ-specific accumulation of poly (lactic-co-glycolic acid) (PLGA) NPs (100 nm, negatively charged) loaded with the near-infrared dye Cyanine 7 (Cy7). NP cytotoxicity was evaluated in HEK293, mMSCs, C2C12, L929, and RAW264.7 cells. Hemocompatibility was assessed using WBCs and RBCs. NPs were administered via the tail vein, carotid, renal, and femoral arteries in BALB/c mice. Administration safety was evaluated by laser speckle contrast imaging and histological analysis. NP biodistribution and accumulation were assessed using in vivo and ex vivo fluorescence tomography and confocal microscopy of cryosections. Results: PLGA-Cy7 NPs demonstrate low cytotoxicity even at high doses and exhibit good hemocompatibility. Administration of NPs through the mouse carotid, renal, and femoral arteries significantly increases accumulation in the target ipsilateral brain hemisphere (31.7-fold) and salivary glands (28.3-fold), kidney (13.7-fold), and hind paw (3.6-fold), respectively, compared to intravenous administration. Injection of NPs through arteries supplying the target organs and tissues does not result in significant changes in blood flow, morphological alterations, or irreversible embolization of vessels, provided the procedure is performed correctly and the optimal dosage is used. Conclusions: These results highlight the potential of intra-arterial delivery of NPs for organ-specific drug targeting, underscoring the synergistic impact of advances in materials science, minimally invasive endovascular surgery, and nanomedicine. Full article

Background: Targeting cancer tumors using PLGA (Poly(D, L-lactide-co-glycolide)) nanoparticles (NPs) requires clathrin-mediated endocytosis (CME) and lysosomal degradation to provide release within cancer cells. However, Caveolae-mediated endocytosis (CavME) provides lysosomal escape, which is favorable in oral applications. Macropinocytosis (MPC) is a non-targeted way of endocytosis, used by immune cells. Methods: In this proof-of-concept study, we investigated how polysaccharide surface coatings modulate the endocytic uptake of FITC-labeled PLGA nanomicelles (FPM) in MCF-7 breast cancer cells using spectrophotometry. This research involved the surface modification of FPM using polysaccharides: cellulose (FPCM) as a polyglucan and Halomonas Levan (FPLM) as a polyfructan, to modify the NP and cell-surface association. Results: MPC was found to be the major internalization pathway for the nanomicelles ~200 nm. However, after surface modification, FPCM and FPM remained highly MPC-dependent with additional CavME/CME involvement, whereas FPLM showed relatively reduced MPC dependence and a higher CME contribution. Conclusion: Overall, the results indicate that simple polysaccharide coatings can bias the relative use of MPC, CME, and CavME for PLGA nanomicelles in MCF-7 cells, providing a basis for pathway-oriented nanocarrier design. Validation by flow cytometry, studies in additional breast cancer cell lines, and transporter-level investigations will be needed to generalize and refine these findings. Full article

Therapeutic cancer vaccines have emerged as promising immunotherapy approaches. TRIMEL, a heat-shocked lysate derived from three melanoma cell lines, constitutes the basis of TAPCells and TRIMELVax cancer vaccines, both of which have shown clinical efficacy but face major limitations in stability and logistics due to the requirement of ultra-low temperature storage. In this study, we evaluated the encapsulation of TRIMEL into poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NP-TRIMEL) as a strategy to enhance stability and preserve immunogenic function under more feasible storage conditions. NP-TRIMEL was synthesized using a double-emulsion method and characterized by hydrodynamic size, zeta potential, morphology, and TRIMEL loading. Functional assays using melanoma patient-derived monocytes and peripheral blood lymphocytes suggested that NP-TRIMEL promoted the generation of TAPCells capable of inducing cytotoxic lymphocytes against allogeneic melanoma cells, even after 24 weeks of storage at 4 °C. Remarkably, NP-TRIMEL showed a two-order-of-magnitude increase in efficiency compared to the original TRIMEL in promoting TAPCells differentiation and lymphocyte activation. These findings provide evidence that tumor cell lysates can be functionally stabilized and even potentiated through nanoencapsulation, reinforcing the concept that delivery platforms not only preserve but also enhance antigen-driven immune responses. Full article

Tinea is a superficial fungal infection of keratinized structures caused by specific filamentous fungi called dermatophytes. Terbinafine, a drug used to treat tinea, is poorly soluble in water, and its delivery into the skin via nanoparticle formulation usingpoly(lactic-co-glycolic acid) (PLGA) has been demonstrated. In this study, we investigated the preparation conditions for nanoparticles (NPs) to achieve efficient intradermal delivery of terbinafine. Terbinafine-loaded PLGA NPs were prepared using the nanoprecipitation method, and the particle size distribution and average particle size were measured using dynamic light scattering. Skin permeability tests were conducted using mouse dorsal skin, and the amount of terbinafine delivered into the skin was measured to evaluate the release behavior in the skin. In the preparation of terbinafine-loaded PLGA NPs, under conditions where the external solution was purified water, the mean volume diameter was 40.49 ± 15.63 nm, the terbinafine-loaded content was 3.31 ± 0.29%, and the entrapment efficiency was 55.08 ± 4.88%. Under conditions of an external solution containing 1.0 × 10⁻³ w/v% arginine(Arg) aq. solution, the mean volume diameter was 41.71 ± 16.08 nm, the terbinafine-loaded content was 5.17 ± 0.37%, and the entrapment efficiency was 86.48 ± 6.01%. The entrapment efficiency and content were higher under the condition using 1.0 × 10⁻³ w/v% Arg aq. solution compared to purified water. In addition, in the skin permeability test, no drug was detected in the receptor solution sampled from both the NPs suspension group and the simple solution group, and no drug was detected in the intradermal solution in the simple solution group. The intradermal drug concentration was 77.94 ± 10.66 µg/g under conditions where purified water was used as the dialysate, and 96.42 ± 61.62 µg/g under conditions using 1.0 × 10⁻³ w/v% arginine, exceeding the reported minimum inhibitory concentration (MIC) of 8.87 µg/g, suggesting the efficacy of terbinafine-loaded PLGA NPs for the treatment of tinea versicolor. Since tinea treatment is a long-term process, it is desirable to deliver a stable amount of drug to the treatment site at all times. Therefore, the nanoparticle preparation conditions using purified water as the external solution, where the intradermal drug concentration exceeded the MIC and remained stable in the skin permeability test, were suggested to be suitable for tinea treatment. Full article

(1) Background: Glioblastoma is the most common and aggressive primary brain tumor in adults, with a median survival time for patients treated with standard chemotherapy often of less than 1 year. Potential anticancer activity against glioblastoma is demonstrated by flavonoids, including fisetin (FIS). Although, its clinical application is limited by poor solubility and chemical instability. This study aimed to conduct a preliminary evaluation of fisetin’s suitability for intravenous delivery by developing and characterizing FIS-loaded poly(lactic-co-glycolic acid) nanoparticles (FIS-PLGA-NPs) and assessing their in vitro cytotoxic potential against glioblastoma. (2) Methods: Six FIS-PLGA nanoparticle formulations were prepared via the emulsification–solvent evaporation method and evaluated for key physicochemical properties. The biological activity of fisetin was examined through cell cycle analysis and apoptosis assays, and the most promising formulation was further assessed using an MTT assay in U-138 MG glioblastoma cells. In parallel, pure fisetin was exposed to ionizing radiation, including the standard sterilization dose of 25 kGy, to evaluate its structural stability and suitability for terminal sterilization approaches. (3) Results: The selected formulation (NP4) exhibited a mean particle size of approximately 330 nm, a zeta potential of −7.2 mV, a polydispersity index of 0.25, and high encapsulation efficiency and drug loading of 83.58% and 13.93%, respectively. Despite its preliminary nature, this formulation retained cytotoxic activity in vitro. Moreover, pure fisetin maintained its structural and chemical integrity following radiation exposure, supporting the feasibility of radiation sterilization prior to nanoparticle incorporation. (4) Conclusions: These findings confirm the feasibility of combining radiosterilizable fisetin with PLGA-based nanoencapsulation and provide an initial foundation for the development of an injectable fisetin delivery system for glioblastoma treatment. Further optimization, particularly surface modification, will be required to enhance colloidal stability and systemic performance. Full article

Treating bacterial infections has become increasingly difficult due to the rise in antibiotic-resistant bacterial strains. Strategies involving the targeted delivery of antibiotics have been proposed to minimize the administered antibiotic doses. This study aims to develop the first double-modified nanovehicle capable of increasing bacterial membranes’ permeability while specifically targeting Staphylococcus aureus, one of the foremost pathogens responsible for global mortality rates. Thus, polymeric NPs composed of poly(lactic-co-glycolic acid) (PLGA) were produced, and their surface was modified with TAT peptide to increase the membranes’ permeability and folic acid (FA) to direct the NPs to S. aureus. The nanosystem showed spherical morphology with sizes of 174 ± 4 nm, a monodisperse population (polydispersity index of 0.08 ± 0.02), and a zeta potential of −2.5 ± 0.1 mV. The NPs remained stable for up to four months during storage. Fluorescence-based flow cytometry analysis proved that the double modification of PLGA NPs increased the interaction of the NPs with S. aureus, with fluorescence increasing from 71 ± 3% to 87 ± 1%. The nanosystem slightly affected the growth curve of S. aureus by extending both the lag time (from 2.5 ± 0.2 to 2.88 ± 0.4 h) and the exponential phase, as evidenced by an increase in the half-maximum growth time (from 3.9 ± 0.2 to 4.4 ± 0.1 h). Furthermore, the nanocarrier showed no toxicity for human dermal fibroblast cells, maintaining a 100% cell viability at the highest concentration tested (100 µM). Therefore, the proposed FA/TAT-functionalized nanocarrier presented promising features to be successfully used as a delivery vehicle of antimicrobials to fight S. aureus. Full article

Background/Objectives: Glaucoma is a neurodegenerative optic disorder which occurs due to persistent elevation of the intraocular pressure. It leads to permanent blindness and currently affects over 75 million individuals worldwide. Nowadays, topical ocular medications are the leading therapy despite their poor ocular penetration and short residence time. Methods: The purpose of this research is to formulate bisoprolol hemifumarate-loaded polylactic-co-glycolic acid (PLGA) nanoparticles and improve their ocular penetration and bioavailability for the treatment of glaucoma by enhancing the delivery of the drug to the posterior part of eye. By using the solvent displacement method, formulations were prepared and optimum formula was elected using Design-Expert^® software. Results: In vitro characterization demonstrated that the optimum formula contained 25 mg BSP, 22.5 mg PLGA, and 60 mg Tween80, yielding high values of drug encapsulation (75%) and zeta potential (−18.7 ± 0.41 mV), with a low particle size (105 ± 0.35 nm) and polydispersity index (0.411 ± 0.71). Transmission electron microscopy and atomic force microscopy showed smooth and spherical nanosized particles. X-ray diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy revealed successful encapsulation of the drug inside the polymeric matrix. Ex vivo confocal laser scanning microscopy proved that there was better uptake of the drug upon using PLGA-NPs. In vitro release profiles indicated biphasic drug release from the PLGA-NPs, confirming a sustained drug release over 12 h. In vivo studies showed that BSP-PLGA-NPs significantly reduced the IOP compared to bisoprolol solution. Quantitative immunohistochemistry showed lower retinal GFAP expression with BSP-PLGA-NPs compared with induced controls and drug solution, which is indicative of attenuated glial activation. Conclusions: These data support improved ocular delivery and an improved pharmacodynamic effect; however, they demonstrate association rather than a direct mechanistic suppression of glial pathways. Full article

Background/Objectives: Palmitoylethanolamide (PEA) is an endogenous lipid mediator with endocannabinoid-like activity. Despite its therapeutic potential in muscle-related inflammatory disorders, including sarcopenia, its clinical use is limited by poor solubility and bioavailability. To overcome these issues, we developed hybrid nanoparticles combining poly(lactic-co-glycolic acid) (PLGA) and lipids to enhance PEA encapsulation and ok delivery. Methods: PEA-loaded hybrid nanoparticles (PEA-Hyb-np) were produced via a modified single-emulsion solvent evaporation method using stearic acid and Gelucire^® 50/13 as lipid components. Characterization included particle size, morphology, PDI, and zeta potential, as well as DSC, FT-IR, and XRD analyses. For the biological evaluation in a C2C12 myoblasts cell culture, coumarin-6-labeled nanoparticles were employed. Results: PEA-Hyb-np showed mean particle sizes of ~150 nm, with internal lipid–polymer phase separation. This structure enabled high encapsulation efficiency (79%) and drug loading (44.2 mg/g). Drug release in physiological and non-physiological media was enhanced due to drug amorphization, confirmed by DSC, FT-IR, and XRD analyses. Cytocompatibility studies showed no toxicity and improved cell viability compared to unloaded nanoparticles. Cellular uptake studies by confocal microscopy and flow cytometry demonstrated efficient and time-dependent internalization. Conclusions: PEA-Hyb-np represent a promising delivery platform to improve the solubility, bioavailability, and therapeutic efficacy of PEA for muscle-targeted applications. Full article

Background/Objectives: Despite the advantages of polycaprolactone (PCL) for drug delivery, it still lacks effective approaches to enhance its encapsulation of drugs. Blending PCL with less hydrophobic polymers can tailor physicochemical properties to overcome these limitations. This study, for the first time, integrates two beneficial approaches—polymer blending and Box–Behnken design (BBD) optimisation—to develop PCL-based blend nanoparticles (NPs) with enhanced encapsulation efficiency (EE), controlled particle size, and improved stability through surface charge modulation. Methods: Drug-loaded blend NPs were developed using a double emulsion method, with different polymer ratios. A BBD model was employed to investigate the influential factors that control the size, charge, and EE. Results: Blending PCL with a less hydrophobic polymer significantly improved EE, achieving 60.96% under optimal conditions. The BBD model successfully predicted conditions for obtaining NPs with optimum size, negative charge, and enhanced drug encapsulation. The drug amount was identified as the most influential factor for EE, while polymer amounts significantly impacted size and charge. Conclusions: Careful control of polymer ratios, drug amount, and surfactant levels was shown to significantly influence particle size, surface charge, and EE, with the balanced 50:50 PCL:PLGA blend achieving optimal physicochemical performance. Using the BBD, the study identified the predicted optimal formulation consisting of 162 mg polymer blend, 8.37 mg drug, and 8% surfactant, which is expected to yield NPs with a size of 283.06 nm, zeta potential of −31.54 mV, and EE of 70%. The application of BBD allowed systematic evaluation of the factors and their interactions, providing robust predictive models. Full article

Drug resistance remains a major obstacle in cancer treatment despite advances in therapeutic regimens. To address this, we explored the potential of Doxorubicin (Dox) delivery in poly (lactide-co-glycolic acid) (PLGA) nanoparticles to enhance Diffuse large B-cell lymphoma (DLBCL) cell death. This research investigates the potential of Doxorubicin and advanced delivery methods. We used PLGA nanoparticles with Oleyl cysteineamide (OCA); its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs. Compared to PLGA-NPs, PLGA-OCA-NPs enhance immunity and induce tumor cell death. They also show significant apoptotic cell death and induced immune responses in DLBCL mouse models. Dox-conjugated PLGA-OCA-NPs (DOX-OCA) exhibit significant in vitro and in vivo anticancer activity compared to free DOX, showing remarkable antitumor effects with reduced systemic toxicity in mouse models. Our findings underscore the promising potential of PLGA-OCA-NPs in DLBCL treatment, offering a hopeful future in cancer therapy. This innovative delivery system offers enhanced immune responses and effectively addresses toxicity concerns, marking a significant step forward in cancer therapy. Full article