Search Results (167)

At emergency sites, bacteria in the environment can cause secondary wound infections. Timely treatment of infected wounds can improve the prognosis. In this study, we designed a closed-loop system for real-time wound infection monitoring and electronically controlled drug release, enabling rapid and stable deployment at disaster sites. Multilayer screen-printed electrodes were developed to detect uric acid (UA), pH, and temperature biomarkers. The electrode’s outermost layer was shielded by a zwitterionic conductive hydrogel (Gel) to prevent environmental interference and achieve systematic antibacterial protection through in situ reduction of silver nanoparticles (AgNPs) on its surface. For rapid and efficient drug delivery, amikacin (Ami) loaded cationic liposomes (Lipo) embedded in the zwitterionic conductive hydrogel (Gel-Lipo@Ami) were integrated as the core therapeutic carrier. This closed-loop system provides timely infection detection and enables in situ treatment during emergency rescues. Full article

Background/Objectives: 5-Fluorouracil (5-FU) and Irinotecan (IRT) are two of the most used chemotherapeutic agents in CRC treatment. However, achieving treatment goals has been hampered by poor drug delivery to tumor sites and associated toxicity from off-target binding to healthy cells. Though the synergism of 5-FU-IRT has provided incremental improvements in clinical outcomes, the short elimination half-life and off-target binding to healthy cells remain significant challenges. We postulated that nanoencapsulation of a combination of 5-FU and IRT in niosomes would prolong the drugs’ half-lives, while over-encapsulation lyophilized powder in Targit^® oral capsules would passively the CRC microenvironment and avoid extensive systemic distribution. Methods: Ranges of formulation and process variables were input into design of experiment (DOE Fusion One) software, to generate screening experiments. Niosomes were prepared using the thin-film hydration method and characterized by size, the polydispersity index (PDI), morphology and intrastructure, and drug loading. Blank niosomes ranged in size from 215 nm to 257 nm. Results: After loading with the 5-FU-IRT combination, the niosomes averaged 251 ± 2.20 nm with a mean PDI of 0.293 ± 0.01. The surfactant-to-cholesterol ratio significantly influenced the niosome size and the PDI. The hydrophilic 5-FU exhibited superior loading compared to the lipophilic IRT molecules, which probably competed with other lipophilic niosome components in niosomes’ palisade layers. In vitro dissolution in biorelevant media showed delayed release until lower intestinal region (IRT) or colonic region (5-FU). Conclusions: Thus, co-nanoencapsulation of 5-FU/IRT in niosomes, lyophilization, and over-encapsulation of powder in colon-specific capsules could passively target the CRC cells in the colonic microenvironment. Full article

Background/Objectives: Clofazimine (CFZ) is a versatile antimicrobial active against several bacterial species, although its reduced aqueous solubility and the occurrence of side effects limit its use. Nanostructured lipid carriers (NLCs) constitute an interesting approach to increase drug bioavailability and safety. However, the development of nanoparticle-based formulations is challenging. In the present work, a combination of smart pharmaceutical technology approaches was proposed to develop CFZ-loaded NLCs, taking advantage of previous knowledge on NLCs screening. Methods: A design space previously established using Artificial Intelligence (AI) tools was applied to develop CFZ-loaded NLC formulations. After formulation characterization, Neurofuzzy Logic (NFL) and in silico docking simulations were employed to enhance the understanding of lipid nanocarriers. Then, the performance of formulations designed following NFL guidelines was characterized in terms of biocompatibility, using murine fibroblasts, and antimicrobial activity against several strains of Staphylococcus aureus. Results: The followed approach enabled CFZ-loaded NLC formulations with optimal properties, including small size and high antimicrobial payload. NFL was useful to investigate the existing interactions between NLC components and homogenization conditions, that influence CFZ-loaded NLCs’ final properties. Also, in silico docking simulations were successfully applied to examine interactions and affinity between the drug and the lipid matrix components. Finally, the designed CFZ-loaded formulations demonstrated suitable biocompatibility, together with antimicrobial activity. Conclusions: The implementation of smart strategies during nanoparticle-based therapeutics development, such as those described in this manuscript, would enable the more efficient design of new systems for suitable antimicrobial delivery. Full article

Background/Objectives: Effective drug delivery systems require precise formulation and understanding of excipient impact on active pharmaceutical ingredient (API) stability and efficacy, as uncontrolled interactions can compromise outcomes. This study developed and validated a semi-solid extrusion (SSE) 3D printing method for polyvinyl alcohol (PVA)-based hydrogel disks with metronidazole (MET). These disks served as a standardized platform to assess excipient influence on MET’s antimicrobial activity, focusing on plasticizers (polyethylene glycol 400, glycerol, propylene glycol, and diethylene glycol monoethyl ether)—excipients that modify hydrogel properties for their application in printing dressing matrices—with the platform’s capabilities demonstrated using in vitro antimicrobial susceptibility testing against Bacteroides fragilis. Methods: Hydrogel inks based on PVA with added plasticizers and MET were prepared. These inks were used to 3D-print standardized disks. The MET content in the disks was precisely determined. The antimicrobial activity of all formulation variants was evaluated using the disk diffusion method against B. fragilis. Results: The incorporated plasticizers did not negatively affect the antimicrobial efficacy of MET against B. fragilis. All printed hydrogel matrices exhibited clear antimicrobial activity. The 3D-printed disks showed high repeatability and precision regarding MET content. Conclusions: SSE 3D printing is viable for manufacturing precise, reproducible MET-loaded PVA hydrogel disks. It provides a standardized platform to evaluate diverse excipient impacts, like plasticizers, on API antimicrobial performance. The tested plasticizers were compatible with MET. This platform aids rational formulation design and screening for optimal excipients in designed formulations and for various pharmaceutical applications. Full article

Cisplatin, which kills cancer cells mainly through DNA crosslinking, has been widely used as a first-line chemotherapeutic agent although it also causes severe side effects. To improve anticancer outcomes, various types of cisplatin-based nanomedicines have been developed, either through direct incorporation or coordination of cisplatin within nanoparticles (NPs). During the formulation and characterization of cisplatin-loaded NPs, quantitative determination of cisplatin is crucial for both clinically used and newly developed NPs. While NPs facilitate cisplatin delivery, the use of different nanomaterials inevitably complicates its determination and increases the cost of quantification. Currently, there is still a significant demand for an accurate, simple, and cost-effective method to determine cisplatin in NPs, which would facilitate the screening and quality control of cisplatin-based nanomedicines. This review aims to discuss the main strategies for quantifying cisplatin, following a summary of the main types of cisplatin-loaded NPs. Application examples of cisplatin determination in NPs are provided, and the key features of each quantification strategy are compared. In addition, NP-based electrochemical sensors are included as an emerging approach for characterizing cisplatin loaded in NPs. Rational selection of an appropriate cisplatin determination method for NPs according to the quantification principle and specific drug-delivery settings is highly recommended. Full article

Prostate cancer is the most common tumor in men in developed countries and it often responds poorly to conventional treatments. Monoclonal antibody (MoAb) therapy, for this pathology, has grown tremendously in the past decades, exploiting naked and conjugated antibodies to cytotoxic payloads to form antibody drug conjugates (ADCs). Several studies have been carried out conjugating biomolecules against prostate-specific membrane antigen (PSMA), highly expressed in this tumor, to cytotoxic drugs. Nano-based formulations show high potential in targeted drug delivery to enhance the bioavailability of drugs. Our research aimed to evaluate the feasibility of setting up a nanoparticle-based multimodal tool for targeted drug delivery, describing the step-by-step approach and to perform a first screening of these fluorescent PEGylated silica nanoparticles employed in selective cancer cell targeting and killing. These nanoparticles featured a core–shell structure to contemporarily conjugate the antibody and the cytotoxic payload monomethyl auristatin E (MMAE) using a step-by-step approach. We compared the cytotoxic effect of this multimodal nanotool near the antibody-MMAE and free MMAE. We found a lower cytotoxicity effect of the nanoparticle-based construct compared to free drugs, likely because of the preservation of the previously observed receptor-mediated endocytosis. Nanomedicine is confirmed as a powerful alternative to organic drug delivery systems, even if some aspects, such as drug loading efficacy, release, scalable manufacturing and long-term stability, need to be deepened. Full article

Background: In this study, exosomes were engineered with anti-CD47 antibody and loaded with rifapentine to improve their ability to target macrophages for drug delivery. Methods: Exosomes from RAW264.7 cell supernatant were extracted by differential centrifugation, antibody-modified, and drug-loaded ultrasonically. After co-culturing with macrophages, transcriptomics and proteomics screened differentially expressed genes and proteins. Western Blot identified macrophage polarization, ELISA detected inflammatory indicators, and an apoptosis kit was used for fluorescence staining. Results: Transcriptome sequencing showed that 406 genes in the macrophages changed significantly, with pathways like TNF and NF-κB. Proteomics identified 7478 proteins, 433 with significant differences. Western Blot indicated M1 polarization. Fluorescence staining showed apoptosis in the antiMExo-RIF group. Conclusions: The study provides multi-omics evidence of the immune mechanism of the engineered exosome drug delivery system in inducing macrophage apoptosis, revealing potential molecular mechanisms and the great potential use of engineered exosomes in treating macrophage-related diseases. Full article

An effective method for purifying the total alkaloid components from Piperis longi fructus extract was developed in this study. The adsorption/desorption processes of the total alkaloid components from Piperis longi fructus were established by resin model screening, adsorption kinetics, and adsorption thermodynamics tests. Moreover, the purified powders were analyzed with UPLC-Q-ZENO-TOF-MS/MS and then their antioxidant activity was tested. The Langmuir equation provided a good fit with the experimental results. The thermodynamic study provides a satisfactory fit for the isotherm data, indicating that the adsorption process is characterized by spontaneity (ΔG° < 0), exothermicity (ΔH° < 0), and an increase in entropy (ΔS° < 0). Furthermore, the kinetic adsorption behavior on D101 resin was effectively modeled by pseudo-second-order kinetics. According to this mechanism, we selected the best adsorption parameters and optimized the on-column elution process to effectively enrich the total alkaloid components. The optimal process was as follows: D101 macroporous resin was added to an alcohol solution (crude drug concentration of 2 g/mL) and then concentrated under a vacuum at 45~55 °C (<−0.08~−0.10 MPa) until alcohol-free. Subsequently, the resin was loaded into the column and eluted with 70% ethanol at a flow rate of 2 BV/h for 10 BV to achieve desorption. The present study provides a more efficient method for the enrichment of the total alkaloidal components of Piperis longi fructus, which will lay the foundation for applications in food additives or functional foods in the future. Full article

Background: Crude extracts are easily available and considered safe and cost-effective in comparison with synthetic extracts and are more accessible compared with purified compounds, making them suitable for initial screening and exploratory studies in drug discovery. Introduction: Cucumis sativus and Cucurbita pepo are medicinal plants that belong to the Cucurbitaceae family, commonly known as cucumber and pumpkin, comprising a series of phytochemicals such as chlorophylls, carotenoids, oleanolic acid, saponin, and triterpenoids. Materials and Methods: In this study, an ethanol extract of Cucumis sativus and Cucurbita pepo whole plants was used to assess their hypoglycemic effects in a fasted, fed, glucose-loaded and streptozotocin-induced diabetes model of albino rats followed by Molecular Spectroscopic (FTIR and UV-Vis) analysis. Blood sugar levels were determined from samples collected at different intervals (0, 1, 3, and 4 h). Results and Conclusions: A significant blood glucose reduction was observed as a result of both plants’ extracts, while the greatest reduction was shown by Cucumis sativus. The UV-Vis profile showed several absorption bands ranging from 200 to 800 nm, showing the presence of flavonoids, phenolic compounds, terpenoids, carotenoids, and chlorophyll. The FTIR spectra reveal the presence of carbohydrates, proteins, lipids, and phenolic compounds, which contribute to the extracts’ nutritional and biological value. Further research is needed to determine the active agents and the likely mechanism of action of both the plants regarding their hypoglycemic effects. Full article

(1) Background: The treatment of Mycobacterium abscessus (M. abscessus) infections resistant to clarithromycin (CLR) is highly challenging. Traditional non-tuberculous mycobacteria (NTM) chemotherapy may disturb the immune homeostasis of the host by increasing oxidative stress; therefore, host-directed immunotherapy is an alternative option for infections caused by M. abscessus. (2) Method: A clinical isolate of CLR-resistant M. abscessus was screened, and then the therapeutic effects of N-acetylcysteine (NAC) against CLR-resistant M. abscessus infection were evaluated in Tohoku Hospital Pediatrics-1 (THP-1) cells and murine models. RNA sequencing and Western blot were used to profile the protective immune responses induced by NAC. The contribution of candidate signaling pathways was confirmed by the corresponding inhibitor and agonist. (3) Results: NAC immunotherapy led to a significant reduction in bacterial loads both in THP-1 cells and murine infection models, which was associated with enhanced antioxidant effects and downregulation of apoptosis signal-regulating kinase 1 (ASK1)–mitogen-activated protein ki-nase/extracellular signal-regulated kinase 3/6 (MKK3/6)–p38 mitogen-activated protein kinase (MAPK)-mediated inflammatory immune responses. The inhibitor of p38 signaling mimicked the protective effect of NAC, while the agonist attenuated it, suggesting that the p38 pathway is crucial in NAC-mediated immune protection against M. abscessus infection. (4) Conclusion: Our study suggests that NAC could be used as a host-directed therapy agent against drug-resistant M. abscessus infection. Full article

Chitosan is widely used in drug delivery applications, due to its biocompatibility, bio-degradability, and low toxicity. Nevertheless, its properties can be enhanced through the physical or chemical modification of its amino and hydroxyl groups. This work explores the electrostatic complexation of two chitosan samples of differing lengths with two poly(N-isopropylacrylamide) (PNIPAM) homopolymers of different molecular weight carrying a chargeable carboxyl end group. This interaction enables the electrostatic binding of PNIPAM side chains onto the chitosan backbone through the amino groups, and could be considered as an alternative grafting method. Dynamic and electrophoretic light scattering techniques were employed in order to study the solution/dispersion properties of the formed complexes as a function of the PNIPAM concentration, or, equivalently, the molar/charge ratio of the two components. The obtained results revealed that their mass, size, and charge mostly depend on the length of the two individual constituents, as well as their mixing ratio. Furthermore, their response to changes in their environment, namely temperature and ionic strength, was also examined, demonstrating the effect of either the thermoresponsiveness of PNIPAM or the electrostatic charge screening, respectively. Fluorescence spectroscopy, utilizing pyrene as a probe, provided information regarding the hydrophobicity of the formed complexes, while images from scanning transmission electron and atomic force microscopies further elucidated their morphology, which was found to be closely related to that of the corresponding chitosan molecule. Finally, their potential as drug delivery vehicles was also investigated, utilizing curcumin as a model drug at various loading concentrations. Full article

Ciprofloxacin (CPL) is an effective antibiotic against Pseudomonas aeruginosa. However, its use is limited by the emergence of multi-resistant strains. In this study, 8–15 nm manganese ferrite (MnFe₂O₄) nanoparticles, aminated and/or PEGylated, have been used as drug-delivery systems of CPL. The magnetic nanoparticles (MNPs) were prepared in the presence of the aliphatic amines octadecylamine (ODA), oleylamine (OAm), or PEG8000 to achieve the appropriate surface chemistry for the direct conjugation of CPL and drug loading into the PEG matrix, respectively. The primary MNPs proved to be biocompatible in calf thymus (CT)-DNA interaction studies, with binding constant values K_b in the range of 4.43–6.5 × 10⁴ (g/mL)⁻¹. ODA as a coater gave rise to MnFe₂O₄ MNPs, with a high percentage of free amines that further allowed for the conjugation of 90.9% CPL, which gradually released via a non-Fickian anomalous transport motif. The 25.1% CPL that loaded in the PEGylated MNPs led to a partial transformation of the nanoflowers into more aggregated forms. The release profile, although steeper, is described by the same model. The isolated magnetic nanocarrier with a high content of CPL was evaluated for its antimicrobial activity against a multi-resistant strain of P. aeruginosa using an automated industrial instrument (BacT/ALERT^®3D), and its molecular profile was outlined by studying its interaction with plasmid DNA (pDNA). The prototype use of BacT/ALERT^®3D allows for the simultaneous screening of multiple samples, while it foreshadows the transition to a preclinical phase. Full article

The preparation of solid dispersions (SDs) of emodin (EMO) represents an effective strategy for enhancing its limited water solubility. However, there is a lack of effective strategies for carrier screening. The molecular mechanism underlying EMO-SDs has yet to be fully elucidated. In this study, we employed a molecular simulation to identify the optimal solubilizing carriers for EMO-SDs, which were subsequently validated through solubilization experiments. Gelucire 50/13 (GEL) was identified as the most effective solubilizing carrier. The formulation of the EMO-SDs was established through solubility testing, utilizing a drug-to-carrier loading ratio of 1:9. The characterization of the interactions between the drug and the carrier was conducted using DSC, FTIR, and NMR spectroscopy. The DSC results indicated that EMO molecules were dispersed within the carrier in an amorphous state, while FTIR and NMR analyses revealed the formation of hydrogen bonds between the drug and carrier molecules. The molecular mechanisms of EMO-SDs were further elucidated through an MD simulation. Findings from the formation mechanism studies demonstrated that the majority of EMO molecules were embedded within the interstices of a loosely aggregated micelle-like structure formed by the carrier molecules. The solubility enhancement mechanism indicated that the carrier molecules surrounded the EMO molecules during the solubilization process, thereby facilitating the interaction of EMO with water. The stability mechanism accounts for the fact that recrystallization of the drug may occur. Full article

Background: Neratinib maleate (NM), a tyrosine kinase inhibitor, is used in the treatment of breast cancer. Current oral therapy of NM suffers from low and variable bioavailability due to the solubility and permeability-related issues of the drug. To overcome the low oral bioavailability, the drug is recommended to be administered at high doses, causing severe gastrointestinal side effects leading to discontinuation of the drug therapy. Methods: In this work, NM-loaded lipid–polymer hybrid nanoparticles (NM-LPNs) were designed and optimized to improve the oral bioavailability of the drug. A systematic approach involving a screening design followed by an optimization design based on the principles of design of experiments (DoE) was used to prepare NM-LPNs. Minimum particle size (PS) ranging between 200 and 300 nm and maximum drug loading (DL (%)) were set as the target physicochemical properties. The optimized NM-LPNs, with a mean PS of 278.57 ± 21.16 nm and a DL (%) of 25.77 ± 1.11%, were further characterized for physicochemical properties, thermal and diffractometric analysis, stability, in vitro drug release, and oral pharmacokinetic studies. Results: The nanoparticles exhibited a burst release followed by a prolonged release up to 12 h in the in vitro drug release studies in pH 6.8 media. Conclusions: The mean C_max and the AUC_last values were found to increase significantly for NM-LPNs by 1.72 times (p < 0.01) and 1.58 times (p < 0.01), respectively, when compared to plain NM in the oral pharmacokinetic studies. The optimized NM-LPN formulation can reduce the oral dose of NM and, thereby, its dose-dependent side effects. Full article

Background/Objectives: Mycobacterium abscessus (MAB) is a highly resilient pathogen that causes difficult-to-treat pulmonary infections, particularly in individuals with cystic fibrosis (CF) and other underlying conditions. Its ability to form robust biofilms within the CF lung environment is a major factor contributing to its resistance to antibiotics and evasion of the host immune response, making conventional treatments largely ineffective. These biofilms, encased in an extracellular matrix, enhance drug tolerance and facilitate metabolic adaptations in hypoxic conditions, driving the bacteria into a persistent, non-replicative state that further exacerbates antimicrobial resistance. Treatment options remain limited, with multidrug regimens showing low success rates, highlighting the urgent need for more effective therapeutic strategies. Methods: In this study, we employed artificial sputum media to simulate the CF lung environment and conducted high-throughput screening of 24,000 compounds from diverse chemical libraries to identify inhibitors of MAB biofilm formation, using the Crystal Violet (CV) assay. Results: The screen established 17 hits with ≥30% biofilm inhibitory activity in mycobacteria. Six of these compounds inhibited MAB biofilm formation by over 60%, disrupted established biofilms by ≥40%, and significantly impaired bacterial viability within the biofilms, as confirmed by reduced CFU counts. In conformational assays, select compounds showed potent inhibitory activity in biofilms formed by clinical isolates of both MAB and Mycobacterium avium subsp. hominissuis (MAH). Key compounds, including ethacridine, phenothiazine, and fluorene derivatives, demonstrated potent activity against pre- and post-biofilm conditions, enhanced antibiotic efficacy, and reduced intracellular bacterial loads in macrophages. Conclusions: This study results underscore the potential of these compounds to target biofilm-associated resistance mechanisms, making them valuable candidates for use as adjuncts to existing therapies. These findings also emphasize the need for further investigations, including the initiation of a medicinal chemistry campaign to leverage structure–activity relationship studies and optimize the biological activity of these underexplored class of compounds against nontuberculous mycobacterial (NTM) strains. Full article