Low Toxicity Research Articles

Enhancing precision targeting of ovarian cancer tumor cells in vivo through extracellular vesicle engineering.

Extracellular vesicles (EVs) function as natural mediators of intercellular communication, secreted by cells to facilitate cell-cell signaling. Due to their low toxicity, immunogenicity, biodegradability, and potential to encapsulate therapeutic drugs, EVs hold significant therapeutic promise. Nevertheless, their limited targeting ability often diminishes their therapeutic impact. Therefore, enhancing EVs by incorporating targeting units onto their membranes could bolster their targeting capabilities, enabling them to accumulate in specific cells and tissues. In this study, we engineered EVs to fuse ephrin-B2 with the EV membrane protein LAMP2b. This modification aimed to direct the engineered EVs toward the ephrin-B4 receptor expressed on the surface of ovarian cancer cells. The engineered EVs retained their inherent properties, including size, expression of EV membrane proteins, and morphology, upon isolation. In vitro experiments using real-time imaging revealed that EVs engineered with the ephrin-B2 ligand exhibited substantial internalization and uptake by ovarian cancer cells, in stark contrast to native EVs. In vivo, the engineered EVs carrying the ephrin-B2 ligand effectively targeted ovarian cancer cells, surpassing the targeting efficiency of control EVs. This innovative approach establishes a novel targeting system, enhancing the uptake of EVs by ovarian cancer cells. Our findings underscore the potential of using EVs to target cancer cells, thereby enhancing the effectiveness of anti-cancer therapies while minimizing off-target effects and toxicity in normal cells and organs.

A review: In-situ gel drug delivery system

The eye is the body's most delicate organ. Pharmaceutical scientists find that designing ocular drug delivery systems is the most difficult because only 5% of administered drugs reach the eye due to the complex anatomical structure of the eye, the cornea's small absorptive surface and low transparency, the cornea's lipophilicity, pre-keratitis (from nasolacrimal drainage), the drug's bonding with proteins in tear fluid, blinking, and the conjunctival sac's low capacity, all of which limit the entry of drug molecules at the site of action and ultimately result in suboptimal ocular therapy. Considerable research is being done on developing more advanced drug delivery methods for ocular administration in an attempt to increase the bioavailability of ophthalmic medications. These innovative drug delivery methods have many benefits over traditional ones, including better release profiles that boost drug delivery efficiency and lower drug toxicity. Numerous studies in this field support the idea that in situ gelling devices can be helpful for the transport of drugs into the eyes. Drug delivery systems known as "in situ gel-forming systems" are in solution before being supplied to the body, but thereafter go through a process called "in situ gelation" to form a gel in response to an external stimulus like pH or temperature. A brief overview of in situ gels, several methods for in situ gelling systems, types of polymers utilized in in-situ gels, their mechanisms of gel formation, and an assessment of polymeric in situ gel are all included in this review.

Privacy-friendly evaluation of patient data with secure multiparty computation in a European pilot study

In multicentric studies, data sharing between institutions might negatively impact patient privacy or data security. An alternative is federated analysis by secure multiparty computation. This pilot study demonstrates an architecture and implementation addressing both technical challenges and legal difficulties in the particularly demanding setting of clinical research on cancer patients within the strict European regulation on patient privacy and data protection: 24 patients from LMU University Hospital in Munich, Germany, and 24 patients from Policlinico Universitario Fondazione Agostino Gemelli, Rome, Italy, were treated for adrenal gland metastasis with typically 40 Gy in 3 or 5 fractions of online-adaptive radiotherapy guided by real-time MR. High local control (21% complete remission, 27% partial remission, 40% stable disease) and low toxicity (73% reporting no toxicity) were observed. Median overall survival was 19 months. Federated analysis was found to improve clinical science through privacy-friendly evaluation of patient data in the European health data space.

Sustainable detergent-disinfectant agent based on whey mineralizate and silver nanoparticles for cleaner production in dairy industry

Detergents and disinfectants for dairy industry must meet a variety of characteristics, including low toxicity, high antibacterial activity, and excellent rinsing of pollutants from working surfaces. This work presents an innovative detergent-disinfectant agent based on whey mineralizate and silver nanoparticles (Ag NPs), which allows reducing production costs and ensuring high cleanliness of treated surfaces compared to analogues. For this purpose, a method for obtaining sols of Ag NPs stabilized with didecyldimethylammonium bromide (Ag NPs-DDAB) was developed and optimized using neural network algorithms. Characterization of Ag NPs-DDAB showed particles with a radius of 4.5 nm and 20 nm, stable in the pH range from 2 to 11. An acute toxicity study of Ag NPs in mice showed LD50 = 4230 μg/kg. Based on the degree of accumulation and inhalation toxicity, Ag NPs-DDAB are classified as low-hazard chemicals. The developed detergent-disinfectant had a washability of about 90%, high antimicrobial activity (0.005 mg/mL) against Penicillium roqueforti and a sanitary and hygienic effect on coliforms, general contamination and pathogenic microorganisms, a low-corrosive effect and low toxicity (315 mg/mL) to Danio rerio. It was concluded that the use of detergent-disinfectant agent will completely eliminate the consumption of water for the equipment cleaning process and can be used to clean an electrodialysis unit’s circuits, enabling the utilization of secondary waste from membrane milk processing and promoting resource efficiency and cleaner production in the dairy industry.

Catalyst Design and Engineering for CO2-to-Formic Acid Electrosynthesis for a Low-Carbon Economy.

Formic acid (FA) has emerged as a promising candidate for hydrogen energy storage due to its favorable properties such as low toxicity, low flammability, and high volumetric hydrogen storage capacity under ambient conditions. Recent analyses have suggested that FA produced by electrochemical carbon dioxide (CO2) reduction reaction (eCO2RR) using low-carbon electricity exhibits lower fugitive hydrogen (H2) emissions and global warming potential (GWP) during the H2 carrier production, storage and transportation processes compared to those of other alternatives like methanol, methylcyclohexane, and ammonia. eCO2RR to FA can enable industrially relevant current densities without the need for high pressures, high temperatures, or auxiliary hydrogen sources. However, the widespread implementation of eCO2RR to FA is hindered by the requirement for highly stable and selective catalysts. Herein, the aim is to explore and evaluate the potential of catalyst engineering in designing stable and selective nanostructured catalysts that can facilitate economically viable production of FA.

Cell cycle checkpoint revolution: targeted therapies in the fight against malignant tumors

Malignant tumors are among the most important causes of death worldwide. The pathogenesis of a malignant tumor is complex and has not been fully elucidated. Studies have shown that such pathogenesis is related to abnormal cell cycle progression. The expression levels of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors as well as functions of the cell cycle checkpoints determine whether the cell cycle progression is smooth. Cell-cycle-targeting drugs have the advantages of high specificity, low toxicity, low side effects, and low drug resistance. Identifying drugs that target the cell cycle and applying them in clinical treatments are expected to promote chemotherapeutic developments against malignant tumors. This article aims to review drugs targeted against the cell cycle and their action mechanisms.

Exploring flavonoid derivatives as potential pancreatic lipase inhibitors for obesity management: An in silico and in vitro study.

Obesity is widely recognized as a major public health issue and is one of the leading causes of death worldwide. Overweight and obesity are prominent lifestyle ailments that not only give rise to additional health issues but also play a role in the development of other chronic diseases, such as cancer, diabetes, metabolic syndrome, and cardiovascular diseases. Orlistat is now the only pharmaceutical drug for the management of obesity. However, prolonged use of orlistat has been associated with detrimental consequences, hence necessitating the development of a new drug with reduced or no adverse reactions. Pancreatic Lipase is a critical enzyme in lipid metabolism. Using naturally occurring compounds as PL inhibitors has garnered significant attention because of their diverse structure and low toxicity. The present work investigates the inhibitory action of flavonoids on PL using in silico and in vitro methods. Thirteen flavonoid derivatives and orlistat were docked with PL. The ADME properties of the flavonoid derivatives were studied, and most of the compounds are in admire range. The stability of the best-docked complexes was checked by REMD. The in silico study demonstrated favorable inhibitory activity of flavonoids compared to orlistat. Consequently, an enzyme inhibitory experiment was conducted to authenticate the in silico results. The lipase inhibitory activity was assessed by using p-nitrophenyl butyrate as the substrate. Kaempferol exhibited significant inhibitory activity against PL, as shown by its IC50 value of 72.7 ± 3µM. This study proposed a natural drug candidate with promising inhibitory efficacy against PL for obesity.

Screening of novel narrow-spectrum benzofuroxan derivatives for the treatment of multidrug-resistant tuberculosis through in silico, in vitro, and in vivo approaches

Tuberculosis remains a serious global health threat, exacerbated by the rise of resistant strains. This study investigates the potential of two benzofuroxan (Bfx) derivatives, 5n and 5b, as targeted treatments for MDR-TB using in silico, in vitro, and in vivo methodologies. In vitro analyses showed that Bfx compounds have significant activity against Mtb H37Rv, with Bfx 5n standing out with a MIC90 of 0.09 ± 0.04 μM. Additionally, their efficacy against MDR and pre-XDR strains was superior compared to commercial drugs. These Bfx compounds have a narrow spectrum for mycobacteria, which helps avoid dysbiosis of the gut microbiota, and they also exhibit high selectivity and low toxicity. Synergism studies indicate that Bfx derivatives could be combined with rifampicin to enhance treatment efficacy and reduce its duration. Scanning electron microscopy revealed severe damage to the morphology of Mtb following treatment with Bfx 5n, showing significant distortions in the bacillary structures. Whole-genome sequencing of the 5n-resistant isolate suggests resistance mechanisms mediated by the Rv1855c gene, supported by in silico studies. In vivo studies showed that the 5n compound reduced the pulmonary load by 3.0 log10 CFU/mL, demonstrating superiority over rifampicin, which achieved a reduction of 1.23 log10 CFU/mL. In conclusion, Bfx derivatives, especially 5n, effectively address resistant infections caused by Mtb, suggesting they could be a solid foundation for future therapeutic developments against MDR-TB.

Polysaccharide-based hydrogels for cartilage regeneration

Cartilage defect is one of the common tissue defect clinical diseases and may finally lead to osteoarthritis (OA) which threat patients’ physical and psychological health. Polysaccharide is the main component of extracellular matrix (ECM) in cartilage tissue. In the past decades, polysaccharide-based hydrogels have shown great potential for cartilage regeneration considering unique qualities such as biocompatibility, enhanced cell proliferation, drug delivery, low toxicity, and many others. Structures such as chain length and chain branching make polysaccharides have different physical and chemical properties. In this review, cartilage diseases and current treatment options of polysaccharide-based hydrogels for cartilage defection repair were illustrated. We focus on how components and structures of recently developed materials affect the performance. The challenges and perspectives for polysaccharide-based hydrogels in cartilage repair and regeneration were also discussed in depth.

Lung cancer cell-derived exosomes: progress on pivotal role and its application in diagnostic and therapeutic potential

Lung cancer is frequently detected in an advanced stage and has an unfavourable prognosis. Conventional therapies are ineffective for the treatment of metastatic lung cancer. While certain molecular targets have been identified as having a positive response, the absence of appropriate drug carriers prevents their effective utilization. Lung cancer cell-derived exosomes (LCCDEs) have gained attention for their involvement in the development of cancer, as well as their potential for use in diagnosing, treating, and predicting the outcome of lung cancer. This is due to their biological roles and their inherent ability to transport biomolecules from the donor cells. Lung cancer-associated cell-derived extracellular vesicles (LCCDEVs) have the ability to enhance cell proliferation and metastasis, influence angiogenesis, regulate immune responses against tumours during the development of lung cancer, control drug resistance in lung cancer treatment, and are increasingly recognised as a crucial element in liquid biopsy evaluations for the detection of lung cancer. Therapeutic exosomes, which possess inherent intercellular communication capabilities, are increasingly recognised as effective vehicles for targeted drug delivery in precision medicine for tumours. This is due to their exceptional biocompatibility, minimal immunogenicity, low toxicity, prolonged circulation in the bloodstream, biodegradability, and ability to traverse different biological barriers. Currently, multiple studies are being conducted to create new means of diagnosing and predicting outcomes using LCCDEs, as well as to develop techniques for utilizing exosomes as effective carriers for medication delivery. This paper provides an overview of the current state of lung cancer and the wide range of applications of LCCDEs. The encouraging findings and technologies suggest that the utilization of LCCDEs holds promise for the clinical treatment of lung cancer patients.

Preparation of natural adhesives with high-strength and low temperature fast-curing properties

The development of natural adhesives to substitute petroleum-based products is crucial for sustainable progress. However, the bond strength of most existing natural adhesives still falls short of that of commercially available adhesives and the curing process often demands prolonged high-temperature treatment. Herein, we prepared pure natural adhesives using gelatin (GE), tung oil (TO), and dopamine (DA) as the main raw materials. The shear strength of the adhesive to wood reached up to 6.35 MPa, a significant improvement over most natural wood adhesives reported. Additionally, the tensile strength of the adhesive to wood reached 10.50 MPa, which is comparable to commercially available neoprene-phenolic wood adhesives (9.99 MPa) and cyanoacrylate instant adhesives (9.48 MPa). In addition, the natural adhesive prepared by us exhibits fast curing performance at room temperature and can be fully cured in only 12 min, which is significantly better than the commercially available adhesive. The adhesives prepared in this study also possessed excellent reversible curing properties, antimicrobial properties, low toxicity, and degradability. These characteristics offer new insights for the advancement and dissemination of natural adhesives.

High‐yield rice with rich nutrition and low toxicity can be obtained under potato–rice cropping system

High‐yield rice with rich nutrition and low toxicity can be obtained under potato–rice cropping system

Biosurfactants: Chemical Properties, Ecofriendly Environmental Applications, and Uses in the Industrial Energy Sector

The exploitation of nature and the increase in manufacturing production are the cause of major environmental concerns, and considerable efforts are needed to resolve such issues. Oil and petroleum derivatives constitute the primary energy sources used in industries. However, the transportation and use of these products have huge environmental impacts. A significant issue with oil-related pollution is that hydrocarbons are highly toxic and have low biodegradability, posing a risk to ecosystems and biodiversity. Thus, there has been growing interest in the use of renewable compounds from natural sources. Biosurfactants are amphipathic microbial biomolecules emerging as sustainable alternatives with beneficial characteristics, including biodegradability and low toxicity. Biosurfactants and biosurfactant-producing microorganisms serve as an ecologically correct bioremediation strategy for ecosystems polluted by hydrocarbons. Moreover, synthetic surfactants can constitute additional recalcitrant contaminants introduced into the environment, leading to undesirable outcomes. The replacement of synthetic surfactants with biosurfactants can help solve such problems. Thus, there has been growing interest in the use of biosurfactants in a broad gamut of industrial sectors. The purpose of this review was to furnish a comprehensive view of biosurfactants, classifications, properties, and applications in the environmental and energy fields. In particular, practical applications of biosurfactants in environmental remediation are discussed, with special focus on bioremediation, removal of heavy metals, phytoremediation, microbial enhanced oil recovery, metal corrosion inhibition, and improvements in agriculture. The review also describes innovating decontamination methods, including nanobioremediation, use of genetically modified microorganisms, enzymatic bioremediation, modeling and prototyping, biotechnology, and process engineering. Research patents and market prospects are also discussed to illustrate trends in environmental and industrial applications of biosurfactants.

Iron-MOFs for Biomedical Applications.

Over the past two decades, iron-based metal-organic frameworks (Fe-MOFs) have attracted significant research interest in biomedicine due to their low toxicity, tunable degradability, substantial drug loading capacity, versatile structures, and multimodal functionalities. Despite their great potential, the transition of Fe-MOFs-based composites from laboratory research to clinical products remains challenging. This review evaluates the key properties that distinguish Fe-MOFs from other MOFs and highlights recent advances in synthesis routes, surface engineering, and shaping technologies. In particular, it focuses on their applications in biosensing, antimicrobial, and anticancer therapies. In addition, the review emphasizes the need to develop scalable, environmentally friendly, and cost-effective production methods for additional Fe-MOFs to meet the specific requirements of various biomedical applications. Despite the ability of Fe-MOFs-based composites to combine therapies, significant hurdles still remain, including the need for a deeper understanding of their therapeutic mechanisms and potential risks of resistance and overdose. Systematically addressing these challenges could significantly enhance the prospects of Fe-MOFs in biomedicine and potentially facilitate their integration into mainstream clinical practice.

Enhanced Delivery of Biomolecules into Caco2 Cells Based on the Cell-Penetrating Ability of Keratin Peptides.

Keratin, as a promising bioresource, possesses significant potential for diverse biological applications due to its favorable biocompatibility, low toxicity, biodegradability, and cell adhesion ability. However, there are few studies on the cell-penetrating ability of keratin peptides (KEPs) for biomolecule delivery. Therefore, this study explored the cell-penetrating ability of KEPs with different molecular weights (Mw) on Caco2 cells using fluorescein-labeled insulin (FITC-INS) as the target intracellular biomolecule. The potential cell-penetrating mechanism was elaborated by combining cellular investigation with the physicochemical characterization of KEPs. The result shows that the KEPs <3 kDa (KEP1) exhibited the highest cell-penetrating ability at 2 mg/mL, allowing efficient delivery of FITC-INS into Caco2 cells without covalent bonding. The cellular uptake mechanism was energy-dependent, mainly involving macropinocytosis. The further fractionation of KEP1 reveals that the most effective components consisted of 8-19 amino acids, including specific hydrophobic peptides (e.g., RVVIEPSPVVV and IIIQPSPVVV), PPII amphipathic peptides (e.g., PPPVVVTFP and FIQPPPVVV), and Cys-rich peptides (e.g., LCAPTPCGPTPL and CLPCRPCGPTPL). Additionally, analysis of the secondary and tertiary structure and amino acid composition illustrated that KEP1 exhibited rich hydrophobic residues and disulfide bonds, which probably contributed to its cell-penetrating ability, as opposed to its small particle size and electrostatic interactions. This study reveals the cell-penetrating ability of KEPs, thus highlighting their potential as biomaterials for noncovalently delivering biomolecules.

Sustainable release artifact in PLGA microspheres for prolonged local aesthetics in postoperative pain management.

The challenge of effectively managing long-term pain after surgery remains a significant issue in clinical settings. Although local anesthetics are preferred for their effective pain relief and few side effects, their short-lasting effect does not fully meet the pain relief needs after surgery. Articaine, widely used for postoperative pain relief as a local anesthetic, is pharmacologically limited by its short half-life, which reduces the duration of its pain-relieving effects. To overcome this issue, this study presents a new approach using poly (lactic-co-glycolic acid) (PLGA) microspheres for controlled articaine release, aiming to extend its analgesic effect while reducing potential toxicity. The PLGA microspheres were shown to extend the release of articaine for at least 72h in lab tests, displaying excellent biocompatibility and low toxicity. When used in a rodent model for postoperative pain, the microspheres provided significantly prolonged pain relief, effectively reducing pain for up to 3days post-surgery, without causing inflammation or tissue damage for over 72h after being administered. The extended release and high safety profile of these PLGA microspheres highlight their promise as a new method for delivering local anesthetics, opening up new possibilities for pain management in the future.

The Effect of Nerolidol on Renal Dysfunction following Bilateral Ureteral Obstruction

Background/Objectives: Obstructive uropathy is a common cause of renal impairment. Recently, there has been a burgeoning interest in exploring natural products as potential alternative remedies for many conditions due to their low toxicity, affordability and wide availability. Methods: We investigated the effect of nerolidol in a rat model of bilateral ureteral obstruction (BUO) injury. Nerolidol, dissolved in a vehicle, was administered orally as a single daily dose of 200 mg/kg to Wistar rats. Sham group (n = 12) underwent sham surgery, whereas the BUO (n = 12) and BUO/NR groups (n = 12) underwent reversible 24-h BUO and received the vehicle or nerolidol, respectively. The treatment started 9 days prior to the BUO/sham surgery and continued for 3 days after reversal. Renal functions were assessed before starting the treatment, just prior to the intervention and 3 days after BUO reversal. Results: Neither nerolidol nor the vehicle affected the basal renal functions. Nerolidol resulted in a significant attenuation in the BUO-induced alterations in renal functional parameters such as serum creatinine and urea, creatinine clearance and urinary albumin-creatinine ratio. Nerolidol also attenuated the changes in several markers associated with renal injury, inflammation, apoptosis and oxidative stress and mitigated the histological alterations. Conclusions: The findings of this study demonstrated the potent reno-protective effects of nerolidol in mitigating the adverse renal effects of bilateral ureteral obstruction. This is attributed to its anti-inflammatory, anti-fibrotic, anti-apoptotic and anti-oxidant properties. These effects were reflected in the partial recovery of renal functions and histological features. These findings may have potential therapeutic implications.

Role of bridging RT in relapsed/refractory diffuse large B-cell lymphoma undergoing CAR-T therapy: a multicenter study.

The optimization of bridging regimen before chimeric antigen receptor (CAR)-T cell therapy in diffuse large B-cell lymphoma (DLBCL) may impact CAR-T efficacy and outcome. This retrospective study evaluates CAR-T outcome after bridging with radiotherapy (RT) and other bridging strategies. Among 148 patients with relapsed/refractory DLBCL who underwent leukapheresis for CAR-T manufacturing, 31 received RT-bridging, 84 chemotherapy (CT), 33 no-bridging or steroid-only. CAR-T cell were infused in 96.8% of RT-group, 89.2% of CT-group and 78.8% of no-bridge-group (p = 0.079). Response to bridging was generally poor, but patients receiving RT had a significant reduction in LDH levels between pre- and post-bridging (p = 0.05). The one-year PFS was 51.2% in the RT-group, 28.2% in the CT-group, and 47.6% in the no-bridge-group (p = 0.044, CT-bridging vs RT-bridging); 1-year OS was 86.7% in the RT-group, 52.7% in the CT-group and 69% in the no-bridge-group (p = 0.025, CT-bridging vs RT-bridging). We observed a higher incidence of ICANS in patients who received CT than in others (20.0% CT-group, 3.3% RT-group, 7.7% no-bridge group; p = 0.05). In conclusion, RT-bridging is associated with lower drop-out rate and CAR-T toxicity, and it might be preferred to other bridging strategies for patients with localized disease or for those with one prevalent symptomatic site.

Piperazine‐derived bisphosphonate‐based ionizable lipid nanoparticles enhance mRNA delivery to the bone microenvironment

Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field. We report bone‐targeting ionizable lipids featuring a robust piperazine backbone, which forms strong interactions with hydroxyapatite ([Ca5(PO4)3OH]), a key component of mineralized tissues. These lipids, conjugated with derivatives of bisphosphates, demonstrate biocompatibility and low toxicity in vitro and in vivo. Our findings demonstrate the role of a piperazine backbone of a novel ionizable lipid that presents a bisphosphonate group to facilitate bone delivery. This research illustrates the rational design of ionizable lipids for next‐generation bone‐targeting delivery systems.

Piperazine-derived bisphosphonate-based ionizable lipid nanoparticles enhance mRNA delivery to the bone microenvironment.

Nucleic acid delivery with mRNA lipid nanoparticles are being developed for targeting a wide array of tissues and cell types. However, targeted delivery to the bone microenvironment remains a significant challenge in the field. We report bone-targeting ionizable lipids featuring a robust piperazine backbone, which forms strong interactions with hydroxyapatite ([Ca5(PO4)3OH]), a key component of mineralized tissues. These lipids, conjugated with derivatives of bisphosphates, demonstrate biocompatibility and low toxicity in vitro and in vivo. Our findings demonstrate the role of a piperazine backbone of a novel ionizable lipid that presents a bisphosphonate group to facilitate bone delivery. This research illustrates the rational design of ionizable lipids for next-generation bone-targeting delivery systems.