ABSTRACT
Helicobacter pylori (H. pylori) is a causative agent of various gastrointestinal diseases and eradication mainly relies on antibiotic treatment, with (AMX) being a key component. However, rising antibiotic resistance in H. pylori necessitates the use of antibiotics combination therapy, often disrupting gut microbiota equilibrium leading to further health complications. This study investigates a novel strategy utilizing AMX-loaded chitosan nanoparticles (AMX-CS NPs), co-administered with prebiotic inulin to counteract H. pylori infection while preserving microbiota health. Following microbroth dilution method, AMX displayed efficacy against H. pylori, with a MIC50 of 48.34 ± 3.3 ng/mL, albeit with a detrimental impact on Lactobacillus casei (L. casei). The co-administration of inulin (500 µg/mL) with AMX restored L. casei viability while retaining the lethal effect on H. pylori. Encapsulation of AMX in CS-NPs via ionic gelation method, resulted in particles of 157.8 ± 3.85 nm in size and an entrapment efficiency (EE) of 86.44 ± 2.19 %. Moreover, AMX-CS NPs showed a sustained drug release pattern over 72 h with no detectable toxicity on human dermal fibroblasts cell lines. Encapsulation of AMX into CS NPs also reduced its MIC50 against H. pylori, while its co-administration with inulin maintained L. casei viability. Interestingly, treatment with AMX-CS NPs also reduced the expression of the efflux pump gene hefA in H. pylori. This dual treatment strategy offers a promising approach for more selective antimicrobial treatment, minimizing disruption to healthy microbial communities while effectively addressing pathogenic threats.
Subject(s)
Chitosan , Gastrointestinal Microbiome , Helicobacter Infections , Helicobacter pylori , Nanoparticles , Humans , Amoxicillin/pharmacology , Chitosan/pharmacology , Inulin/pharmacology , Anti-Bacterial Agents/pharmacology , Helicobacter Infections/drug therapy , Drug Resistance, MicrobialABSTRACT
Functionalized metal oxide nanoparticles (NPs) have demonstrated specific binding affinity to antigens or receptors presented on the cancer cell surface, favouring selective targeting and minimizing side effects during the chemotherapy. Placenta-specific protein 1 (PLAC-1) is a small cell surface protein overexpressed in certain types of breast cancer (BC); therefore, it can be used as a therapeutic target. The objective of this study is to develop NPs that can bind PLAC-1 and hence can inhibit the progression and metastatic potential of BC cells. Zinc oxide (ZnO) NPs were coated with a peptide (GILGFVFTL), which possesses a strong binding ability to PLAC-1. The physical attachment of the peptide to ZnO NPs was verified through various physicochemical and morphological characterization techniques. The selective cytotoxicity of the designed NPs was investigated using PLAC-1-bearing MDA-MB 231 human BC cell line and compared to LS-180 cells that do not express PLAC-1. The anti-metastatic and pro-apoptotic effects of the functionalized NPs on MDA-MB 231 cells were examined. Confocal microscopy was used to investigate the mechanism of NPs uptake by MDA-MB 231 cells. Compared to non-functionalized NPs, peptide functionalization significantly improved the targeting and uptake of the designed NPs by PLAC-1-expressing cancer cells with significant pro-apoptotic and anti-metastatic effects. The uptake of peptide functionalized ZnO NPs (ZnO-P NPs) occurred via peptide-PLAC1 interaction-assisted clathrin-mediated endocytosis. These findings highlight the potential targeted therapy of ZnO-P NPs against PLAC-1-expressing breast cancer cells.
Subject(s)
Breast Neoplasms , Metal Nanoparticles , Nanoparticles , Pregnancy Proteins , Zinc Oxide , Humans , Female , Zinc Oxide/pharmacology , Zinc Oxide/chemistry , Cell Line, Tumor , Breast Neoplasms/drug therapy , Nanoparticles/chemistry , Metal Nanoparticles/chemistry , Peptides/pharmacologyABSTRACT
Microfluidics technology has emerged as a promising methodology for the fabrication of a wide variety of advanced drug delivery systems. Owing to its ability for accurate handling and processing of small quantities of fluidics as well as immense control over physicochemical properties of fabricated micro and nanoparticles (NPs), microfluidic technology has significantly improved the pharmacokinetics and pharmacodynamics of drugs. This emerging technology has offered numerous advantages over the conventional drug delivery methods for fabricating of a variety of micro and nanocarriers for poorly soluble drugs. In addition, a microfluidic system can be designed for targeted drug delivery aiming to increase the local bioavailability of drugs. This review spots the light on the recent advances made in the area of microfluidics including various methods of fabrication of drug carriers, their characterization, and unique features. Furthermore, applications of microfluidic technology for the robust fabrication and development of drug delivery systems, the existing challenges associated with conventional fabrication methodologies as well as the proposed solutions offered by microfluidic technology have been discussed in details.HighlightsMicrofluidic technology has revolutionized fabrication of tunable micro and nanocarriers.Microfluidic platforms offer several advantages over the conventional fabrication methods.Microfluidic devices hold great promise in controlling the physicochemical features of fabricated drug carriers.Micro and nanocarriers with controllable release kinetics and site-targeting efficiency can be fabricated.Drug carriers fabricated by microfluidic technology exhibited improved pharmacokinetic and pharmacodynamic profiles.
Subject(s)
Microfluidics , Nanoparticles , Microfluidics/methods , Drug Delivery Systems , Drug CarriersABSTRACT
Colorectal cancer (CRC) accounts for approximately 10% of all new cancer cases worldwide with significant morbidity and mortality. The current imaging techniques are lacking diagnostic precision while traditional chemotherapeutic strategies are limited by their adverse side effects and poor response in advanced stages. Targeted nanoparticles (NPs) can specifically bind to surface antigens on cancer cells and provide effective delivery of diagnostic and chemotherapeutic agent. Placenta-specific protein 1 (PLAC-1) is overexpressed in CRC and can be used as a target for detection and treatment of the disease. The aim of this work was to develop a targeted nanotheranostic agent for early diagnosis and inhibition of the malignant progression and metastasis of CRC. Graphene oxide quantum dots (QD) were covalently labeled with a peptide (GILGFVFTL) having high affinity to PLAC-1. The covalent coupling between the QD and the peptide was confirmed using a series of physicochemical and morphological characterization techniques. Confocal microscopy was used to evaluate the uptake of QD and QD-P in HCT-29, HT-116 and LS-180 CRC cell lines. Selective targeting of antigen PLAC-1 overexpressed on HT-29 and HCT-116 cells was measured by immunofluorescence. Cell proliferation, cell invasion and extent of PLAC-1 expression in CRC cells after treatment with QD and QD-P were determined. The prepared QD-P showed a significant increase in targeting and specific uptake in cells expressing the antigen PLAC-1 compared to non-functionalized QD. Treatment with QD-P also increased the cell cytotoxicity, reduced the invasiveness of HT-29 and HCT-116 cells by 38% and 62%, respectively, and downregulated the expression of PLAC-1 by 53% and 33%, respectively. These results highlight the potential use of QD-P as a theranostic agent for the detection and treatment of CRC cells expressing the antigen PLAC-1.
Subject(s)
Antineoplastic Agents , Colorectal Neoplasms , Quantum Dots , Humans , Quantum Dots/chemistry , Precision Medicine , Peptides/chemistry , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/drug therapyABSTRACT
Prompt epinephrine (Epi) injection using auto-injectors is the initial life-saving out-of-hospital treatment for anaphylaxis. However, patients and healthcare providers are eagerly awaiting a more convenient alternative dosage form that would overcome auto-injectors drawbacks. Previously, we extensively evaluated multiple alternative fast-disintegrating sublingual Epi tablet (FDSTs) formulations. However, the sublingual stability of Epi and effect of modifying the sublingual microenvironment pH on its stability and transport pathways were not yet fully investigated. Results depicted that Epi remained sufficiently stable at various pHs in human saliva and porcine sublingual tissue's extract. Epi permeability (EP) through excised porcine sublingual membrane was greatest at pH 8.0 (p < 0.05), 11-fold higher than the negative control (Epi at pH 6.8). Sodium carbonate (Na Carb) 0.75% was the most efficient buffer to modify Epi solution pH to 8.0. Both sodium dodecyl sulfate (SDS) 0.075% and palmitoyl-DL-carnitine chloride (PCC) 1.2% increased paracellular EP 10-fold and 3-fold, respectively; however, both demonstrated a delayed enhancement (>5 min). Meanwhile, Na Carb and SDS combination increased EP 23-fold without a delay. It is evident that pH-modifiers or their SDS combination showed promising potential to enhance Epi sublingual permeability and further reduce the required Epi dose using FDSTs as a feasible alternative to Epi auto-injectors.
Subject(s)
Anaphylaxis , Administration, Sublingual , Anaphylaxis/drug therapy , Animals , Epinephrine , Humans , Permeability , Swine , Tablets/therapeutic useABSTRACT
Driving nanomaterials to specific cell populations is still a major challenge for different biomedical applications. Several strategies to improve cell binding and uptake have been tried thus far by intrinsic material modifications or decoration with active molecules onto their surface. In the present work, we covalently bound the chemokine CXCL5 on fluorescently labeled amino-functionalized SiO2 nanoparticles to precisely targeting CXCR2+ immune cells. We synthesized and precisely characterized the physicochemical features of the modified particles. The presence of CXCL5 on the surface was detected by z-potential variation and CXCL5-specific electron microscopy immunogold labeling. CXCL5-amino SiO2 nanoparticle cell binding and internalization performances were analyzed in CXCR2+ THP-1 cells by flow cytometry and confocal microscopy. We showed improved internalization of the chemokine modified particles in the absence or the presence of serum. This internalization was reduced by cell pre-treatment with free CXCL5. Furthermore, we demonstrated CXCR2+ cell preferential targeting by comparing particle uptake in THP-1 vs. low-CXCR2 expressing HeLa cells. Our results provide the proof of principle that chemokine decorated nanomaterials enhance uptake and allow precise cell subset localization. The possibility to aim at selective chemokine receptor-expressing cells can be beneficial for the diverse pathological conditions involving immune reactions.
Subject(s)
Chemokine CXCL5/chemistry , Nanoparticles/chemistry , Receptors, Interleukin-8B/chemistry , Chemokine CXCL5/metabolism , Endocytosis/immunology , Endocytosis/physiology , HeLa Cells , Humans , Receptors, Interleukin-8B/metabolism , Silicon Dioxide/chemistry , Substrate Specificity/immunology , THP-1 CellsABSTRACT
Nanomaterials are now well-established components of many sectors of science and technology. Their sizes, structures, and chemical properties allow for the exploration of a vast range of potential applications and novel approaches in basic research. Biomedical applications, such as drug or gene delivery, often require the release of nanoparticles into the bloodstream, which is populated by blood cells and a plethora of small peptides, proteins, sugars, lipids, and complexes of all these molecules. Generally, in biological fluids, a nanoparticle's surface is covered by different biomolecules, which regulate the interactions of nanoparticles with tissues and, eventually, their fate. The adsorption of molecules onto the nanomaterial is described as "corona" formation. Every blood particulate component can contribute to the creation of the corona, although small proteins represent the majority of the adsorbed chemical moieties. The precise rules of surface-protein adsorption remain unknown, although the surface charge and topography of the nanoparticle seem to discriminate the different coronas. We will describe examples of adsorption of specific biomolecules onto nanoparticles as one of the methods for natural surface functionalization, and highlight advantages and limitations. Our critical review of these topics may help to design appropriate nanomaterials for specific drug delivery.
ABSTRACT
The development of new strategies for enhancing drug delivery to the brain represents a major challenge in treating cerebral diseases. In this paper, we report on the synthesis and structural characterization of a biocompatible nanoparticle (NP) made up of poly(lactic-co-glycolic acid) (PLGA)-polyethylene glycol (PEG) co-polymer (namely PELGA) functionalized with the membranotropic peptide gH625 (gH) and the iron-mimicking peptide CRTIGPSVC (CRT) for transport across the blood-brain barrier (BBB). gH possesses a high translocation potency of the cell membrane. Conversely, CRT selectively recognizes the brain endothelium, which interacts with transferrin (Tf) and its receptor (TfR) through a non-canonical ligand-directed mechanism. We hypothesize that the delivery across the BBB of PELGA NPs should be efficiently enhanced by the NP functionalization with both gH and CRT. Synthesis of peptides and their conjugation to the PLGA as well as NP physical-chemical characterization are performed. Moreover, NP uptake, co-localization, adhesion under dynamic conditions, and permeation across in vitro BBB model are evaluated as a function of gH/CRT functionalization ratio. Results establish that the cooperative effect of CRT and gH may change the intra-cellular distribution of NPs and strengthen NP delivery across the BBB at the functionalization ratio 33% gHâ»66% CRT.
Subject(s)
Cerebellum/cytology , Drug Carriers/chemistry , Endothelium/chemistry , Nanoparticles/chemistry , Peptides/chemistry , Polymers/chemical synthesis , Animals , Biocompatible Materials/chemistry , Blood-Brain Barrier/chemistry , Blood-Brain Barrier/metabolism , Cell Membrane/chemistry , Cell Membrane/metabolism , Cells, Cultured , Cerebellum/chemistry , Cerebellum/metabolism , Drug Design , Endothelium/cytology , Endothelium/metabolism , Lactates/chemistry , Mice , Peptides/metabolism , Polyethylene Glycols/chemistry , Polyglycolic Acid/chemistry , Polymers/chemistry , Receptors, Transferrin/metabolism , Transferrin/metabolismABSTRACT
The innate immune system consists of several complex cellular and molecular mechanisms. During inflammatory responses, blood-circulating monocytes are driven to the sites of inflammation, where they differentiate into tissue macrophages. The research of novel nanomaterials applied to biomedical sciences is often limited by their toxicity or dangerous interactions with the immune cell functions. Platinum nanoparticles (PtNPs) have shown efficient antioxidant properties within several cells, but information on their potential harmful role in the monocyte-to-macrophage differentiation process is still unknown. Here, we studied the morphology and the release of cytokines in PMA-differentiated THP-1 pre-treated with 5 nm PtNPs. Although NP endocytosis was evident, we did not find differences in the cellular structure or in the release of inflammatory cytokines and chemokines compared to cells differentiated in PtNP-free medium. However, the administration of PtNPs to previously differentiated THP-1 induced massive phagocytosis of the PtNPs and a slight metabolism decrease at higher doses. Further investigation using undifferentiated and differentiated neutrophil-like HL60 confirmed the harmlessness of PtNPs with non-adherent innate immune cells. Our results demonstrate that citrate-coated PtNPs are not toxic with these immune cell lines, and do not affect the PMA-stimulated THP-1 macrophage differentiation process in vitro.
ABSTRACT
5-FU is a chemotherapy drug commonly used for the treatment of human cancers; however drug resistance represents a major challenge for its clinical application. In the present study, we reporte that rpL3 induced by 5-FU treatment in Calu-6 cells represses CBS transcription and reduces CBS protein stability leading to a decrease of CBS protein levels. rpL3 also regulates negatively the activation of NFκB by preventing NFκB nuclear translocation through IκB-α up-regulation. Furthermore, we demonstrate that rpL3 significantly enhances the apoptosis of 5-FU treated Calu-6 cells promoting the overexpression of the pro-apoptotic proteins Bax and the inhibition of the anti-apoptotic protein Bcl-2. We finally demonstrate that rpL3 potentiates 5-FU efficacy inhibiting cell migration and invasion. Our results suggest that combination of rpL3 and 5-FU is a promising strategy for chemotherapy of lung cancers lacking functional p53 that are resistant to 5-FU.