Surface functionalization affects the retention and bio-distribution of orally administered mesoporous silica nanoparticles in a colitis mouse model
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ABSTRACT:
SUBMITTER: Schmid R
PROVIDER: S-EPMC10656483 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Biological drugs are increasingly important for patients and industry due to their application in the treatment of common and potentially life-threatening diseases such as diabetes, cancer, and obesity. While most marketed biopharmaceuticals today are injectables, the potential of mucoadhesive delivery systems based on dendron-coated mesoporous silica nanoparticles for oral delivery of biological drugs is explored in this project. We hypothesize that specifically designed dendrons can be employed as mucoadhesive excipients and used to decorate the surface of nanoparticles with properties to embed a drug molecule. We initially tested a novel synthesis method for the preparation of dendrons, which was successfully validated by the chemical characterization of the compounds. The interaction between dendrons and mucin was studied through isothermal titration calorimetry and quartz crystal microbalance with dissipation monitoring and proved to be spontaneous and thermodynamically favorable. Dendrons were conjugated onto 244.4 nm mesoporous silica nanoparticles and characterized for chemical composition, size, and surface charge, which all showed a successful conjugation. Finally, dynamic light scattering was used to study the interaction between nanoparticles and porcine gastric mucin, whereas the interaction between nanoparticles and porcine intestinal mucus was characterized by rheological measurements. This study shows a deeper biophysical understanding of the interaction between nanoparticles and mucin or native porcine intestinal mucus, further leveraging the current understanding of how dendrons can be used as excipients to interact with mucin. This will provide knowledge for the potential development of a new generation of mucoadhesive nanoformulations for the oral delivery of biopharmaceuticals.
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Project description:The arsenic (+3 oxidation state) methyltransferase (As3mt) gene encodes a 43 kDa protein that catalyzes methylation of inorganic arsenic. Altered expression of AS3MT in cultured human cells controls arsenic methylation phenotypes, suggesting a critical role in arsenic metabolism. Because methylated arsenicals mediate some toxic or carcinogenic effects linked to inorganic arsenic exposure, studies of the fate and effects of arsenicals in mice which cannot methylate arsenic could be instructive. This study compared retention and distribution of arsenic in As3mt knockout mice and in wild-type C57BL/6 mice in which expression of the As3mt gene is normal. Male and female mice of either genotype received an oral dose of 0.5 mg of arsenic as arsenate per kg containing [(73)As]-arsenate. Mice were radioassayed for up to 96 h after dosing; tissues were collected at 2 and 24 h after dosing. At 2 and 24 h after dosing, livers of As3mt knockouts contained a greater proportion of inorganic and monomethylated arsenic than did livers of C57BL/6 mice. A similar predominance of inorganic and monomethylated arsenic was found in the urine of As3mt knockouts. At 24 h after dosing, As3mt knockouts retained significantly higher percentages of arsenic dose in liver, kidneys, urinary bladder, lungs, heart, and carcass than did C57BL/6 mice. Whole body clearance of [(73)As] in As3mt knockouts was substantially slower than in C57BL/6 mice. At 24 h after dosing, As3mt knockouts retained about 50% and C57BL/6 mice about 6% of the dose. After 96 h, As3mt knockouts retained about 20% and C57BL/6 mice retained less than 2% of the dose. These data confirm a central role for As3mt in the metabolism of inorganic arsenic and indicate that phenotypes for arsenic retention and distribution are markedly affected by the null genotype for arsenic methylation, indicating a close linkage between the metabolism and retention of arsenicals.
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Project description:Rationale: Oxidative stress, resulting from excessive reactive oxygen species (ROS), plays an important role in the initiation and progression of inflammatory bowel disease (IBD). Therefore, developing novel strategies to target the disease location and treat inflammation is urgently needed. Methods: Herein, we designed and developed a novel and effective antioxidant orally-administered nanoplatform based on simulated gastric fluid (SGF)-stabilized titanium carbide MXene nanosheets (Ti3C2 NSs) with excellent biosafety and multiple ROS-scavenging abilities for IBD therapy. Results: This broad-spectrum and efficient ROS scavenging performance was mainly relied on the strong reducibility of Ti-C bound. Intracellular ROS levels confirmed that Ti3C2 NSs could efficiently eliminate excess ROS against oxidative stress-induced cell damage. Following oral administration, negatively-charged Ti3C2 NSs specifically adsorbed onto the positively-charged inflamed colon tissue via electrostatic interaction, leading to efficient therapy of dextran sulfate sodium salt (DSS)-induced colitis. The therapeutic mechanism mainly attributed to decreased ROS levels and pro-inflammatory cytokine secretion, and increased M2-phenotype macrophage infiltration and anti-inflammatory cytokine secretion, efficiently inhibiting inflammation and alleviating colitis symptoms. Due to their excellent ROS-scavenging performance, Ti3C2-based woundplast also promoted skin wound healing and functional vessel formation. Conclusions: Our study introduces redox-mediated antioxidant MXene nanoplatform as a novel type of orally administered nanoagents for treating IBD and other inflammatory diseases of the digestive tract.
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Project description:Mesoporous silica nanoparticles (MSNs) are very promising nanomaterials for treating bacterial infections when combined with pharmaceutical drugs. Herein, we report the preparation of two nanomaterials based on the immobilization of ciprofloxacin in mesoporous silica nanoparticles, either as the counter-ion of the choline derivative cation (MSN-[Ch][Cip]) or via anchoring on the surface of amino-group modified MSNs via an amide bond (MSN-Cip). Both nanomaterials were characterized by TEM, FTIR and solution 1H NMR spectroscopies, elemental analysis, XRD and N2 adsorption at 77 K in order to provide the desired structures. No cytotoxicity from the prepared mesoporous nanoparticles on 3T3 murine fibroblasts was observed. The antimicrobial activity of the nanomaterials was determined against Gram-positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Klebsiella pneumoniae) bacteria and the results were promising against S. aureus. In the case of B. subtilis, both nanomaterials exhibited higher antimicrobial activity than the precursor [Ch][Cip], and in the case of K. pneumoniae they exhibited higher activity than neutral ciprofloxacin.
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Project description:Inflammatory bowel diseases, such as ulcerative colitis, cause significant morbidity and decreased quality of life. The currently available treatments are not effective in all patients, can be expensive and have potential to cause severe side effects. This prompts the need for new treatment modalities. Enoxaparin, a widely used antithrombotic agent, is reported to possess anti-inflammatory properties and therefore we evaluated its therapeutic potential in a mouse model of colitis. Acute colitis was induced in male C57BL/6 mice by administration of dextran sulfate sodium (DSS). Mice were treated once daily with enoxaparin via oral or intraperitoneal administration and monitored for colitis activities. On termination (day 8), colons were collected for macroscopic evaluation and cytokine measurement, and processed for histology and immunohistochemistry. Oral but not intraperitoneal administration of enoxaparin significantly ameliorated DSS-induced colitis. Oral enoxaparin-treated mice retained their body weight and displayed less diarrhea and fecal blood loss compared to the untreated colitis group. Colon weight in enoxaparin-treated mice was significantly lower, indicating reduced inflammation and edema. Histological examination of untreated colitis mice showed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and the presence of edema, while all aspects of this pathology were alleviated by oral enoxaparin. Reduced number of macrophages in the colon of oral enoxaparin-treated mice was accompanied by decreased levels of pro-inflammatory cytokines. Oral enoxaparin significantly reduces the inflammatory pathology associated with DSS-induced colitis in mice and could therefore represent a novel therapeutic option for the management of ulcerative colitis.
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Project description:BackgroundRecent clinical studies suggest that the prophylactic use of recombinant factor VIIa (rFVIIa) markedly reduces the number of bleeding episodes in hemophilic patients with inhibitors. Given the short biological half-life of rFVIIa, it is unclear how rFVIIa could be effective in prophylactic treatment.ObjectivesTo examine the extravascular distribution of pharmacologically administered rFVIIa to obtain clues on how rFVIIa could work in prophylaxis.MethodsRecombinant mouse FVIIa tagged with AF488 fluorophore (AF488-FVIIa) was administered into mice via the tail vein. At different time intervals following the administration, mice were exsanguinated and various tissues were collected. The tissue sections were processed for immunohistochemistry to evaluate distribution of rFVIIa.ResultsrFVIIa, immediately following the administration, associated with the endothelium lining of large blood vessels. Within 1 h, rFVIIa bound to endothelial cells was transferred to the perivascular tissue surrounding the blood vessels and thereafter diffused throughout the tissue. In the liver, rFVIIa was localized to sinusoidal capillaries and accumulated in hepatocytes. In bone, rFVIIa was accumulated in the zone of calcified cartilage and some of it was retained there for a week. The common finding of the present study is that rFVIIa in extravascular spaces was mostly localized to regions that contain TF expressing cells.ConclusionsThe present study demonstrates that pharmacologically administered rFVIIa readily associates with the vascular endothelium and subsequently enters into extravascular spaces where it is likely to bind to TF and is retained for extended time periods. This may explain the prolonged pharmacological effect of rFVIIa.
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Project description:Pharmacological therapies for cardiovascular diseases are limited by short-term pharmacokinetics and extra-cardiac adverse effects. Improving delivery selectivity specifically to the heart, wherein therapeutic drug levels can be maintained over time, is highly desirable. Nanoparticle (NP)-based pericardial drug delivery could provide a strategy to concentrate therapeutics within a unique, cardiac-restricted compartment to allow sustained drug penetration into the myocardium. Our objective was to explore the kinetics of myocardial penetration and retention after pericardial NP drug delivery. Fluorescently-tagged poly(lactic-co-glycolic acid) (PLGA) NPs were loaded with BODIPY, a fluorophore, and percutaneously administered into the pericardium via subxiphoid puncture in rabbits. At distinct timepoints hearts were examined for presence of NPs and BODIPY. PLGA NPs were found non-uniformly distributed on the epicardium following pericardial administration, displaying a half-life of ~2.5days in the heart. While NPs were mostly confined to epicardial layers, BODIPY was capable of penetrating into the myocardium, resulting in a transmural gradient. The distinct architecture and physiology of the different regions of the heart influenced BODIPY distribution, with fluorophore penetrating more readily into atria than ventricles. BODIPY proved to have a long-term presence within the heart, with a half-life of ~7days. Our findings demonstrate the potential of utilizing the pericardial space as a sustained drug-eluting reservoir through the application of nanoparticle-based drug delivery, opening several exciting avenues for selective and prolonged cardiac therapeutics.
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