Continuous Production of Stable Polymeric Nanoparticles for Oral Drug Delivery

Minimal bioavailability of hydrophobic compounds limits their biomedical and biological applications. In this thesis, we have developed a continuous and scalable process to generate stable polymeric nanoparticles encapsulating hydrophobic drugs (such as beta-carotene, SR13668, and curcumin), based upon our understanding of the competitive kinetics of flash nanoprecipitation and spray drying. A custom-designed multi-inlet vortex mixer (MIVM) was employed to implement the process of flash nanoprecipitation (FNP). Flow patterns in the MIVM were microscopically visualized by mixing iron nitrate and potassium thiocyanate to precipitate Fe(SCN)x(3-x)+. Effects of physical parameters (including Reynolds number, supersaturation rate, interaction force, and drug loading rate) on size distribution of the nanoparticle suspensions were investigated. The prepared nanoparticle suspensions through FNP were then spray dried to (1) achieve particle long-term stability, (2) quickly remove organic solvents used for nanoprecipitation, and (3) be able to conveniently adjust the nanoparticle concentration prior to use. Excipients such as sucrose, trehalose and leucine were used as "spacers" to prevent permanent aggregation during the spray drying process. The optimized condition was achieved by thoughtful consideration of the glass transition temperatures of the polymers and transport processes of evaporation and particle diffusion. The nanoparticles were then re-suspended prior to animal tests. Bioavailability and bioactivity of the nanoparticles were verified in animals for two compounds when orally dosed – SR13668 (a cancer preventive agent) and curcumin (a potential agent to attenuate morphine tolerance and dependence). Enhanced bioavailability of PLGA-SR13668 nanoformulation was observed in mice and beagle dogs, compared with formulations of Labrasol® and neat drug in 0.5% methylcellulose. Mice behavioral studies, include tail-flick, hot plate, and precipitate withdrawal experiments, were conducted to demonstrate the effects of curcumin nanoformulation on attenuating morphine tolerance and dependence. Significant analgesia was observed in both tail-flick and hot plate experiments, while free curcumin at same concentration showed minimal effect

The results of Pearson correlation analysis.

BackgroundSubjective well-being has a significant impact on an individual’s physical and mental health. Socioeconomic status, class identity, and social activity participation play important roles in subjective well-being. Therefore, the aim of this study was to uncover the mechanisms through which these factors influence subjective well-being.MethodsA total of 1926 valid samples were recruited using the Chinese General Social Survey 2021 (CGSS 2021). The Chinese Citizen’s Subjective Well-Being Scale (SWBS-CC) was employed to assess subjective well-being. Socioeconomic status was measured using income and education, and class identity and social activity participation were measured using Likert scales. Pearson correlation analysis and the chain mediation model were conducted to explore the relationship between these factors. Finally, the Bootstrap method was used to examine the path coefficients.ResultsA significant correlation was found between socioeconomic status, class identity, social activity, and subjective well-being (p ConclusionsThe study showed that socioeconomic status, class identity, and social activity had significant effects on subjective well-being. Class identity and social activity partially mediated the effects of socioeconomic status on subjective well-being, and they had a chain mediating effect between socioeconomic status and subjective well-being. Therefore, policymakers have the opportunity to enhance subjective well-being in lower socioeconomic status groups by promoting individual class identity and encouraging greater social activity participation.</div

Multiple stepwise regression results.

BackgroundSubjective well-being has a significant impact on an individual’s physical and mental health. Socioeconomic status, class identity, and social activity participation play important roles in subjective well-being. Therefore, the aim of this study was to uncover the mechanisms through which these factors influence subjective well-being.MethodsA total of 1926 valid samples were recruited using the Chinese General Social Survey 2021 (CGSS 2021). The Chinese Citizen’s Subjective Well-Being Scale (SWBS-CC) was employed to assess subjective well-being. Socioeconomic status was measured using income and education, and class identity and social activity participation were measured using Likert scales. Pearson correlation analysis and the chain mediation model were conducted to explore the relationship between these factors. Finally, the Bootstrap method was used to examine the path coefficients.ResultsA significant correlation was found between socioeconomic status, class identity, social activity, and subjective well-being (p ConclusionsThe study showed that socioeconomic status, class identity, and social activity had significant effects on subjective well-being. Class identity and social activity partially mediated the effects of socioeconomic status on subjective well-being, and they had a chain mediating effect between socioeconomic status and subjective well-being. Therefore, policymakers have the opportunity to enhance subjective well-being in lower socioeconomic status groups by promoting individual class identity and encouraging greater social activity participation.</div

Self-assembling process of flash nanoprecipitation in a multi-inlet vortex mixer to produce drug-loaded polymeric nanoparticles

We present an experimental study of self-assembled polymeric nanoparticles in the process of flash nanoprecipitation using a multi-inlet vortex mixer (MIVM). beta-Carotene and polyethyleneimine (PEI) are used as a model drug and a macromolecule, respectively, and encapsulated in diblock copolymers. Flow patterns in the MIVM are microscopically visualized by mixing iron nitrate (Fe(NO(3))(3)) and potassium thiocyanate (KSCN) to precipitate Fe(SCN) (x) ((3-x)+) . Effects of physical parameters, including Reynolds number, supersaturation rate, interaction force, and drug-loading rate, on size distribution of the nanoparticle suspensions are investigated. It is critical for the nanoprecipitation process to have a short mixing time, so that the solvent replacement starts homogeneously in the reactor. The properties of the nanoparticles depend on the competitive kinetics of polymer aggregation and organic solute nucleation and growth. We report the existence of a threshold Reynolds number over which nanoparticle sizes become independent of mixing. A similar value of the threshold Reynolds number is confirmed by independent measurements of particle size, flow-pattern visualization, and our previous numerical simulation along with experimental study of competitive reactions in the MIVM

Bootstrap test results for multiple intermediary models.

Bootstrap test results for multiple intermediary models.</p

The conceptual model based on previous research and theory.

The conceptual model based on previous research and theory.</p

Single-Molecule Kinetics Reveals a Hidden Surface Reaction Intermediate in Single-Nanoparticle Catalysis

Detecting and characterizing reaction intermediates is not only important and powerful for elucidating reaction mechanisms but also challenging in general because of the low populations of intermediates in a reaction mixture. Studying surface reaction intermediates in heterogeneous catalysis presents additional challenges, especially the ubiquitous structural heterogeneity among the catalyst particles and the accompanying polydispersion in reaction kinetics. Here we use single-molecule fluorescence microscopy to study two complementary types of Au nanocatalystsmesoporous-silica-coated Au nanorods (i.e., Au@mSiO₂ nanorods) and bare 5.3 nm pseudospherical Au nanoparticlesat the single-particle, single-turnover resolution in catalyzing the oxidative deacetylation of amplex red by H₂O₂, a synthetically relevant and increasingly important probe reaction. For both nanocatalysts, the distributions of the microscopic reaction time from a single catalyst particle clearly reveal a kinetic intermediate, which is hidden when the data are averaged over many particles or only the time-averaged turnover rates are examined for a single particle. This intermediate is further resolvable by single-turnover kinetics at the subparticle level. Detailed single-molecule kinetic analysis leads to a quantitative reaction mechanism and supports that the intermediate is likely a surface-adsorbed one-electron-oxidized amplex red radical. The quantitation of kinetic parameters further allows for the evaluation of the large reactivity inhomogeneity among the individual nanorods and pseudospherical nanoparticles, and for Au@mSiO₂ nanorods, it uncovers their size-dependent reactivity in catalyzing the first one-electron oxidation of amplex red to the radical. Such single-particle, single-molecule kinetic studies are expected to be broadly useful for dissecting reaction kinetics and mechanisms

Introduction

Introductio

Electric Field-Controlled Ion Transport In TiO₂ Nanochannel

On the basis of biological ion channels, we constructed TiO₂ membranes with rigid channels of 2.3 nm to mimic biomembranes with flexible channels; an external electric field was employed to regulate ion transport in the confined channels at a high ionic strength in the absence of electrical double layer overlap. Results show that transport rates for both Na⁺ and Mg²⁺ were decreased irrespective of the direction of the electric field. Furthermore, a voltage-gated selective ion channel was formed, the Mg²⁺ channel closed at −2 V, and a reversed relative electric field gradient was at the same order of the concentration gradient, whereas the Na⁺ with smaller Stokes radius and lower valence was less sensitive to the electric field and thus preferentially occupied and passed the channel. Thus, when an external electric field is applied, membranes with larger nanochannels have promising applications in selective separation of mixture salts at a high concentration

Table1_Modification of m5C regulators in sarcoma can guide different immune infiltrations as well as immunotherapy.xls

BackgroundRecent studies have found that 5-methylcytosine (m5C) modulators are associated with the prognosis and treatment of cancer. However, the relevance of m5C modulators in sarcoma prognosis and the tumour microenvironment is unclear.MethodsWe selected 15 m5C regulators and performed unsupervised clustering to identify m5C modification patterns and differentially expressed genes associated with the m5C phenotype in The Cancer Genome Atlas (TCGA) sarcomas. The extent of immune cell infiltration in different clustering groups was explored using single-sample gene set enrichment analysis and estimation algorithms. A principal component analysis algorithm-based m5C scoring protocol was performed to assess the m5C modification patterns of individual tumors.ResultsWe identified two distinct m5C modification patterns in the TCGA sarcoma cohort, which possess different clinical outcomes and biological processes. Tumour microenvironment analysis revealed two groups of immune infiltration patterns highly consistent with m5C modification patterns, classified as immune inflammatory and immune desert types. We constructed m5C scores and found that high m5C scores were closely associated with leiomyosarcoma and other subtypes, and were associated with poorer prognosis, lower PD-L1 expression, and poorer immunotherapy outcomes. The best application was validated against the m5C database.ConclusionWe constructed an m5C score for sarcoma based on the TCGA database and identified a poorer prognosis in the high m5c score group. The stability and good prognostic predictive power of the m5C score was verified by an external database. We found that sarcomas in the low m5C score group may have a better response to immunotherapy.</p