Photoresponsive Azobenzene Nanocluster-Modified Liposomes: Mechanism Analysis Combining Experiments and Simulations.

Stimuli-responsive behaviors and controlled release in liposomes are pivotal in nanomedicine. To this end, we present an approach using a photoresponsive azobenzene nanocluster (AzDmpNC), prepared from azobenzene compounds through melting and aggregation. When integrated with liposomes, they form photoresponsive vesicles. The morphology and association with liposomes were investigated by using transmission electron microscopy. Liposomes loaded with calcein exhibited a 9.58% increased release after UV exposure. To gain insights into the underlying processes and elucidate the mechanisms involved. The molecular dynamic simulations based on the reactive force field and all-atom force field were employed to analyze the aggregation of isomers into nanoclusters and their impacts on phospholipid membranes, respectively. The results indicate that the nanoclusters primarily aggregate through π-π and T-stacking forces. The force density inside the cis-isomer of AzDmpNC formed after photoisomerization is lower, leading to its easier dispersion, rapid diffusion, and penetration into the membrane, disrupting the densification.

Contribution of nicotinamide as an intracyclic N dopant to the structure and properties of carbon dots synthesized using threeα-hydroxy acids as C sources.

Fixed carbon source and different dopants are mainly used to study the effect of heteroatoms on the structure and properties of carbon dots (CDs). As reactants, some dopants with conjugated structure and high nitrogen content may have important contributions to the structure and properties of doped CDs in addition to providing heteroatoms. Herein, to study the effect of fixed dopant on the structure and properties of CDs, three different CDs were synthesized using nicotinamide (NAA) and three commonα-hydroxy acids (4-5 carbon atoms), and the optimal conditions were determined by orthogonal experimentation. Transmission electron microscopic micrographs showed that the average size of CDs based on nicotinamide are relatively large, up to 19.40 nm. X-ray photoelectron spectroscopy and Fourier-transform infrared spectroscopy demonstrated that these CDs have graphite nitrogen and several functional group structures. Ultraviolet-visible absorption spectra, fluorescence emission spectra, and fluorescence lifetime illustrated that these CDs have similar emission centers (460-470 nm) and fluorescence processes. The influence of carbon source on the surface structure of CDs was determined by systematically analyzing the response of these CDs in different pH ranges. DFT calculations revealed the distribution characteristics of the electrons in the excited state at the HOMO and LUMO energy levels of CDs. All the above characterizations and calculations proved that NAA is a desirable dopant with an important contribution to the structure and properties of CDs.

Interleukin-1ß Plays a Pivotal Role via the PI3K/Akt/mTOR Signaling Pathway in the Chronicity of Mesial Temporal Lobe Epilepsy.

OBJECTIVE: Mesial temporal lobe epilepsy (MTLE) is the most common type of refractory epilepsy. It is often associated with hippocampal sclerosis, which is histopathologically characterized by selective neuron loss, mossy fiber sprouting, and synapse reconstruction, and is the primary cause of refractory epilepsy. Its mechanism has not been fully elucidated. Substantial evidence now supports that inflammatory pathways are activated in epilepsy foci. We have confirmed that the interleukin-1ß (IL-1ß) level is involved in the epileptogenesis of MTLE, and we further investigated how it works in its chronicity in this study. METHODS: The MTLE model was induced by pilocarpine, and Western blot and co-immunoprecipitation were used to detect proteins related to the PI3K/Akt/mammalian target of rapamycin (mTOR) signaling pathway in the hippocampi of MTLE rats and MTLE children. Meanwhile, primary hippocampal neurons were cultured and transfected by lentivirus, and the same methods were used to test the related protein expression; fluorescent dye FM4-64 was used to measure synaptic vesicle endocytosis (SVE) of neurons. RESULTS: We revealed that mTOR is continuously activated in the rat MTLE model and children with MTLE, and it correlated with the IL-1ß level. We further proved that IL-1ß activates neurons via the PI3K/Akt/mTOR signaling pathway, accompanied by the upregulation of MAP2 and the enhancement of SVE in hippocampal neurons. CONCLUSION: Our findings suggest that IL-1ß can activate mTOR, followed by activated neurons, which is critical in the pathogenesis of MTLE chronicity. These findings contribute to the understanding of the pathogenesis of MTLE, and targeting inflammation modulators in MTLE may provide new pathways for therapy of refractory epilepsy.

Changes in microglial inflammation-related and brain-enriched MicroRNAs expressions in response to in vitro oxygen-glucose deprivation.

Microglia plays important role in central nervous system immune surveillance and has emerged as an essential cellular component for understanding brain diseases. MicroRNAs (miRs) are small, noncoding RNAs that regulate the post-transcriptional expression of protein-coding mRNAs, which may have key roles in microglial activation in response to brain ischemia and other stressors. Primary cultured rat microglial cells were prepared, and then microglial activation model was established by oxygen-glucose deprivation (OGD) method. Morphological observation, CD11b/c immunofluorence, MTT assay and Propidium iodide staining were done to test microglia viability at different OGD time points (0, 5, 10, 15, 30, 60 min). qPCR were performed to detect the dynamic changes in expressions of inflammation-related miRs (146a, 21, 181a, 221, and 222) and brain-enriched miRs (124, 134, 9, 132, and 138) in resting microglia and after challenge with OGD for the same time points. The activation and viability of the microglia was time dependent. Similarly, expressions of different miRs in microglia were significantly upregulated and reached the peak at different time points before reaching the baseline level with extension of OGD. Our data demonstrates for the first time that OGD as a model of an ischemic insult modulates the expressions of some inflammation-related and brain-enriched miRs. These changes may help to explore the molecular basis of microglia activation on the post-transcriptional level in response to different time points of OGD.

Effects of MRP8, LPS, and lenalidomide on the expressions of TNF-α , brain-enriched, and inflammation-related microRNAs in the primary astrocyte culture.

Astrocytes are now recognized as a heterogeneous class of cells with many important and diverse functions in healthy and diseased central nervous system (CNS). MicroRNAs (miRNAs) are small, noncoding RNAs which may have key roles in astrocytes activation in response to various stimuli. We performed quantitative real-time PCR (qPCR) to detect changes in the expressions of brain-enriched miRNAs (124, 134, 9, 132, and 138), inflammation-related miRNAs (146a, 21, 181a, 221, and 222), and tumor necrosis factor alpha (TNF- α ) in the rat primary astrocyte cultures after stimulation with myeloid-related protein 8 (MRP8) and lipopolysaccharides (LPS). Further, we inhibited the expression of TNF- α in the astrocytes by using TNF- α inhibitor (lenalidomide) and tested for the first time the effect of this inhibition on the expressions of the same tested miRNAs. Stimulation of the astrocytes with MRP8 or LPS leads to significant upregulation of miRNAs (124, 134, 9, 132, 146a, 21, 181a, 221, and 222), while miRNA-138 was downregulated. TNF- α inhibition with lenalidomide leads to opposite expressions of the tested miRNAs. These miRNAs may play an important role in activation of the astrocytes and may be a novel target for cell-specific therapeutic interventions in multiple CNS diseases.

Unveiling the binding details and esterase-like activity effect of methyl yellow on human serum albumin: spectroscopic and simulation study.

The food sector uses methyl yellow (MY) extensively as a colorant. The primary transporter in vivo that influences MY absorption, metabolism, distribution, and excretion is human serum albumin (HSA). Exploring the binding process and looking at how HSA and MY work physiologically at the molecular level is therefore very important. Experiments using steady-state fluorescence and fluorescence lifetimes proved that HSA and MY's quenching mechanisms were static. The HSA-MY complex's binding constant was estimated using thermodynamic parameters to be around 104 M-1. The hydrophobic forces were a major factor in the binding process, as evidenced by the negative ΔG, positive ΔH, and ΔS, which suggested that this contact was spontaneous. Site tests showed that MY linked to HSA's site I. Circular dichroism and three-dimensional fluorescence analysis revealed that the 1.33% α-helix content dropped and the amino acid microenvironment altered. While HSA's protein surface hydrophobicity decreased when engaging MY, the binding of MY to HSA reduced in the presence of urea. The stability of the system was assessed using molecular modeling. Additionally, HSA's esterase-like activity decreased when MY was present, and Ibf/Phz affected the inhibition mechanism of MY on HSA. These findings offer a distinctive perspective for comprehending the structure and functioning of HSA and evaluating the safety of MY.

MOFs-alginate/polyacrylic acid/poly (ethylene imine) heparin-mimicking beads as a novel hemoadsorbent for bilirubin removal in vitro and vivo models.

Metal-organic frameworks (MOFs) have a potential application in blood purification, but their microcrystalline nature has hampered their industrial application. Here, novel MOFs-polymer beads based on UiO, sodium alginate, polyacrylic acid, and poly (ethylene imine) were prepared and applied as a whole blood hemoadsorbent for the first time. The amidation among polymers immobilized UiO66-NH2 into the network of the optimal product (SAP-3), and the NH2 of UiO66-NH2 significantly increased the removal rate (70 % within 5 min) of SAP-3 on bilirubin. The adsorption of SAP-3 on bilirubin mainly obeyed the pseudo-second-order kinetic, Langmuir isotherm and Thomas models with a maximum adsorption capacity (qm) of 63.97 mg·g-1. Experimental and density functional theory simulation results show that bilirubin was mainly adsorbed by UiO66-NH2via electrostatic force, hydrogen bonding, and π-π interactions. Notably, the adsorption in vivo show that the total bilirubin removal rate in the whole blood of the rabbit model was up to 42 % after 1 h of adsorption. Given its excellent stability, cytotoxicity, and hemocompatibility, SAP-3 has a great potential in hemoperfusion therapy. This study proposes an effective strategy for settling the powder property of MOFs and could provide experimental and theoretical references for application of MOFs in blood purification.

Interleukin-1ß and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy.

PURPOSE: Increasing evidence indicates that neuroinflammation plays a critical role in the pathogenesis of mesial temporal lobe epilepsy (MTLE). The aim of this study was to investigate the dynamic expression of interleukin (IL)-1ß as a proinflammatory cytokine and microRNA (miR)-146a as a posttranscriptional inflammation-associated microRNA (miRNA) in the hippocampi of an immature rat model and children with MTLE. METHODS: To study the expression of IL-1ß and miR-146a, we performed a reverse transcription polymerase chain reaction, Western blot, and real-time quantitative PCR on the hippocampi of immature rats at 11 days of age. Expression was monitored in the acute, latent, and chronic stages of disease (2 h and 3 and 8 weeks after induction of lithium-pilocarpine status epilepticus, respectively), and in control hippocampal tissues corresponding to the same timeframes. Similar expression methods were applied to hippocampi obtained from children with MTLE and normal controls. KEY FINDINGS: The expression of IL-1ß and miR-146a in both children and immature rats with MTLE differs according to the stage of MTLE development. Both IL-1ß and miR-146a are significantly up-regulated, but in opposite ways: IL-1ß expression is highest in the acute stage, when expression of miR-146a is at its lowest level; miR-146a expression is highest in the latent stage, when IL-1ß expression is at its lowest level. Both IL-1ß and miR-146a are up-regulated in the chronic stage, but not as much as in the other stages. SIGNIFICANCE: Our study is the first to focus on the expression of miR-146a in the immature rat model of lithium-pilocarpine MTLE and in children with MTLE. We have detected that the expression of proinflammatory cytokine IL-1ß and posttranscriptional inflammation-associated miR-146a is variable depending on the disease stage. Furthermore, both IL-1ß and miR-146a are up-regulated in immature rats and children with MTLE. Our findings elucidate the role of inflammation in the pathogenesis of MTLE in the immature rat model and children. Therefore, modulation of the IL-1ß-miR-146a axis may be a novel therapeutic target in the treatment of MTLE.

Effects of microsize on the biocompatibility of UiO67 from protein-adsorption behavior, hemocompatibility, and histological toxicity.

The biocompatibility of metal-organic frameworks (MOFs) is necessary to humans but is far from being sufficiently addressed. This study focused on the effects of microsize on the biocompatibility of MOFs by selecting UiO67 with micron and submicron size as the MOFs models. Under the dose metric of surface area, the binding constant between UiO67 and human serum albumin (HSA) gradually increased with increased UiO67 size. Submicron UiO67 induced stronger conformational transformation and more greatly affected the protein surface hydrophobicity than micron UiO67. Micron UiO67 also inhibited the esterase-like activity of HSA through competitive inhibition mechanism, whereas submicron UiO67 inhibited it through noncompetitive inhibition mechanism. The size of UiO67 had little effect on hemocompatibility. A smaller size of UiO67, corresponded with a higher IC50 value for 293 T and LO2 cells, and the adsorption of HSA can effectively improve cytotoxicity. In vivo toxicity evaluations revealed that all UiO67 did not cause obvious distortion of organs, and they were metabolized primarily in the kidney. These results provided useful information about the toxicity of MOFs and experimental references for the development of MOFs-based engineering materials.

Study on the interaction between 2,6-dihydroxybenzoic acid nicotine salt and human serum albumin by multi-spectroscopy and molecular dynamics simulation.

As a new form of nicotine introduction for novel tobacco products, the interaction of nicotine salt with biological macromolecules may differ from that of free nicotine and thus affect its transport and distribution in vivo. Hence, the mechanism underlying the interaction between 2,6-dihydroxybenzoic acid nicotine salt (DBN) and human serum albumin (HSA) was investigated by multi-spectroscopy, molecular docking, and dynamic simulation. Experiments on steady-state fluorescence and fluorescence lifetime revealed that the quenching mechanism of DBN and HSA was dynamic quenching, and binding constant was in the order of 10^4 L mol-1. Thermodynamic parameters exhibited that the binding was a spontaneous process with hydrophobic forces as the main driving force. Fluorescence competition experiments revealed that DBN bound to site I of HSA IIA subdomain. According to the results of synchronous fluorescence, 3D fluorescence, FT-IR spectroscopy, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulation, DBN did not affect the basic skeleton structure of HSA but changed the microenvironment around the amino acid residues. Computer simulations positively corroborated the experimental results. Moreover, DBN decreased the surface hydrophobicity and weakened the esterase-like activity of HSA, leading to the impaired function of the latter. This work provides important information for studying the interaction between DBN as a nicotine substitute and biological macromolecules and contributes to the further development and application of DBN.

Hierarchical core-shell nanoplatforms constructed from Fe3O4@C and metal-organic frameworks with excellent bilirubin removal performance.

Hemoperfusion has become the third-generation treatment strategy for patients suffering from hyperbilirubinemia, but adsorbents used for bilirubin removal mostly face intractable problems, such as unsatisfactory adsorption performance and poor hemocompatibility. Metal-organic frameworks (MOFs) are promising adsorbents for hemoperfusion due to their high specific surface areas and easily modified organic ligands. However, their microporous properties and separation have hampered their application. Here, a novel hierarchical core-shell nanoplatform (named Double-PEG) with tailored binding sites and pore sizes based on Fe3O4@C and Uio66-NH2 was constructed. Notably, Double-PEG showed excellent bilirubin uptake of up to 1738.30 mg g-1 and maintained excellent bilirubin removal efficiency in simulated biological solutions. A study on the adsorption mechanism showed that the adsorption of Double-PEG towards bilirubin tended to be chemical adsorption and in accordance with the Langmuir model. Besides, the good separability, recyclability, cytotoxicity and hemocompatibility of Double-PEG show great potential in hemoperfusion therapy. The finding of this study may provide a novel insight into the application of MOF materials in the field of hemoperfusion.

Molecular recognition patterns between vitamin B12 and human serum albumin explored through STD-NMR and spectroscopic methods.

Ligand-receptor molecular recognitionis the basis of biological process. The Saturation Transfer Difference-NMR (STD-NMR) technique has been recently used to gain qualitative and quantitative information about physiological interactions at atomic-resolution. The molecular recognition patterns between Vitamin B12 (VB12) and human serum albumin (HSA) were investigated by STD-NMR supplemented by other spectroscopies and molecular docking. STD-NMR delivered a complete picture that the substituent groups on the tetrapyrrole ring of VB12 interacted with site III of HSA through binding epitope mapping and competitive probe experiments. STD-NMR and fluorescence results proved the moderate binding capability of VB12 and clarified a static, spontaneous, and temperature-sensitive binding mechanism. 3D-fluorencence, FT-IR and circular dichroism spectra showed a compact protein structure by interacting with VB12. Size distribution and surface hydrophobicity showed the surface properties changes of HSA caused by the binding of VB12. Computer simulation confirmed the recognition mode in theory and was compared with experiments. This work is beneficial for understanding the safety and biological action of VB12, and will attract researchers interested in NMR technology.

Lentinan as a natural stabilizer with bioactivities for preparation of drug-drug nanosuspensions.

Lentinan is a natural ß-glucan with various bioactivities and is combined with chemotherapy drugs for cancer treatment. Regorafenib is an oral multi-kinase inhibitor approved by FDA for treatment of metastatic colorectal cancer, advanced hepatocellular carcinoma, and metastatic gastrointestinal stromal tumors. Regorafenib has poor water solubility and multiple toxicities. We report drug-drug nanosuspensions of regorafenib and lentinan. Results of dynamic light scattering and scanning electron microscopy showed that the mean particle size of the regorafenib-lentinan nanosuspensions was approximately 200 nm and was uniformly distributed. Transmission electron microscopy findings indicated that lentinan stabilized the nanosuspensions by steric manner. Hydrogen bonds and hydrophobic interactions were found between regorafenib and lentinan by molecular dynamics simulation. The results of cytotoxicity assay and pharmacokinetics study in rats showed that the regorafenib-lentinan nanosuspensions reduced the toxicity and enhanced the in vitro anticancer activity and oral bioavailability of regorafenib. Lentinan as a natural stabilizer has the potential using for drug nanosuspensions. Drug-drug nanosuspensions are a new form of combination therapies that can reduce the number of drugs taken by patients and improve their compliance.

A pH-sensitive T7 peptide-decorated liposome system for HER2 inhibitor extracellular delivery: an application for the efficient suppression of HER2+ breast cancer.

HER2+ breast cancer is highly aggressive and proliferative even after multiple chemotherapy regimens. At present, the available clinical treatment duration of chemotherapeutic agents is limited by severe toxicity to noncancerous tissues, which are attributed to insufficient targeting. Here, we designed an active-targeted and pH-responsive liposome to improve the treatment. The ideas were as follows: (1) using liposome as a nano-delivery system for HER2 inhibitor (lapatinib; LAP) to reduce the toxicity; (2) modifying the capsule with T7 peptide for specific targeted delivery to the tumor cells, and (3) enabling the capsule with the pH-sensitive ability and triggering sustained drug release at extracellular weakly acidic microenvironment to emerge toxicity in tumors and to improve curative effects. It was found that T7 peptide-modified pH-sensitive liposome (T7-LP) was more effective and safer than free drug and unmodified liposome, and reduced drug-induced side effects and noncancerous toxicity. These results support the application potential of T7-LP in improving the efficacy of LAP in HER2+ breast cancer treatment. It might be a novel LAP formulation as a clinical agent.

How hydrophilic group affects drug-protein binding modes: Differences in interaction between sirtuins inhibitors Tenovin-1/Tenovin-6 and human serum albumin.

Introduction of hydrophilic groups can improve the solubility of leading drugs but inevitably affect their interaction with proteins. This study selected sirtuin inhibitors Tenovin-1 (T1) and Tenovin-6 (T6) as drug models to determine differences in binding mode to human serum albumin (HSA). T1 and T6 quenched the endogenous fluorescence of HSA via static quenching mechanism. Introduction of hydrophilic groups greatly reduced the binding constant, i.e., from 1.302 × 104 L mol-1 for the HSA-T6 system to 0.128 × 104 L mol-1 for the HSA-T1 system. HSA-T1 system was mainly driven by electrostatic interactions while that of HSA-T6 system was hydrophobic interaction and both systems were spontaneous reactions. Site marker experiments and molecular docking indicated that both systems mainly bound to the hydrophobic site I of HSA. Molecular dynamics (MD) simulation analysis further revealed that Tyr148, Tyr150 and Arg257 residues played a key role in this recognition process for both systems. In particular, T6 maintained additional several hydrogen bonds with the surrounding residues. T1 had almost no effect on the esterase-like activity of HSA, but T6 inhibited the hydrolysis of p-NPA. Furthermore, differential scanning calorimetry (VP-DSC), circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy confirmed that HSA in the T6 system undergone a more significant conformational transition than that in the T1 system.

Self-assembled phospholipid-based mixed micelles for improving the solubility, bioavailability and anticancer activity of lenvatinib.

The clinical efficacy of lenvatinib (LFT) is limited by its poor aqueous solubility and low bioavailability. In this work, LFT-loaded soy phospholipid and sodium glycocholate mixed micelles (LFT-MMs) were prepared through classical co-precipitation. And it was served as an oral administration to address these shortcomings. The preparation conditions were optimized by single-factor experiments. The mass ratio of PC, SGC and LFT, and the species of dispersing media were proved to be decisive factors in controlling the properties of LFT-MMs. The optimal LFT-MMs presented prominent enhancement (500-fold) in LFT solubility, high encapsulation efficiency (87.6 %) as well as suitable stability (>1 month at 4 °C). The biocompatibility of LFT-MMs was estimated by in vitro serum stability measurement and hemolysis test. It showed that serum proteins hardly adhered to the surface of LFT-MMs, and insignificant hemolytic rate (<0.5 %) was observed at the micelles concentration below 1 mg/mL. Cytotoxicity test (MTT assay) was carried out to judge the in vitro antitumor activity. LFT-MMs showed an enhanced inhibitory activity against two main kinds of differentiated thyroid cancer cells over LFT and LFT Mesylate. To estimate the in vivo oral bioavailability of LFT-MMs, SD rats were used as animal model. Notably, the relative bioavailability of LFT-MMs compared with the original form of LFT was 176.7 %. These superior characteristics indicated that the mixed micelles are promising water-soluble formulations suitable for LFT oral delivery.

Characterizing the interaction between methyl ferulate and human serum albumin by saturation transfer difference NMR.

Methyl ferulate (MF) is an alkyl ferulate ester that widely exists in edible plants and has application value in the food and medicine industries. Thus, its effect on biological macromolecules should be considered. In this study, we exploit saturation transfer difference NMR (STD-NMR) to characterize the interaction of all protons of MF with human serum albumin (HSA) at the molecular level. STD-NMR and K a (1.298 × 103 M-1) revealed that protons H1-6 and H8 bound to HSA with a medium affinity. Binding epitope mapping further showed that the aromatic ring played a key role in the HSA-MF interaction. STD-NMR site-marker-displacement experiments and circular dichroism spectroscopy revealed that MF prefered to bind to site II of HSA without changing the basic skeleton of HSA. Computer simulations confirmed these experimental results. Overall, this work elucidates the molecular level interaction of MF with HSA and provides new insights into the possibility of the potential applications of MF in the food and medicine industries.

Preparation of a carboxymethyl ß-cyclodextrin polymer and its rapid adsorption performance for basic fuchsin.

The presence of dyes in a water system has potential adverse effects on the ecological environment. The conventional cyclodextrin (CD) polymer only has CD cavities as adsorption sites and exhibits slow adsorption for dye removal. In this study, we designed a novel carboxymethyl ß-CD polymer (ß-CDP-COOH). The structural properties of ß-CDP-COOH were characterized as an irregular cross-linked polymer with negative surface charge, and the introduction of carboxymethyl groups greatly enhanced the adsorption ability of the ß-CD polymer to basic fuchsin (BF). The maximum removal efficiency of ß-CDP-COOH (96%) could be achieved within 1 min, whereas that of conventional ß-CD polymer (70%) was achieved after 50 min. The adsorption mechanism revealed that the adsorption behavior of ß-CDP-COOH could be effectively fitted with the pseudo-second-order kinetic model and Langmuir isotherm. Both CD cavities and carboxymethyl groups were effective adsorption sites, so ß-CDP-COOH had an advantage in adsorption capacity over the conventional ß-CD polymer. This study indicated that ß-CDP-COOH is a potential highly efficient adsorbent for the removal of cationic dye contaminants.

Binding properties of sodium glucose co-transporter-2 inhibitor empagliflozin to human serum albumin: spectroscopic methods and computer simulations.

Empagliflozin is an oral sodium glucose co-transporter-2 inhibitor for type 2 diabetes mellitus. The interaction between empagliflozin and human serum albumin (HSA) was investigated experimentally and theoretically. Fluorescence quenching and time-resolved fluorescence spectroscopy indicated that the quenching mechanism of empagliflozin and HSA was dynamic and that the effective binding constant at body temperature was 3.495 × 103 M-1. Thermodynamic parameters showed that hydrophobic forces were the major binding force in the interaction between empagliflozin and HSA. Circular dichroism, Fourier transform infrared, and 3 D fluorescence spectroscopy revealed that empagliflozin showed a slight change in secondary structure without changing the basic carbon framework of HSA. Site marker displacement experiments revealed that empagliflozin bound to site I of HSA, which was supported by molecular docking. Molecular dynamic simulations indicated that empagliflozin could bind to HSA stably. This study provided insights into the binding mechanism between empagliflozin and HSA.Communicated by Ramaswamy H. Sarma.

Microcrystalline cellulose as an effective crystal growth inhibitor for the ternary Ibrutinib formulation.

The objective of present study is to explore whether polysaccharide could be a crystal growth inhibitor in poorly soluble antitumor drug Ibrutinib (IBR) formulation. In this work, small molecular ligands (amino or organic acids) in co-amorphous system (CAS) were preliminarily screened. A polysaccharide, microcrystalline cellulose (MCC) was selected to stabilize amorphous drug and enhance pharmacokinetic properties. Fourier-transform infrared, Raman, and X-ray photoelectron spectroscopy confirmed the ionic interaction of the ternary IBR formulation. Moreover, the biosafety of the ternary formulation was the same as that of IBR while the in vitro performance advantage of the ternary formulation was converted into higher bioavailability in vivo experiments. Overall, MCC as an effective crystal growth inhibitor in the novel ternary IBR formulation is a promising approach to improve the dissolution rate of crystalline drugs and the stability of amorphous drugs, as well as providing a theoretical basis for clinical applications.