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.

Cyclodextrin and its derivatives as effective excipients for amorphous ulipristal acetate systems.

Many efforts have been devoted to screening new solid-state forms of poorly soluble drugs in the pharmaceutical industry, thus modulating the drug properties without changing the pharmacological nature. It is a wise strategy to prepare amorphous series with cyclodextrin (CD) and its derivatives as excipients to enhance the aqueous solubility, dissolution, and bioavailability of water-insoluble drugs. In this study, four binary amorphous mixtures of ulipristal acetate (UPA) with CDs (ß-CD, γ-CD, dimethyl-ß-CD, hydroxypropyl-ß-CD) were prepared by the co-milling method and characterized in the solid-state. According to powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC), UPA existed in the noncrystalline form in the four binary amorphous mixtures. Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance (NMR) indicated that UPA interacted with the four CDs, which was also verified by molecular docking. Compared with the crystalline and amorphous UPA, the solubility, dissolution, and stability of the drug in the four amorphous UPA systems were significantly improved, so they were considered potentially advantageous solid forms. Our research shows that CDs can be used as new effective excipients in amorphous systems for active pharmaceutical ingredients (API).

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.

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.

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.

Co-pyrolysis of spent radioactive ion exchange resin and manganese dioxide: Decrease the decomposition temperatures of functional groups.

With the development of the nuclear industry and clean energy, spent radioactive ion exchange resin has become a major concern that needs to be solved urgently. In this study, the mixed resin (sulfonic aid and quaternary ammonium polystyrene beads, 1:2, v/v) is co-pyrolyzed with manganese dioxide in a tube furnace, selecting argon as the reaction atmosphere. Manganese dioxide exhibits unique catalytic and oxidative activity, and a low mass remaining efficiency of 34.14% is obtained under low heating temperature of 300 â„ƒ. The required decomposition temperatures of functional groups and benzene are decreased by approximately 100 â„ƒ, and that of polymer chain is decreased by 130 â„ƒ. The TGA analysis shows the decomposition temperature rule of functional groups and base polymer. The FT-IR spectra and XPS analysis reveal the bridging effects of manganese sulfonate and sulfide group. The SEM diagrams prove that the two processes including depolymerization and reunion could be found in co-pyrolysis. The XRD analysis indicates manganese dioxide undergoes the reduction path of MnO2→Mn3O4→MnO, and MnS is formed with the decomposition of manganese sulfonate. The possible mechanism of solid-phase reaction is proposed to explain the promotion of manganese dioxide on co-pyrolysis.

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.

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.

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.

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.

Chitosan/Sulfobutylether-ß-Cyclodextrin Nanoparticles for Ibrutinib Delivery: A Potential Nanoformulation of Novel Kinase Inhibitor.

In this study, a novel Bruton's tyrosine kinase inhibitor, ibrutinib, was loaded into chitosan/sulfobutylether-ß-cyclodextrin nanoparticles (NPs). NPs have gained high loading efficiency for the hydrophobic drug due to the inclusion of cyclodextrin. Ibrutinib-loaded NPs with an average diameter of 277.9 nm and ζ-potential of +19.1 mV were obtained after regulating several influencing factors. Electrostatic reaction between mucin and NPs indicated that the NPs had a mucoadhesive property. Kinase catalytic phosphorylation was monitored by capillary zone electrophoresis and found that chitosan/sulfobutylether-ß-cyclodextrin NPs did not weaken ibrutinib activity on the target kinase. In vitro drug release studies revealed that ibrutinib-loaded NPs exhibited a significantly slower gastric-release rate. This study applied a feasible nanocarrier for ibrutinib delivery, and the potential nanoformulation maintains drug activity and shows a sustained release property. These outcomes are helpful for the formulation exploitation of tyrosine kinase inhibitors.

Solid dispersions of telaprevir with improved solubility prepared by co-milling: formulation, physicochemical characterization, and cytotoxicity evaluation.

Telaprevir (TVR) is typically a poorly soluble drug with an extremely low bioavailability of 1.7%. Polymorph modifications cannot improve the solubility of TVR because it only has a single unsolvated crystalline form. Co-crystals also provide limited bioavailability enhancement for TVR. Thus, in this study, we increased the solubility and dissolution rate of TVR through formulations of TVR-polymer solid dispersions. Three solid dispersions of TVR were successfully prepared by co-milling with polyvinylpyrrolidone K30 (PVP), polyethylene glycol 6000, and hydroxypropyl methylcellulose (HPMC), which were characterized by different techniques. According to X-ray powder diffraction and differential scanning calorimetry results, TVR presented in amorphous form in all solid dispersions. The fourier transform infrared spectra results indicated that TVR may connect with polymers through the N-H···O or O-H···O hydrogen bonds, which were verified by molecular docking. TVR-PVP and TVR-HPMC displayed a good stability at conventional RH levels, and their thermostabilities were better than those of milled TVR. Among the three solid dispersions, TVR-HPMC showed significant solubility and dissolution rate advantages in different media. Moreover, TVR-HPMC displayed the same anticancer efficacy with crystalline TVR and presented no toxic side effects to normal liver cells. Thus, TVR-HPMC showed potential application value.

Protein corona of metal-organic framework nanoparticals: Study on the adsorption behavior of protein and cell interaction.

Nanoscale metal-organic frameworks (NMOFs) have attracted considerable attention for controlled drug delivery. However, the interaction between nanoparticles and the biological macromolecules of physiological system must be valued because the formed protein corona will endow NMOFs with new biorecognition properties. In this study, we carried out detailed protein adsorption studies in vitro and cell uptake tests of HeLa cells for nanospherical Uio66 and nanooctahedral Uio67. Uio67 with higher binding constants to human serum albumin needed to combine more protein molecules to achieve colloidal stability state than that needed by Uio66, and this phenomenon led Uio67 to aggregate under the same incubation condition due to the formation of a single-layer protein. Uio67 also induced an evident conformation change in protein to stabilize the combination. In particular, the cell uptake efficiencies of the two systems showed a significant thickness dependence on the protein corona. When samples incubated in 10% fetal bovine serum (FBS), the intracellular rate was the highest for both systems, but the rate was not proportional to the FBS concentration. Results of this work are important to the development of the considerable potential NMOFs-based medicals and also provide additional insight into protein corona.

Co-amorphous palbociclib-organic acid systems with increased dissolution rate, enhanced physical stability and equivalent biosafety.

The preparation of co-amorphous drug systems by adding a small molecular excipient is a promising formulation in the modern pharmaceutical industry to improve the solubility, dissolution rate, and bioavailability of poorly soluble drugs. In this study, palbociclib co-amorphous systems with organic acids (succinic, tartaric, citric, and malic acid) at molar ratios of 1 : 1 were prepared by co-milling and characterized by differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR) and solid-state nuclear magnetic resonance (SS-NMR). These solid-state investigations have confirmed the formation of co-amorphous salts between PAL and organic acids. The solubility, dissolution rate and stability of the four co-amorphous drug systems were significantly improved compared with these of crystalline and amorphous palbociclib. The biosafety of the co-amorphous drug systems was the same as that of palbociclib without affecting the efficacy of the drug and eliciting toxic side effects. These comprehensive approaches for the palbociclib-acid co-amorphous drug systems provided a theoretical basis for its clinical applications.

Investigation on the Interaction of Dabrafenib with Human Serum Albumin Using Combined Experiment and Molecular Dynamics Simulation: Exploring the Binding Mechanism, Esterase-like Activity, and Antioxidant Activity.

Dabrafenib is a novel targeted antimelanoma drug. The present work explored the binding mechanism of dabrafenib-human serum albumin (HSA) and the effect on the esterase-like activity and antioxidant activity of HSA by using 19F NMR, spectroscopy methods, and molecular dynamics simulation. The results of 19F NMR, fluorescence, and time-resolved fluorescence spectroscopy revealed that dabrafenib spontaneously binds to the subdomain IIIA of the HSA by hydrophobic action and forms a static complex. The binding affects the esterase-like activity of HSA but not its antioxidant activity. According to the results of molecular dynamics simulation, dabrafenib interacts with Arg410 and Tyr411, which are the key residue associated with the esterase-like activity of HSA. Meanwhile, dabrafenib does not interact with Cys34, the key residue associated with the antioxidant activity of HSA. The results of circular dichroism spectroscopy and molecular dynamics simulation show that the conformation of HSA is not affected by the binding of dabrafenib. This study can provide useful information for understanding the pharmacokinetic properties of dabrafenib.

Study of the interaction of broad-spectrum antimicrobial drug sitafloxacin with human serum albumin using spectroscopic methods, molecular docking, and molecular dynamics simulation.

Sitafloxacin (STFX) is a new generation of broad-spectrum oral fluoroquinolones. STFX has significantly enhanced antibacterial activity than most similar drugs. Clinically, this drug is mainly used to treat respiratory and urinary tract infections and other serious bacterial infections. In this study, the interaction between sitafloxacin and human serum albumin (HSA) was investigated by spectroscopic methods and molecular simulations. Fluorescence quenching experiments showed that the interaction mechanism between STFX and HSA was static quenching, which was confirmed by time-resolved fluorescence. Thermodynamic parameters and docking results indicated that hydrophobic and electrostatic forces played a key role in this mechanism. Probe experiments and molecular docking results indicated that the major binding of STFX was at site I. 3D fluorescence showed that the insertion of STFX had minimal impact on the microenvironment. Analysis of the protein secondary structure showed that the insertion of STFX had little effect on the secondary structure of the protein. Hydrophobicity experiments showed the slight decrease in the overall hydrophobicity index of the system. Molecular dynamics simulations further validated the stability of the HSA-STFX complex. This study are useful for further drug development, in vivo toxicity studies, and can provide guidance for the clinical application of STFX to study its pharmacokinetic properties.

Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent.

ABSTRACT The PI3K/mTOR pathway is one of the most frequently aberrantly activated pathways in human malignancies, such as renal cell carcinoma (RCC), and contributes to resistance to antitumor therapies. Thus, PI3K/mTOR is an attractive target for the development of antitumor agents. In this study, we evaluated the preclinical effects of a novel inhibitor SN202. We examined Akt/mTOR activities in renal cancer cells after SN202 treatment. The preclinical effects of SN202 on tumor growth were evaluated in renal cancer cells in vitro and in murine xenografts in vivo. SN202 inhibits PI3Kα, PI3Kγ, and mTOR, the corresponding IC50 values were 3.2, 3.3, and 1.2 nM, respectively. In A498, 786-0, and ACHN renal cancer cell lines, SN202 inhibits cell proliferation in a dose-dependent manner and significantly inhibits 786-0 cell growth. Western blot analysis revealed that SN202 decreases the phosphorylation of PI3K downstream signaling molecules, Akt and S6K, in 786-0 renal cancer cells. Furthermore, oral administration of SN202 results in significant inhibition in human renal carcinoma xenografts in nude mice and favourable pharmacokinetic properties in rats. These results suggest that SN202 might be a promising therapeutic agent against RCC as a dual PI3K/mTOR inhibitor.

Quantitative Monitoring the Anti-Solvent Crystallization and Storage Process for Nandrolone by Near-Infrared Spectroscopy.

A novel hydrate (SH2O) of nandrolone was prepared by anti-solvent methods. The crystallization processes with 2 schemes (A and B) were monitored by in-line near-infrared (NIR) spectroscopy. The amounts of SH2O in powder samples obtained by the anti-solvent crystallization and storage process were quantified by NIR combined with chemometrics methods. In-line NIR spectra from 4500 to 8000 cm-1 were chosen to capture physicochemical changes during the whole crystallization process. The combination of the principal component results with offline characterization (scanning electron microscopy, powder X-ray diffraction, NIR) data showed that both schemes yielded high purity SH2O products, but the crystallization speed of scheme B was significantly accelerated. It was demonstrated that in-line NIR spectroscopy combined with principal component analysis can be very useful to monitor in real time and control the anti-solvent crystallization process. Moreover, the solubility and the solid-state transformation of nandrolone under different storage conditions were investigated. The apparent solubility of SH2O was 2.19-2.44 times of Form I, and SH2O was relatively stable when stored at a high relative humidity and temperature below 25°C.

Combined spectroscopy methods and molecular simulations for the binding properties of trametinib to human serum albumin.

Trametinib is a novel anticancer drug for treating metastatic cutaneous melanoma. The present study probed into the binding of trametinib to human serum albumin (HSA) through spectroscopy methods and molecular simulations. Trametinib could quench the fluorescence of HSA through static quenching which could be probed via fluorescence spectroscopy and time-resolved fluorescence. Thermodynamic parameters and docking results indicated that hydrogen bonds and van der Waals forces play crucial roles in this binding process, which exerts almost no effect on the HSA conformation under synchronous fluorescence, three-dimensional fluorescence, circular dichroism spectra, and molecular dynamics simulations. Site marker displacement experiments and molecular docking reveal that trametinib primarily binds to Sudlow site I of HSA. In addition, the trametinib-HSA interaction was hardly influenced by varying amino acid (glutamine, alanine, glycine, and valine) concentrations. This study can provide useful information for the pharmacokinetic properties of trametinib.