Lysine-Polydopamine Nanocrystals Loaded with the Codrug Abemaciclib-Flurbiprofen for Oral Treatment of Cancer.

Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with chemotherapeutic agents for the treatment of colorectal cancer (CRC) are a promising therapeutic strategy. NSAIDs can effectively boost the antitumor efficacy of chemotherapeutic agents by inhibiting the synthesis of COX-2. However, hazardous side effects and barriers to oral drug absorption are the main challenges for combination therapy with chemotherapeutics and NSAIDs. To address these issues, a safe and effective lysine-polydopamine@abemaciclib-flurbiprofen (Flu) codrug nanocrystal (Lys-PDA@AF NCs) was designed. Abemaciclib (Abe), a novel and effective inhibitor of the CDK4/6 enzyme, and Flu were joined to prepare Abemaciclib-Flu codrug (AF) by amide bonds, and then the AF was made into nanocrystals. Lysine-modified polydopamine was selected as a shell to encapsulate nanocrystals to enhance intestinal adhesion and penetration and lengthen the duration time of drugs in vivo. Nuclear magnetic resonance, Fourier transform infrared, Massspectrometry, X-ray photoelectron spectroscopy, Transmission electron microscopy, and drug loading were used to evaluate the physicochemical characteristics of the nanocrystals. In our study, Abe and Flu were released to exert their synergistic effect when the amide bond of AF was broken and the amide bond was sensitive to cathepsin B which is overexpressed in most tumor tissues, thus increasing the selectivity of the drug to the tumor. The results showed that Lys-PDA@AF NCs had higher cytotoxicity for CRC cell with an IC50 of 4.86 µg/mL. Additionally, pharmacokinetics showed that Abe and Flu had similar absorption rates in the Lys-PDA@AF NCs group, improving the safety of combination therapy. Meanwhile, in vivo experiments showed that Lys-PDA@AF NCs had excellent antitumor effects and safety. Overall, it was anticipated that the created Lys-PDA@AF NCs would be a potential method for treating cancer.

Glycyrrhetinic acid modified chlorambucil prodrug for hepatocellular carcinoma treatment based on DNA replication and tumor microenvironment.

Chlorambucil (CLB) is widely used in the treatment of solid tumors. However, CLB has poor water solubility, short half-life and side effects such as leucopenia and thrombocytopenia, in addition to the inhibition of tumor immune microenvironment. In our study, chlorambucil-chitosan (CLB-CS) prodrug micelles were successfully prepared, and glycyrrhetinic acid (GA) was selected, which could improve the immunosuppressive microenvironment and actively targeted liver cancer cells. At the tumor site, CLB blocked the cell cycle and promoted apoptosis. In addition, GA improved the tumor microenvironment by increasing the proportion of CD4+T and CD8+T cells at the tumor site, and promoting the differentiation of CD4+T cells into Th1 cells, thereby reducing the proportion of Treg and Th2 cell subsets, so as to offset the adverse factors of CLB against tumor immunity. By interfering with DNA replication and modulating the tumor microenvironment, GA/CLB-CS micelles enabled the effective treatment of liver cancer.

Phase-change mesoporous Prussian blue nanoparticles for loading paclitaxel and chemo-photothermal therapy of cancer.

Complete treatment of cancer remains a major challenge today. Herein, a biocompatible drug delivery system named as PCM + PTX@mPBs/PEG was constructed. In this system, Paclitaxel (PTX) was blended with phase-change material (PCM) and loaded in mesoporous Prussian blue nanoparticles (mPBs), and chelated with polyethylene glycol at surface. The blank PCM@mPBs/PEG had uniform particle size distribution, large pore size to load drug, excellent photothermal efficiency and good biocompatibility. After loading PTX, PCM + PTX@mPBs/PEG was demonstrated with a high loading capacity and the drug presented temperature-responsive release characteristics. In addition, PTX can be released under the exposure of an NIR laser. In vitro cell experiments showed that nanoparticles can be exposed to near-infrared irradiation to increase uptake in cells, which enhanced anticancer activity. After tail vein injection of PCM + PTX@mPBs/PEG suspension in tumor-bearing mice, PCM + PTX@mPBs/PEG can accumulate at the tumor site through passive transport. The tumor was effectively suppressed by phototherapy and chemotherapy with few side effects. In summary, compared with photothermal therapy or chemotherapy alone, the prepared PCM + PTX@mPBs/PEG showed synergistic photothermal and chemotherapeutic effects on cancer treatment of mice.

Enantioseparation of lysine derivatives on amylose tris (3, 5-dimethylphenylcarbamate) as chiral stationary phase with high separation factor.

Enantioseparation of lysine derivatives by chiral high-performance liquid chromatography (HPLC) was accomplished using two chiral stationary phases (CSPs, Chiralpak IA and Chiralpak IC) based on polysaccharides under normal phase (NP) conditions. All analytes were completely separated. The impacts of polar modifiers, analyte structure and column temperature on chiral separation were discussed. Moreover, the relationship between structure and retention was investigated. The van't Hoff equation was employed to evaluate the thermodynamic parameters of the chiral separation process. The data suggest that the chiral separation process was enthalpy-driven. Surprisingly, two uncommon phenomena were observed: (1) high separation factors on Chiralpak IA and (2) different binding mechanisms with CSP and the two enantiomers.

Micelle-enhanced and terbium-sensitized spectrofluorimetric determination of gatifloxacin and its interaction mechanism.

A terbium-sensitized spectrofluorimetric method using an anionic surfactant, sodium dodecyl benzene sulfonate (SDBS), was developed for the determination of gatifloxacin (GFLX). A coordination complex system of GFLX-Tb(3+)-SDBS was studied. It was found that SDBS significantly enhanced the fluorescence intensity of the complex (about 11-fold). Optimal experimental conditions were determined as follows: excitation and emission wavelengths of 331 and 547nm, pH 7.0, 2.0x10(-4)moll(-1) terbium (III), and 2.0x10(-4)moll(-1) SDBS. The enhanced fluorescence intensity of the system (DeltaI(f)) showed a good linear relationship with the concentration of GFLX over the range of 5.0x10(-10) to 5.0x10(-8)moll(-1) with a correlation coefficient of 0.9996. The detection limit (3sigma) was determined as 6.0x10(-11)moll(-1). This method has been successfully applied to the determination of GFLX in pharmaceuticals and human urine/serum samples. Compared with most of other methods reported, the rapid and simple procedure proposed in the text offers higher sensitivity, wider linear range, and better stability. The interaction mechanism of the system is also studied by the research of ultraviolet absorption spectra, surface tension, solution polarity and fluorescence polarization.

An in-line capillary electrophoresis assay for the high-throughput screening of histone deacetylase inhibitors.

Histone deacetylases (HDACs) are important enzymes that cause chromatin structure contraction and transcription repression, which can downregulate some cancer-suppression genes and lead to the occurrence of cancer. HDAC-specific inhibition is an effective approach to cancer therapy. Hence, a method with which to investigate HDAC activity is needed. We developed an in-line capillary electrophoresis method based on electrophoretically mediated microanalysis. The optimized conditions were thoroughly validated, and the method was applied to determine the enzyme's kinetic parameters and the inhibition characteristics of three potent probe inhibitors. The obtained values were comparable to the literature data. Hence, the presented method, with its advantages of miniaturization and full automation, could be used for kinetic and inhibition studies of HDACs, which are targets for drug discovery, in the early stages of new drug development.

Enantioseparation of angiotensin II receptor type 1 blockers: evaluation of 6-substituted carbamoyl benzimidazoles on immobilized polysaccharide-based chiral stationary phases. Unusual temperature behavior.

Enantioseparation of thirteen 6-substituted carbamoyl benzimidazoles by high-performance liquid chromatography (HPLC) was investigated using two immobilized polysaccharide-based chiral stationary phases (CSPs), Chiralpak IC and Chiralpak IA, in normal-phase mode. Most of the examined compounds were completely resolved. The effects of a polar alcohol modifier, analyte structure, and column temperature on the chiral recognition were investigated. Furthermore, the structure-retention relationship was evaluated, and thermodynamic parameters were calculated from plots of ln k' or ln α versus 1/T. The thermodynamic parameters indicated that the separations were enthalpy-driven. Moreover, nonlinear van't Hoff plots were obtained on Chiralpak IA. However, two unusual phenomena were observed: (1) an unusual increase in retention with increasing temperature with linear van't Hoff plots on Chiralpak IC and (2) an extremely high Tiso value (i.e., several thousand degrees centigrade).

Binding induced colocalization activated hybridization chain reaction on the surface of magnetic nanobead for sensitive detection of adenosine.

Herein, a sensitive and enzyme-free assay for adenosine detection has been developed on the basis of binding induced colocalization activated hybridization chain reaction (HCR) strategy on the surface of magnetic nanobead. First, the recognition probe was fabricated and divided into two parts: the Apt-1 that composed a part of adenosine aptamer and toehold domain, and the Apt-2 that consisted of another part of adenosine aptamer and branch migration domain. The Apt-1 was immobilized on a streptavidin-magnetic nanobead (streptavidin-MNBs) that played the roles of enrichment and separation. Then the recognition event of adenosine could bring the two parts of aptamer together and induce the colocalization of toehold domain and branch migration domain, which could serve as an integrated initiator to trigger the HCR, producing a long nicked double-stranded polymer. Finally, the intercalating dye SYBR Green I was inserted into the polymer, generating an enhanced fluorescence signal. In this strategy, the initiator was divided into two parts and could be suppressed effectively in the absence of adenosine. Utilizing the separated function, the spontaneous hybridization of H1 and H2 could be avoided, and a low background could be acquired. Moreover, through the double amplification of HCR and multimolecules binding of SYBR Green I, highly sensitive and enzyme-free detection were achieved. The detection limit for adenosine detection was 2.0×10(-7)mol/L, which was comparable or superior to the previous aptasensors. Importantly, adenosine analysis in human urines has been performed, and this strategy could significantly distinguish the adenosine content in normal human urines and cancer patient urines, suggesting that this proposed assay will become a reliable and sensitive adenosine detection method in early clinical diagnosis and medical research.

[Study on retention time shift correction of fingerprint chromatograms of soybean isoflavones].

A method has been developed to improve the reproducibility of retention time on the fingerprint chromatograms of soybean isoflavones by high performance liquid chromatography (HPLC). Alltech C18 column and Diamonsil C18 column were used on LC-10AT system and Aglient 1100 system respectively, the mobile phase being acetic acid solution (pH 3.2)-methanol, flow rate being 0.6 mL/min, detection wavelength at 261 nm. All experiments were performed at room temperature. Under the chromatographic conditions of soybean isoflavone fingerprints, five substances as standards were used to establish the calibration curves. The shift of retention time of the fingerprint chromatogram in which peak area percentage is more than 1.5% was corrected by linear equation. The results show that the absolute error of retention times is diminished from 5.868 min to 0.854 min after calibration. This method is a good way to correct the shift of retention time for chromatographic fingerprints obtained from different C18 columns or different HPLC systems. In addition, the calibration results improve the reproducibility greatly and can be applied in different laboratories conveniently.