In recent years, central nervous system (CNS) diseases have become serious threat to human life and health. The existence of the blood-brain barrier (BBB), which prevents most drugs from entering the brain, has made the treatment of CNS diseases a major problem in the field of medicine and pharmacy. The advent of nanotechnology has given drugs the potential to penetrate the blood-brain barrier, and the rapid development of siRNA drugs has brought light to patients with CNS disorders. However, the delivery of nanocarriers to the brain encounters many obstacles and the conditions that can be met for brain delivery as siRNA nanocarriers are also very demanding. This paper therefore reviews the research progress and the advantages and disadvantages of lipokinase nanoparticles, chitosan nanoparticles, polyethyleneimine nanoparticles, dendrimer nanoparticles, nanogels, nanomicelles, nanoemulsions, exosomes, cells, and siRNA adducts as siRNA brain delivery systems, with a view to exploring a suitable siRNA nanodelivery system for blood-brain barrier penetration.

OBJECTIVE To study the chemical constituents from the roots of Ardisia crenata var. bicolor. METHODS The 70% ethanol extract from A. crenata was isolated and purified by silica, Sephadex LH-20, ODS, and preparative RP-HPLC, then the structures of obtained compounds were identified by physicochemical properties and spectral data. RESULTS Twelve compounds were isolated and identified as isolariciresinol-3α-O-β-D-glucopyranoside (1), isolariciresinol-4-O-β-D-glucopyranoside (2), lyoniresinol (3), lyoniside (4), isolariciresinol (5), lyoniresinol-3α-O-β-D-glucopyranoside (6), psychotrianoside G (7), pridentigenin E (8), 3β-O-{β-D-glucopyranosyl-(l→2)-α-L-arabinopyranoside}-cyclamiretin A (9), ardisimamilloside H (10), 3β-O-{α-L-rhamnopyranosyl-(1→2)-β-D-glucopyranosyl(1→4)-α-L-arabinopyranosl}-3β-hydroxy-13β,28-epoxy-16α-hydroxy-30-al (11), foegraecumoside L (12). CONCLUSION Compounds 1-6 and 12 are isolated from Ardisia for the first time,and compounds 1-9, 12 are isolated from this plant for the first time.

OBJECTIVE To investigate the levels of tricarboxylic acid cycle (TCA)-related metabolites in human epidermal growth factor receptor 2 (HER2)-positive breast cancer trastuzumab-resistant and trastuzumab-sensitive cells, as well as to screen potential biomarkers of trastuzumab resistance. METHODS Targeted metabolomics was adopted to detect TCA-related metabolite levels including citrate, cis-aconitate, isocitrate, alpha-ketoglutarate, succinic acid,fumaric acid,malic acid and oxaloacetic acid based on ultra-high-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) in trastuzumab-resistant and trastuzumab-sensitive cells. The linearity, accuracy and precision of the method were validated. Then, orthogonal partial least-squares discrimination analysis (OPLS-DA) was used to compare the relative differential expression in trastuzumab-resistant and trastuzumab-sensitive cells. Differentially expressed metabolites were screened according to P<0.05, fold change (FC)>1.5 or FC<0.67. Finally, a multivariable model based on SVM and receiver operating characteristic (ROC) curve analysis was used to assess the classification accuracy of each metabolite. RESULTS For all TCA-related metabolites, the standard curves were linear, the correlation coefficients (r) were greater than 0.994, the established method accuracy was 94%-105% and the precision coefficient of variation (CV, %) was less than 15%. Trastuzumab-resistant and trastuzumab-sensitive cells were clearly separated from each other in the OPLS-DA model. Malic acid, succinic acid and fumaric acid were significantly upregulated in trastuzumab-resistant cells (P<0.05) compared to trastuzumab-sensitive cells. The areas under the curves (AUCs) of malic acid, succinic acid and fumaric acid were greater than 0.9 and the SVM model yielded the highest AUC of 1.000. CONCLUSION TCA-related metabolites are differentially expressed in trastuzumab-resistant and trastuzumab-sensitive cells. Succinic acid, fumaric acid and malic acid can serve as biomarkers that may provide potential value for the diagnosis of trastuzumab resistance in HER2-positive breast cancer.

OBJECTIVE To establish a nano sustained release drug delivery system polysuccinimide(PSI) and hydroxyapatite(HAP) with a hard core-soft coating structure and study the delivery of anti-tumor drug regorafenib. METHODS HAP and PSI were synthesize in the article. The optimal formulation and preparation process of the regorafenib-PSI-HAP was determined by single factor analysis and the box-behnken design(BBD) response surface method. The encapsulation efficiency, drug loading captivity, drug release in vitro, particle size and distribution, Zeta potential and SEM images of regorafenib-PSI-HAP were examined. RESULTS The UV spectrophotometry results showed that the maximum absorption wave of the regorafenib was at 264 nm, the stand curve was A=94.461ρ+0.0304, r²=0.999 8. Meanwhile, between the 2-20 μg·mL^-1 of the regorafenib solutions possessed a good linear relationship at this wave. The optimal formulation prepared using MEM detected by BBD was that the concentration of regorafenib was 7.28 mg·mL^-1, the mass ratio of HAP to regorafenib was 0.63, and the mass ratio of PSI to HAP was 3.93. The in vitro drug release test showed that PSI-HAP exhibited pH-sensitive drug release, the regorafenib-PSI-HAP can be released totally above pH 7 solution. The PSD was around 300 nm, and Zeta potential was between -10 and -17 mV which was similar to the human cell membrane. CONCLUSION The proposed drug delivery system can be integrated into non-agglomerated spherical nanoparticles of uniform size through a facile preparation process. The particles are easy to sterilize, and large-scale production may be achieved easily. The drug release of PSI-HAP is pH sensitive and stable. Both PSI and nano HAP possess the effect of anti-tumor cell proliferation which is very suitable for the delivery of anti-tumor drugs such as regorafenib in vivo.

OBJECTIVE To evaluate the effects of drug release for gliclazide sustained-release tablets in ethanolic media and conduct the risk assessment for the dose dumping. METHODS Release profiles of gliclazide sustained-release tablets from 3 manufactures in different ethanolic media were determined by HPLC.Release mechanisms were analyzed and the risk of dose dumping was evaluated by the similar factors (f₂) of the release data. RESULTS Release profiles of formulations in the presence of 5%, 20% and 40% ethanol of pH 7.4 phosphate buffer media at 100 r·min^-1 were similar.The erosion rate was the key factor that affected the release profiles of gliclazide sustained-release tablets. CONCLUSION The commercial formulations are considered to be robust against alcohol effects and the risk of alcohol-induced dose dumping is relatively little.

OBJECTIVE To study the components of Rhizoma Anemarrhenae-Cortex Phellodendri Chinesis (RA-PC) herb-pair absorbed into blood in normal rabbits. METHODS Rabbits were fed with the decoction of RA-PC herb pair (4.5 g·kg^-1) once a day for 7 days, then blood samples were taken. High-performance liquid chromatography-quadrupole-electrostatic field orbital trap (UPLC-Q-Exactive Orbitrap-MS) technique was applied for the analysis, and fragments were split in both positive and negative ion modes. The compositions into blood were determined according to retention time, accurate relative molecular mass, and secondary mass spectra. RESULTS A total of 54 components were identified in the drug-containing serum of rabbits, including 46 prototype components, which were alkaloids, flavonoids, saponins, glycosides, phenolic acids, phenylpropanoids, lactones, and phenolic derivatives. The nine metabolites were derived from berberine, jatrorrhizine, berberrubine, and mangiferin, respectively. CONCLUSION RA-PC contains 46 chemical components that can enter blood of normal rabbits, and may also contains four chemical components which are metabolized into nine metabolites.

OBJECTIVE To develop a generalized “discovery-confirmation” strategy for DNA adducts based on liquid chromatography-triple quadrupole mass spectrometry (LC-QQQ-MS) and liquid chromatography-high resolution mass spectrometry (LC-HRMS), study the direct and metabolic reactivity of the potentially genotoxic substance lucidin (Luc) with three 2'-deoxynucleosides in Rubia cordifolia L., and screen and confirm possible Luc-specific DNA adducts. METHODS Three 2'-deoxynucleosides with the same fragmentation pathways with DNA adducts in mass spectrometry were used to develop and optimize a non-targeted screening method for unknown DNA adducts in QQQ-MS neutral loss and pseudo-neutral loss scanning modes, as well as a confirmatory method for adduct targeting in HRMS data-dependent scanning mode. Luc was incubated with 2'-deoxynucleoside under phase I metabolically activated and inactivated conditions, respectively, and the resulting specific DNA adducts were screened and then structurally verified by characteristic MS spectra of fragmentations. RESULTS The optimized pseudo-neutral loss scanning is sensitive to the detection of deoxyribonucleoside deglycosylation at the pg·mL^-1 level. Six Luc-DNA adducts, containing two 2'-deoxycytidine (dC) adducts, two 2'-deoxyadenosine (dA) adducts, and two 2'-deoxyguanosine (dG) adducts, were identified and confirmed in vitro incubation model of Luc and 2'-deoxynucleoside, and their structures were characterized. Luc-DNA adduct production increased with increasing Luc exposure and exposure time, and there were significant dose-response and time-response relationships, and the binding did not require metabolic activation to occur. CONCLUSION The established discovery-confirmation strategy for DNA adducts is highly sensitive and accurate. It can provide structural information of the adducts at the molecular level. This is suitable for the assessment of DNA damage caused by the presence of Luc and provides strong data support for the study and re-evaluation of its toxicity mechanism. It also offers an important methodological reference for the rapid screening of potential genotoxic components in Chinese herbal medicines.

OBJECTIVE To analyze the quality status of Xinnaojing Tablets by multi-index comprehensive evaluation. METHODS Samples were tested according to the statutory standards. Several new methods were established and adopted for multi-index comprehensive evaluation. RESULTS All samples were qualified in statutory tests. But quality defects were found in some samples by multi-index comprehensive exploratory studies. The main problems involved poor quality of raw materials, low feeding, or lack of process control. CONCLUSION Multi-index comprehensive evaluation is more capable of evaluating the real quality status of Xinnaojing Tables. To ensure the safety and effectiveness of the midication, manufacturers should pay attention to the quality of raw materials and process control, especially on Borneolum Syntheticum, Aucklandiae Radix, and Uncariae Ramulus Cum Uncis.

OBJECTIVE To develop the methods for biological activity assay and immunological characteristics analysis of anti-SARS-CoV-2 neutralizing antibodies. METHODS The binding affinity of 9MW3311 Fab and S1-RBD were analyzed by biolayer interferometry. Enzyme linked immunosorbent assay (ELSA) and fluorescence activated cell sorter (FACS) were used to evaluate the relative binding activity to S protein and blocking activity to angiotensin converting enzyme 2(ACE2) of 9MW3311 antigenbinding fragments (Fab). In vitro cytological activity of neutralizing antibody was evaluated by pseudovirus system. The binding affinities of neutralizing antibody Fc with Fc receptor (Fcγ) and Fc receptor neonatal (FcRn) receptor were determined by surface plasmon resonance (SPR). The binding activity of Fc and complement component 1 (C1q) receptor was determined by ELISA. The antibody-dependent cell-mediated cytotoxicity(ADCC) and complement dependent cytotoxicity(CDC) of neutralizing antibodies were determined by peripheral blood mononuclear cell (PBMC) method. The antibody-dependent enhancement (ADE) effect was evaluated using pseudovirus system. RESULTS The affinity constants (KD) of 9MW3311 and reference to S1-RBD were 1.15×10^-9, 1.01×10^-9, 1.15×10^-9 and 9.45×10^-10, respectively. ELISA and FACS showed that the binding activities of neutralizing antibodies were 101%, 96%, 100% and 98%, 113%, 108%, respectively. ELISA and FACS showed that the blocking activities of neutralizing antibodies against ACE2 were 100%, 95%, 91% and 94%, 101%, 94%, respectively. The neutralizing activities of the three batches of neutralizing antibodies against pseudovirus were 91%, 93% and 108%, respectively. The three batches of 9MW3311 and reference showed the same affinity constants (KD) with Fcγ and FcRn. 9MW3311 showed no ADCC and CDC activity. L234A/L235A (LALA) mutant of 9MW3311 could effectively avoid ADE effect. CONCLUSION The methods for analysis of the biological activity and immunological characteristics of anti-SARS-CoV-2 neutralizing antibodies are preliminarily established and can be used for routine quality control and release.

OBJECTIVE To evaluate the cost-effectiveness of PEG-rhG-CSF versus rhG-CSF in patients with epithelial ovarian cancer in central China for preventing chemotherapy-induced neutropenia. METHODS Two Markov models form healthcare system perspective were developed to evaluate the economics of PEG-rhG-CSF versus rhG-CSF using cost-utility analysis. Cost and probability input data were primarily obtained from a retrospective real-world study conducted in four tertiary hospitals from January 2019 to December 2020. One-way sensitivity analysis,probability sensitivity analysis and scenario analysis were used to verify the robustness of the results. RESULTS The basic analysis showed that, compared with rhG-CSF, PEG-rhG-CSF resulted in higher QALYs and lower cost, gained 0.27 QALYs more while spending 2279.63 yuan less, and the incremental cost-effectiveness ratios were ￥-8393.9/QALY. Sensitivity analysis and scenario analysis revealed robust results. CONCLUSION PEG-rhG-CSF is economically advantageous in Chinese patients with epithelial ovarian cancer for preventing chemotherapy-induced neutropenia.

OBJECTIVE To explore the quality control of real-world data in the drug clinical comprehensive evaluation, and promote the scientific and rational application of real-world data in the drug comprehensive clinical evaluation. METHODS Literature on the quality control of real-world research data in drug clinical comprehensive evaluation was reviewed, and the work experience of the drug clinical comprehensive evaluation center in the province where the author is located was integrated to explore the content and process of quality control of real-world research data in drug clinical comprehensive evaluation. RESULTS AND CONCLUSION Quality control of real-world research data generally includes internal and external controls. Evaluation methods comprise qualitative assessment, quantitative assessment, and comprehensive assessment. The implementation phase can be divided into the project initiation phase and the data governance phase, with a round of data quality control conducted in each phase. This study summarizes the content and process of quality control for real-world research data in the drug clinical comprehensive evaluation, providing a reference for researchers and decision-makers to correctly produce and use evidence from real-world data for drug clinical comprehensive evaluation.