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Core-shell lipid-polymeric nanoparticles for enhanced oral bioavailability and antihypertensive efficacy of KY5 peptide

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Chinese Chemical Letters 2023年第4期34卷 158-163页

作者： Jingmei Yuan Mengran Guo Shengnan Zhao Jinhua Li Xinchun Wang Jian Yang Zhaohui Jin Xiangrong Song Department of Critical Care Medicine Department of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China School of Applied Chemistry and Biological Technology Shenzhen PolytechnicShenzhen 518055China First Affiliated Hospital of the Medical College Shihezi UniversityShihezi 832008China

Hypertension is the leading risk factor for death and disability, and hypertensive patients always need long-term oral antihypertensive drugs. Some bioactive peptides that extracted from animals or plants have shown excellent advantages on antihypertension. However, the oral delivery of these peptides is always failure on account of instability and poor absorption in the gastrointestinal tract. Herein, we developed a core-shell lipid-polymeric nanoparticle for oral delivery of a highly efficient antihypertensive peptide KY5(KY5-CSs). KY5-CSs had a particle size of 216.7 ± 2.5 nm, with a narrow PDI of 0.07 ± 0.01.The zeta potential was-4.1 ± 0.1 m V. It exhibited good stability in 4 ℃ and possessed a controlled release behavior in gastrointestinal tract. The cellular uptake study proved that the lipid shell imparted unique capability of permeation across the mucus layer and internalization by Caco-2/HT-29 cells. In addition, KY5-CSs enhanced in situ intestinal absorption in SD rats. The pharmacokinetic studies and antihypertensive efficacy showed a superior oral absorption and antihypertensive effect of KY5-CSs than KY5-NPs. In conclusion, the core-shell lipid-polymeric nanoparticles will provide attractive potential for oral delivery of antihypertensive peptides.

关键词： Hypertension Core-shell lipid-polymeric nanoparticles KY5 Antihypertensive peptides Oral delivery

Oral nanoparticles containing naringenin suppress atherosclerotic progression by targeting delivery to plaque macrophages

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Nano Research 2023年第1期16卷 925-937页

作者： Mengran Guo Zhongshan He Zhaohui Jin Lingjing Huang Jingmei Yuan Shugang Qin Xinchun Wang Lili Cao Xiangrong Song Department of Critical Care Medicine Department of Anesthesiology and Translational Neuroscience CenterDepartment of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China First Affiliated Hospital of the Medical College Shihezi UniversityShihezi 832008China College of Medicine Chengdu UniversityChengdu 610000China

Atherosclerosis is the main cause of ischemic stroke and myocardial infarction diseases.Nanoparticles have shown unique benefits for atherosclerosis treatment by targeting the lesional macrophages of plaques.However,most of the nanocarriers are administered intravenously,which is inconvenient and may cause complications.Herein,we developed an oral lipid-polymer based nanoparticles(FA-LNPs)decorated with folic acid,which can not only effectively overcome intestinal mucosal-epithelial barrier by increasing the transmembrane transport through intestinal epithelial and the accumulation in Peyer’s patches but also actively target to the aortic plaque sites and accumulate in lesional macrophages.Subsequently,naringenin(Nrg),one of the antiinflammation drugs,was designed to be the oral nanomedicine(FA-LNPs/Nrg)for the first time via the encapsulation of FALNPs.FA-LNPs/Nrg presented highly anti-atherosclerotic efficacy.After the atherosclerotic ApoE−/−mice were treated by FALNPs/Nrg via oral administration for three months,the aortic lesion area,plaque area,and necrotic core area of the aortic root were significantly decreased.Meanwhile,the lipid-related blood parameters recovered to normal levels.Our study provides a promising approach to atherosclerosis treatment based on the novel oral targeting delivery system.

关键词： atherosclerosis macrophages Peyer’s patches oral delivery folic acid naringenin

A lipid-based LMP2-mRNA vaccine to treat nasopharyngeal carcinoma

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Nano Research 2023年第4期16卷 5357-5367页

作者： Mengran Guo Xing Duan Xingchen Peng Zhaohui Jin Hai Huang Wen Xiao Qian Zheng Yongqi Deng Na Fan Kepan Chen Xiangrong Song Department of Critical Care Medicine Department of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610000China West China School of Pharmacy Sichuan UniversityChengdu 610000China

Nasopharyngeal carcinoma(NPC)is a serious and highly invasive epithelial malignancy that is closely associated with Epstein‒Barr virus(EBV).Due to the lack of therapeutic vaccines for NPC,we selected EBV latent membrane protein 2(LMP2)as a preferable targeting antigen to develop a lipid-based LMP2-mRNA(mLMP2)vaccine.Full-length mLMP2 expressing LMP2 was first synthesized using an in vitro transcription method and then encapsulated into(2,3-dioleacyl propyl)trimethylammonium chloride(DOTAP)-based cationic liposomes to obtain the mRNA vaccine(LPX-mLMP2).The cell assays showed that the antigenpresenting cells were capable of highly efficient uptake of LPX-mLMP2 and expression of LMP2.LMP2 could subsequently be presented to form the peptide-major histocompatibility complex(pMHC).Furthermore,LPX-mLMP2 could accumulate in the spleen,express antigens,promote the maturation of dendritic cells and stimulate antigen-specific T-cell responses in vivo.It dramatically inhibited the tumor growth of the LMP2-expressing tumor model after three doses of vaccination.Additionally,the proliferation of antigen-specific T cells in the tumor site made a good sign for the promise of mRNA vaccines in virus-induced cancer.Overall,we provided a newly developed antigen-encoding mRNA vaccine with advantages against NPC.We also demonstrated that mRNA vaccines are attractive candidates for cancer immunotherapy.

关键词： mRNA vaccine latent membrane protein 2(LMP2) nasopharyngeal carcinoma Epstein-Barr virus(EBV) tumorinfiltrating lymphocytes

Comparison of solid dispersion and nanosuspension for improvement of drug absorption

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Asian Journal of Pharmaceutical Sciences 2016年第1期11卷 10-11页

作者： Qiang Fu Mengran Guo Zhonggui He School of Pharmacy Shenyang Pharmaceutical University

Currently, drug discovery technology is heavily dependent oncombinatorial chemistry and high throughput screening, resultingin more and more poorly water-soluble drugs, eitherclass II (low solubility and high permeability) or IV (low solubilityand low permeability) in the standard biopharmaceuticalclassification system. Owing to the importance of solubility/dissolution for oral absorption, formulation scientists face agreat challenge.Thus, strategies have been proposed to improvethe solubility and dissolution rate. Among these approaches,solid dispersion [1] and nanosuspension [2] are the most usuallyused. However, which one is better for improving the in vitrodissolution and in vivo bioavailability?

关键词： Nanosuspension Solid dispersion In vitro In vivo

Preparation, optimization and in vitro–in vivo investigation for capsules of the choline salt of febuxostat

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Asian Journal of Pharmaceutical Sciences 2016年第6期11卷 715-721页

作者： Xuemei Han Wanpeng Qi Wenxiang Dong Mengran Guo Panqin Ma Jing Wang School of Pharmacy Shenyang Pharmaceutical UniversityNo.103Wenhua RoadShenyang 110016China Kangya of Ningxia Pharmaceuticals Co.Ltd No.57FuanWest LaneYinchuan 750002China

The objective of the present study was to exhibit the enhanced water-solubility and in vivo oral absorption when febuxostat(FXT) became the salt formation of choline. The formation of the choline salt of febuxostat was confirmed by X-ray powder diffraction, infrared spectroscopy analysis and differential scanning calorimetry. The direct filling method was used to develop a capsule formulation. Cellactose 80 was used as the filler due to its good fluidity, while cross-linked polyvinylpyrrolidone(PVPP) and magnesium stearate(MS) were used as the disintegrant and lubricant, respectively. Then the in vitro release of the formulation was carried out in five different dissolution media including HCl solution(pH 1.2),acetate buffer(pH 4.5), phosphate buffer(pH 6.8 and pH 7.2) and water. Evident improvement of release for choline febuxostat(CXT) was presented in water while the dissolution degree was decreased for CXT in the medium of phosphate buffer(pH 6.8) in comparison with FXT. Furthermore, the pharmacokinetics of CXT was studied in rats using UPLC-MS/MS compared with FXT. The data acquired illustrated that AUC0-24 h of CXT and FXT were22,245.96 ± 7342.92 μg·h/l and 12,249.70 ± 2024.04 μg·h/l, respectively. The relative bioavailability of CXT to FXT was about 181.6% and the P value of AUC0-24 h was less than 0.05. It showed significant difference between the two drugs after oral administration. In conclusion, the water-solubility and oral bioavailability were both improved remarkably for the choline salt of febuxostat and choline salinization was proved an effective way to increase the in vivo absorption for FXT.

关键词： Choline febuxostat Characterization Preparation In vitro release Bioavailability

A novel oral prodrug-targeting transporter MCT 1: 5-fluorouracil-dicarboxylate monoester conjugates

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Asian Journal of Pharmaceutical Sciences 2019年第6期14卷 631-639页

作者： Yixin Sun Dongyang Zhao Gang Wang Qikun Jiang Mengran Guo Qiming Kan Zhonggui He Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China School of Pharmacy Guangxi University of Chinese MedicineNangning 530200China School of Pharmacy Shenyang Pharmaceutical UniversityNo.103Wenhua RoadShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China

Monocarboxylate transporter 1(MCT1)is responsible for oral absorption of short-chain monocarboxylic acids from small intestine,hence,it’s likely to serve as an ideal design target for the development of oral prodrugs.However,potential application of MCT1 to facilitate the oral delivery is still unclear.Irregular oral absorption,poor permeability and bioavailability greatly limit the oral delivery efficiency of 5-fluorouracil(5-FU).Herein,we design three 5-FU-fatty acid conjugates targeting intestinal MCT1 with different lipophilic linkages.Interestingly,due to high MCT1 affinity and good gastrointestinal stability,5-FUoctanedioic acid monoester prodrug exhibited significant improvement in membrane permeability(13.1-fold)and oral bioavailability(4.1-fold)compared to 5-FU.More surprisingly,stability experiment in intestinal homogenates showed that 5-FU prodrugs could be properly activated to release 5-FU within intestinal cells,which provides an ideal foundation for the improvement of oral bioavailability.In summary,good gastrointestinal stability,high membrane permeability and appropriate intestinal cell bioactivation are the important factors for high-efficiency 5-FU oral prodrugs,and such work provides a good platform for the development of novel oral prodrugs targeting intestinal transporters.

关键词： 5-Fluorouracil Prodrugs Monocarboxylate transporter 1 Permeability Oral bioavailability

Sodium alginate coating simultaneously increases the biosafety and immunotherapeutic activity of the cationic mRNA nanovaccine

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Acta Pharmaceutica Sinica B 2023年第3期13卷 942-954页

作者： Xing Duan Yi Zhang Mengran Guo Na Fan Kepan Chen Shugang Qin Wen Xiao Qian Zheng Hai Huang Xiawei Wei Yuquan Wei Xiangrong Song Department of Critical Care Medicine Department of Clinical PharmacyFrontiers Science Center for Disease-related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China West China Hospital Sichuan UniversityChengdu 610041China

The extraordinary advantages associated with mRNA vaccines,including their high efficiency,relatively low severity of side effects,and ease of manufacture,have enabled them to be a promising immunotherapy approach against various infectious diseases and cancers.Nevertheless,most mRNA delivery carriers have many disadvantages,such as high toxicity,poor biocompatibility,and low efficiency in vivo,which have hindered the widespread use of mRNA vaccines.To further characterize and solve these problems and develop a new type of safe and efficient mRNA delivery carrier,a negatively charged SA@DOTAP-mRNA nanovaccine was prepared in this study by coating DOTAP-mRNA with the natural anionic polymer sodium alginate(SA).Intriguingly,the transfection efficiency of SA@DOTAP-mRNA was significantly higher than that of DOTAP-mRNA,which was not due to the increase in cellular uptake but was associated with changes in the endocytosis pathway and the strong lysosome escape ability of SA@DOTAP-mRNA.In addition,we found that SA significantly increased the expression of LUC-mRNA in mice and achieved certain spleen targeting.Finally,we confirmed that SA@DOTAP-mRNA had a stronger antigen-presenting ability in E.G7-OVA tumor-bearing mice,dramatically inducing the proliferation of OVA-specific CLTs and ameliorating the antitumor effect.Therefore,we firmly believe that the coating strategy applied to cationic liposome/mRNA complexes is of potential research value in the field of mRNA delivery and has promising clinical application prospects.

关键词： Negatively charged mRNA vaccine Sodium alginate Cationic liposome DOTAP Lysosomes escape Cancer Immunotherapy Toxicity

Transient Simulation and Optimization of Regional Integrated Energy System

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Energy Engineering 2022年第3期119卷 1031-1045页

作者： Xueqin Tian mengran Cui Tong Xu Jinfei Sun Xinlei Wang Jiangxiang guo De-Gejirifu Na Wang State Grid Economic and Technological Research Institute Co. Ltd.Beijing102209China Qingdao University of Technology Qingdao266033China

A modeling method of regional integrated energy system based on bus method and transient simulation is proposed,and the system optimization is based on the dynamic balance of supply and demand in the whole year energy supply cycle.A CCHP systemof gas turbine coupled with ground source heat pump and electric refrigeration unit is constructed.The energy relationship of the systemis described by bus structure,and the transient calculationmodel is built on TRNSYS platform.The weighted sum of annual total cost saving rate,primary energy saving rate and environmental pollutant shadow cost saving rate is taken as the optimized objective function,and on the basis of annual dynamic balance,the Hooke-Jeeves algorithm is used for optimization of the system configuration.A complex commercial area in Beijing is taken as an example,and different weighting coefficients are set for optimization of the system configuration.The results show that,from the perspective of economy,environmental benefit and primary energy consumption,performance of the system increases and then decreases with rise of gas turbine power;under the simulated cooling/heating load,the maximum number of optimum configuration is seen in the combination of 35 kW gas turbine+723 kW GSHP and 1178 kW electric chiller;in comparison with traditional distributed system,the annual cost saving rate,primary energy saving rate and environmental pollutant shadow cost saving rate of the system are 29.4%,49.6%and 58.2%,respectively.

关键词： Integrated energy system transient simulation multi-objective optimization

Dynamic Simulation and Performance Analysis on Multi-Energy Coupled CCHP System

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Energy Engineering 2022年第2期119卷 723-737页

作者： Xueqin Tian Jinfei Sun Tong Xu mengran Cui Xinlei Wang Jianxiang guo De-gejirifu Na Wang State Grid Economic and Technological Research Institute Co. Ltd.Beijing102209China Qingdao University of Technology Qingdao266033China

Although the Combined Cooing,Heating and Power System(hereinafter referred to as“CCHP”)improves the capacity utilization rate and energy utilization efficiency,single use of CCHP system cannot realize dynamic matching between supply and demand loads due to the unbalance features of the user’s cooling and heating loads.On the basis of user convenience and wide applicability of clean air energy,this paper tries to put forward a coupled CCHP system with combustion gas turbine and ASHP ordered power by heat,analyze trends of such parameters as gas consumption and power consumption of heat pump in line with adjustment of heating load proportion of combustion gas turbine,and optimize the system ratio in the method of annual costs and energy environmental benefit assessment.Based on the analysis of the hourly simulation and matching characteristics of the cold and hot load of the 100 thousand square meter building,it is found that the annual cost of the air source heat pump is low,but the energy and environmental benefits are poor.It will lead to 6.35%shortage of cooling load in summer.Combined with the evaluation method of primary energy consumption and zero carbon dioxide emission,the coupling system of CHHP and air source heat pump with 41%gas turbine load ratio is the best configuration.This system structure and optimization method can provide some reference for the development of CCHP coupling system.

关键词： CCHP(Combined Cooling,Heating and Power System) ASHP(Air Source Heat Pump) annual costs absorption cooling transient simulation