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Elaborately engineering of a dual-drug co-assembled nanomedicine for boosting immunogenic cell death and enhancing triple negative breast cancer treatment

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Asian Journal of Pharmaceutical Sciences 2022年第3期17卷 412-424页

作者： Chen Wang Han Yu Xiaohong Yang Xuanbo zhang Yuequan Wang Tianrui Gu shenwu zhang Cong Luo Shenyang Pharmaceutical University Shenyang 110016China

Pure drug-assembled nanosystem provides a facile and promising solution for simple manufacturing of nanodrugs,whereas a lack of understanding of the underlying assembly mechanism and the inefficient and uncontrollable drug release still limits the development and application of this ***,a simple and practical nanoassembly of DOX and DiR is constructed on basis of their co-assembly *** interaction forces are found to drive the co-assembly ***,DOX release from the nanoassembly can bewell controlled by the acidic tumormicroenvironment and laser irradiation,resulting in favorable delivery efficiency of DiR and DOX in vitro and in *** expected,the nanoassembly with high therapeutic safety completely eradicated the mice triple negative breast cancer cells(4T1)on BALB/c mice,owing to synergistic chemo-photothermal *** interestingly,DiR and DOX synergistically induce immunogenic cell death(ICD)of tumor cells after treatment,enabling the mice to acquire immune memory against tumor growth and *** a facile nanoassembly technique provides a novelmultimodal cancer treatment platform of chemotherapy/phototherapy/immunotherapy.

关键词： Carrier-free Pure drug co-assembly Immune activation Synergistic chemo-photothermal therapy

Pure photosensitizer-driven nanoassembly with core-matched PEGylation for imaging-guided photodynamic therapy

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Acta Pharmaceutica Sinica B 2021年第11期11卷 3636-3647页

作者： shenwu zhang Yuequan Wang Zhiqiang Kong Xuanbo zhang Bingjun Sun Han Yu Qin Chen Cong Luo Jin Sun Zhonggui He Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacy Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital&InstituteShenyang 110042China

Pure drug-assembled nanomedicines(PDANs)are currently under intensive investigation as promising nanoplatforms for cancer ***,poor colloidal stability and less tumor-homing ability remain critical unresolved problems that impede their clinical ***,we report a core-matched nanoassembly of pyropheophorbide a(PPa)for photodynamic therapy(PDT).Pure PPa molecules are found to self-assemble into nanoparticles(NPs),and an amphiphilic PEG polymer(PPaPEG_(2K))is utilized to achieve core-matched PEGylating modification via the p-p stacking effect and hydrophobic interaction between the PPa core and the PPa-PEG_(2K) *** to PCL-PEG_(2K) with similar molecular weight,PPa-PEG_(2K) significantly increases the stability,prolongs the systemic circulation and improves the tumor-homing ability and ROS generation efficiency of *** a result,PPa/PPa-PEG_(2K) NPs exert potent antitumor activity in a 4T1 breast tumor-bearing BALB/c mouse xenograft ***,such a core-matched nanoassembly of pure photosensitizer provides a new strategy for the development of imaging-guided theragnostic nanomedicines.

关键词： Pure drug-assembled nanomedicines Pure photosensitizer Pyropheophorbide a Core-matched Self-assembly Nanoassembly Imaging-guided Photodynamic therapy

Investigating the crucial roles of aliphatic tails in disulfide bond-linked docetaxel prodrug nanoassemblies

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Asian Journal of Pharmaceutical Sciences 2021年第5期16卷 643-652页

作者： Yuequan Wang Cong Luo Shuang Zhou Xinhui Wang Xuanbo zhang Shumeng Li shenwu zhang Shuo Wang Bingjun Sun Zhonggui He Jin Sun Shenyang Pharmaceutical University Shenyang 110016China

Disulfide bond-bridging strategy has been extensively utilized to construct tumor specificity-responsive aliphatic prodrug nanoparticles(PNPs) for precise cancer therapy. Yet, there is no research shedding light on the impacts of the saturation and cis-trans configuration of aliphatic tails on the self-assembly capacity of disulfide bond-linked prodrugs and the in vivo delivery fate of PNPs. Herein, five disulfide bond-linked docetaxelfatty acid prodrugs are designed and synthesized by using stearic acid, elaidic acid, oleic acid, linoleic acid and linolenic acid as the aliphatic tails, respectively. Interestingly, the cistrans configuration of aliphatic tails significantly influences the self-assembly features of prodrugs, and elaidic acid-linked prodrug with a trans double bond show poor self-assembly capacity. Although the aliphatic tails have almost no effect on the redox-sensitive drug release and cytotoxicity, different aliphatic tails significantly influence the chemical stability of prodrugs and the colloidal stability of PNPs, thus affecting the in vivo pharmacokinetics, biodistribution and antitumor efficacy of PNPs. Our findings illustrate how aliphatic tails affect the assembly characteristic of disulfide bond-linked aliphatic prodrugs and the in vivo delivery fate of PNPs, and thus provide theoretical basis for future development of disulfide bond-bridged aliphatic prodrugs.

关键词： Docetaxel Aliphatic prodrug Disulfide bond Self-assembly capacity In vivo drug delivery fate

Precisely engineering a dual-drug cooperative nanoassembly for proteasome inhibition-potentiated photodynamic therapy

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Chinese Chemical Letters 2022年第4期33卷 1927-1932页

作者： Fujun Yang Qingyu Ji Rui Liao Shumeng Li Yuequan Wang Xuanbo zhang shenwu zhang Haotian zhang Qiming Kan Jin Sun Zhonggui He Bingjun Sun Cong Luo Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmacology School of Life Science and BiopharmaceuticsShenyang Pharmaceutical UniversityShenyang 110016China

Photodynamic therapy(PDT) has been widely investigated for cancer therapy. The intracellular accumulation of reactive oxygen species(ROS)-damaged protein facilitates tumor cell apoptosis. However, there is growing evidence that the ubiquitin-proteasome pathway(UPP) significantly impedes PDT by preventing the enrichment of ROS-damaged proteins in tumor cells. To tackle this challenge, we report a facile dual-drug nanoassembly based on the discovery of an interesting co-assembly of bortezomib(BTZ, a proteasome inhibitor) and pyropheophorbide a(PPa) for proteasome inhibition-mediated PDT *** precisely engineered nanoassembly with the optimal dose ratio of BTZ and PPa demonstrates multiple advantages, including simple fabrication, high drug co-loading efficiency, flexible dose adjustment,good colloidal stability, long systemic circulation, favorable tumor-specific accumulation, as well as significant enrichment of ROS-damaged proteins in tumor cells. As a result, the cooperative nanoassembly exhibits potent synergistic antitumor activity in vivo. This study provides a novel dual-drug engineering modality for multimodal cancer treatment.

关键词： Bortezomib Pyropheophorbide a Precisely cooperative nanoassembly Proteasome inhibition Photodynamic therapy Multimodal cancer therapy

A natural compound-empowered podophyllotoxin prodrug nanoassembly magnifies efficacy-toxicity benefits in cancer chemotherapy

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Asian Journal of Pharmaceutical Sciences 2024年第4期19卷 103-114页

作者： Ziqi Lin Yuequan Wang Wenwen Li Fei Sun Qingzhi Lv shenwu zhang Xiaohong Liu Feng Qin Cong Luo Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Joint International Research Laboratory of Intelligent Drug Delivery Systems of Ministry of Education Shenyang Pharmaceutical UniversityShenyang 110016China College of Pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China School of Pharmacy Binzhou Medical UniversityYantai 264003China

Small-molecule prodrug nanoassembly technology with a unique advantage in off-target toxicity reduction has been widely used for antitumor drug ***,prodrug activation remains a rate-limiting step for exerting therapeutic actions,which requires to quickly reach the minimum valid concentrations of free ***,we find that a natural compound(BL-193)selectively improves the chemotherapy sensitivity of breast cancer cells to podophyllotoxin(PPT)at ineffective dose *** on this,we propose to combine prodrug nanoassembly with chemotherapy sensitization to fully unleash the chemotherapeutic potential of ***,a redox-sensitive prodrug(PSSF)of PPT is synthesized by coupling 9-fluorenyl-methanol(Fmoc-OH)with PPT linked via disulfide ***,PSSF with aπ-conjugated structure readily co-assembles with BL-193 into stable ***,BL-193 serves as an excellent chemosensitizer that creates an ultra-low-dose chemotherapeutic windowfor ***,prodrug design and precise hybrid nanoassembly well manage off-target *** expected,such a BL-193-empowered prodrug nanoassembly elicits potent antitumor *** study offers a novel paradigm to magnify chemotherapy efficacy-toxicity benefits.

关键词： Podophyllotoxin Prodrug Chemosensitization Hybrid nanoassembly Cancer chemotherapy

Oxidation-strengthened disulfide-bridged prodrug nanoplatforms with cascade facilitated drug release for synergetic photochemotherapy

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Asian Journal of Pharmaceutical Sciences 2020年第5期15卷 637-645页

作者： Bin Yang Lin Wei Yuequan Wang Na Li Bin Ji Kaiyuan Wang Xuanbo zhang shenwu zhang Shuang Zhou Xiaohui Yao Hang Song Yusheng Wu Haotian zhang Qiming Kan Tao Jin Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Ministry of Education Heilongjiang UniversityHarbin 150500China Sino-Russian Joint Graduate School Heilongjiang UniversityHarbin 150080China Department of Laboratory Medicine The First Affiliated HospitalChina Medical UniversityShenyang 110001China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China School of Life Sciences Heilongjiang UniversityHarbin 150080China

One of the major barriers in utilizing prodrug nanocarriers for cancer therapy is the slow release of parent drug in *** cells generally display the higher oxidative level than normal cells,and also displayed the heterogeneity in terms of redox homeostasis *** previously found that the disulfide bond-linkage demonstrates surprising oxidationsensitivity to form the hydrophilic sulfoxide and sulphone ***,we develop oxidation-strengthened prodrug nanosystem loaded with pyropheophorbide a(PPa)to achieve light-activatable cascade drug release and enhance therapeutic *** disulfide bond-driven prodrug nanosystems not only respond to the redox-heterogeneity in tumor,but also respond to the exogenous oxidant(singlet oxygen)elicited by *** the prodrug nanoparticles(NPs)are activated under irradiation,they would undergo an oxidative self-strengthened process,resulting in a facilitated drug cascade *** IC50 value of the PPa@PTX-S-S NPs without irradiation was 2-fold higher than those of NPs plus *** vivo,the PPa@PTX prodrug NPs display prolonged systemic circulation and increased accumulation in tumor *** PPa@PTXS-S NPs showed much higher efficiency than free PTX or the PPa@PTX-C-C NPs to suppress the growth of 4 T1 ***,this novel oxidation-strengthened disulfide-bridged prodrug-nanosystem has a great potential in the enhanced efficacy of cancer synergetic photochemotherapy.

关键词： Prodrug nanoplatform Disulfide bond Pyropheophorbide a Redox-heterogeneity Accurate therapy

Erythrocyte membrane-camouflaged carrier-free nanoassembly of FRET photosensitizer pairs with high therapeutic efficiency and high security for programmed cancer synergistic phototherapy

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Bioactive Materials 2021年第8期6卷 2291-2302页

作者： Xuanbo zhang Jianchen Xiong Kaiyuan Wang Han Yu Bingjun Sun Hao Ye Zhiqiang Zhao Ning Wang Yuequan Wang shenwu zhang Wutong Zhao Haotian zhang Zhonggui He Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyangLiaoning110016PR China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang110016PR China

Phototherapy has been intensively investigated as a non-invasive cancer treatment ***,its clinical translation is still impeded by unsatisfactory therapeutic efficacy and severe *** achieve high therapeutic efficiency and high security,a nanoassembly of Forster Resonance Energy Transfer(FRET)photosensitizer pairs is developed on basis of dual-mode photosensitizer co-loading and photocaging *** proof-of-concept,an erythrocyte-camouflaged FRET pair co-assembly of chlorine e6(Ce6,FRET donor)and 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide(DiR,FRET acceptor)is investigated for breast cancer ***,Ce6 in the nanoassemby is quenched by DiR and could be unlocked for photodynamic therapy(PDT)only when DiR is photobleached by 808-nm *** a result,Ce6-caused phototoxicity could be well *** cascaded laser irradiation(808-660 nm),tumor-localizing temperature rise following laser irradiation on DiR not only induces tumor cell apoptosis but also facilitates the tumor penetration of NPs,relieves tumor hypoxia,and promotes the PDT efficacy of *** FRET pair-based nanoassembly provides a new strategy for developing multimodal phototherapy nanomedicines with high efficiency and good security.

关键词： FRET pair Carrier-free Nanoassembly Erythrocyte membrane-camouflaged Programmed synergistic phototherapy

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基于应用框架的C4~ISR仿真软件开发

电子科技 2007年第7期20卷 66-68页

作者：张慎武徐学洲居真奇西安电子科技大学软件研究所陕西西安710071 中国电子科技集团第二十八研究所五部江苏南京210007

基于应用框架的软件开发是一种面向特定领域的软件重用技术。介绍了框架定义和相关概念,说明了C^4ISR仿真软件体系结构,提出了一种C^4ISR仿真软件通用开发框架。

关键词：软件重用应用框架 C^4 ISR 仿真软件

CFD simulation of pressure fluctuation characteristics in the gas-solid fluidized bed:Comparisons with experiments

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Petroleum Science 2011年第2期8卷 211-218页

作者： Wang Qingcheng zhang Kai Gu Hongyan Beijing shenwu Thermal Energy Technology Co. LTD Beijing 102200 China State Key Laboratory of Heavy Oil Processing China University of Petroleum Beijing 102249 China National Engineering Lab for Biomass Power Generation Equipment North China Electric Power University Beijing 102206 China Electrical Engineering College Guizhou University Guiyang 550025 China

A simple hydrodynamic model based on two-fluid theory, taking into account the effect of discrete particles on both the gas- and solid-phase momentum equations, was used to numerically investigate the pressure fluctuation characteristics in a gas-solid fluidized bed with the aid of CFX 4.4, a commercial CFD software package, by adding user-defined Fortran subroutines. Numerical simulations together with typical experimental measurements show that pressure fluctuations originate above the distributor when a gas pulse is injected into the fluidized bed. The pressure above the bubble gradually increases due to the presence of a rising bubble. When the bubble passes through the bed surface, the pressure near the bed surface gradually decreases to a lower value. Moreover, the pressure signals in the bubbling fluidized beds show obviously periodic characteristics. The major frequency of pressure fluctuations at the same vertical position is affected slightly by the operating gas velocity, and the amplitude of pressure fluctuations is related to both the operating gas velocity and the vertical height. In this study, the influence of the operating gas velocity on the pressure wave propagation velocity can be ignored, and only two peak frequencies in the power spectrum of the pressure fluctuations are observed which are associated with the bubble formation above the distributor and its eruption at the bed surface.

关键词： Gas-solid fluidized bed CFD simulation experimental measurements propagation ofpressure fluctuations pressure wave velocity pressure fluctuation frequency