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Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He chutong tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province Hangzhou 310058China Joint International Research Laboratory of Intelligent Drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial Institute of Drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

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Fine-tuning the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies via branched aliphatic functionalization

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Nano Research 2024年第4期17卷 2908-2918页

作者： Guanting Li Fengli Xia Hongying Xiao Shunzhe Zheng Shuwen Fu Han Qiao Qianhui Jin Xuanbo Zhang Dun Zhou chutong tian Jin Sun Zhonggui He Bingjun Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmaceutics College of PharmacyShenyang Pharmaceutical UniversityShenyang 110016China Emergency Department The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001China

Small-molecule prodrug nanoassemblies have emerged as efficient antitumor drug delivery systems.However,in the case of camptothecins-based prodrug nanoassemblies,linear aliphatic side chain modification often results in rod-shaped or irregularly shaped nanoassemblies,which are highly unfavorable for sterilization through filtration,and may cause capillary blockage upon intravenous injection.The rational design of camptothecins-based prodrug nanoassemblies remains a challenge.Herein,we propose that branched aliphatic alcohol(BAA)functionalization could fine-tune the structure-tolerance-antitumor efficacy axis of prodrug nanoassemblies.Correspondingly,four SN38-BAA prodrugs were synthesized by conjugating 7-ethyl-10-hydroxycamptothecin(SN38)with BAAs of varying lengths via a tumor redox-responsive disulfide bond,which self-assemble into uniform spherical nanoparticles.The length of BAA was found to significant impact the multiple drug delivery process,including colloidal stability,drug release profiles and pharmacokinetics.Overall,SN38-C21 NPs(SN38-11-heneicosanol nanoparticles),featuring the longest BAA,showcased multiple therapeutic advantages,ultimately culminating the optimal antitumor efficacy and tolerance.The findings underscore the potential of BAA functionalization in strengthening the therapeutic outcomes of prodrug nanoassemblies,and provide valuable insights for developing translational camptothecins-based nanomedicines.

关键词： prodrug nanoassembly self-assembly antitumor efficacy tolerance 7-ethyl-10-hydroxycamptothecin(SN_(3)8)

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A novel fixed-combination timolol-netarsudillatanoprost ophthalmic solution for the treatment of glaucoma and ocular hypertension

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Asian Journal of Pharmaceutical Sciences 2022年第6期17卷 938-948页

作者： Tao Wang Yunran Zhang Meiling Chi Chen Zhao Linlin Cao chutong tian K.Kamei Ying Zheng Qikun Jiang Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Changzhou pharmaceutical factory co.LTD Jiangsu 213000China Department of Pharmaceutics The Second Hospital of Dalian Medical UniversityDalian 116023China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacaoChina

Currently commercial fixed-concomitant three agents have multiple problems such as multiple dosing administration,poor efficacy and side effects.Once-daily fixed-combination timolol-netarsudil-latanoprost ophthalmic solution(FC-TNL)has the ability to treat glaucoma by lowering the intraocular pressure(IOP)with great efficacy and improving patient compliance.However,the commercialized netarsudil dimesylate precipitated when the p H of the solution was above 5.4,or when maleic acid,the salt of commercial timolol maleate,was mixed with netarsudil dimesylate.Consequently,the homologous salt engineering strategy was used to make netarsudil dimesylate soluble in p H 4.8–5.2 solution by synthesizing timolol mesylate.Next,the morphology of timolol mesylate was observed by scanning electron microscopy,differential scanning calorimetry,thermogravimetric analysis,and powder X-ray diffraction.The prepared FC-TNL showed good stability during refrigeration storage.Additionally,FC-TNL exerted no influence on the intraocular penetration of each active compounds in the pharmacokinetic study.Importantly,oncedaily FC-TNL exerted potent IOP-lowering effect and protective effect on retinal ganglion cells.The FC-TNL was stable,safe and effective,being a promising glaucoma therapeutic.

关键词： Glaucoma Intraocular pressure Homologous salt engineering strategy Timolol mesylate Fixed-combination timolol-netarsudil-latanoprost ophthalmic solution

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Boosting SN38-based oral chemotherapy to combine reductionbioactivated structured lipid-mimetic prodrug with ascorbic acid

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Nano Research 2022年第10期15卷 9092-9104页

作者： Helin Wang Qi Lu Yifan Miao Jiaxuan Song Mingyang Zhang Zixuan Wang Haotian Zhang Zhonggui He chutong tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China

The reduction-responsive disulfide bonds have been widely used as bioactive linkages to facilitate a rapid release of anticancer drugs into tumor cells.However,the activation can be hindered by the kinetics of the thiol-disulfide exchange reactions.Supplementing with an additional reductant is a promising strategy to further boost drug release.Herein,inspired by the specific absorption mechanism of triglyceride fat,structured lipid-mimetic oral prodrugs of 7-ethyl-10-hydroxycamptothecin(SN38)were designed to improve intestinal permeability and bypass the first-pass effect.SN38 prodrugs were prepared into lipid formulations that could self-emulsify into nano-sized particles after entering the gastrointestinal tract.Surprisingly,we found that the oral bioavailability of the prodrug lipid formulation could be up to 2.69-fold higher than that of the parent SN38,indicating an effective oral delivery.In addition,the reduction-responsive disulfide bond was used as a linker,and ascorbic acid(ASC)was coadministrated to further promote the efficient release of SN38 from the prodrug.ASC enhanced the oral antitumor effect of the reduction-responsive oral prodrug and exhibited good safety.In summary,the combination of a structured lipid-mimetic prodrug and ASC was firstly demonstrated to boost the oral chemotherapy effect of the difficult-for-oral chemotherapeutics.

关键词： oral chemotherapy structured lipid-mimetic prodrug 7-ethyl-10-hydroxycamptothecin(SN38) ascorbic acid

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Artificial tumor microenvironment regulated by first hemorrhage for enhanced tumor targeting and then occlusion for synergistic bioactivation of hypoxia-sensitive platesomes

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Acta Pharmaceutica Sinica B 2022年第3期12卷 1487-1499页

作者： Wenhui Tao Dongyang Zhao Guanting Li Lingxiao Li Songhao Li Hao Ye chutong tian Yutong Lu Shuying Li Yinghua Sun Zhonggui He Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmaceutical and Engineering College of Pharmaceutical and EngineeringShenyang Pharmaceutical UniversityShenyang 110016China Department of Pharmaceutics College of PharmacyShenyang Pharmaceutical UniversityShenyang J10016China

The unique characteristics of the tumor microenvironment(TME)could be exploited to develop antitumor nanomedicine strategies.However,in many cases,the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity.Given the amplified characteristics of TME regulated by vascular disrupting agents(VDAs),nanomedicines may achieve unexpected improved efficacy.Herein,we fabricate platelet membrane-fusogenic liposomes(PML/DP&PPa),namely“platesomes”,which actively load the hypoxia-activated pro-prodrug DMG-PR104A(DP)and physically encapsulate the photosensitizer pyropheophorbide a(PPa).Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate(CA4P),PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P.First,CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention(EPR)effect,and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa.Besides,CA4P-induced vascular occlusion inhibits oxygen supply,followed by photodynamic therapy-caused acute tumor hypoxia.This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis.Thus,such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation,and provides a preferable solution to high-efficiency cancer therapy.

关键词： Tumor microenvironment Vascular disrupting agents Biomimetic platesomes Photosensitizers Hypoxia-activated prodrugs Nanomedicine delivery Combination therapy Antitumor and antimetastasis

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Erratum to:Boosting SN38-based oral chemotherapy to combine reduction-bioactivated structured lipid-mimetic prodrug with ascorbic acid

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Nano Research 2023年第4期16卷 6010-6011页

作者： Helin Wang Qi Lu Yifan Miao Jiaxuan Song Mingyang Zhang Haotian Zhang Zhonggui He Zixuan Wang chutong tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyang 110016China

Erratum to Nano Research 2022,15(10):9092-9104 https://***/10.1007/s12274-022-4544-7 Figure 9 was unfortunately mistakenly typeset.This error did not affect any of the conclusions from the published paper.

关键词： chemotherapy Figure combine

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2023年度国家自然科学基金药剂学领域项目申请与资助情况述评

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沈阳药科大学学报 2024年第5期41卷 670-674页

作者：田楚彤张泉韩立炜国家自然科学基金委员会医学科学部北京100085 沈阳药科大学无涯创新学院辽宁沈阳110016 南开大学药学院天津300071

目的为了给药剂学领域科研工作者提供参考,本文对2023年度国家自然科学基金药剂学领域项目申请与资助情况进行述评。方法通过统计整理2023年度国家自然科学基金药物学学科申请代码H3408药剂学领域面上项目、青年科学基金项目和地区科... 详细信息

目的为了给药剂学领域科研工作者提供参考,本文对2023年度国家自然科学基金药剂学领域项目申请与资助情况进行述评。方法通过统计整理2023年度国家自然科学基金药物学学科申请代码H3408药剂学领域面上项目、青年科学基金项目和地区科学基金项目的申请与资助情况,归纳分析申请项目的主要研究内容和存在问题。结果 2023年度药剂学领域申请项目的主要研究方向包括核酸药物递送、新型药物递送系统与肿瘤免疫联合及仿生递药系统等。申请项目尚存在药物递送系统设计单纯求新但可行性受限、对其他学科的新技术新方法理解不透彻难以产生实质性交叉融合、对研究冷门方向关注不足等问题。结论药剂学科研工作者需要不断创新研究思路,凝练重要科学问题,应对疾病新疗法迅速发展大背景下药剂学所面临的挑战,才能有力推动药剂学科的发展。

关键词：药剂学国家自然科学基金申请情况资助情况研究方向

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C2Net-YOLOv5: A Bidirectional Res2Net-Based Traffic Sign Detection Algorithm

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Computers, Materials & Continua 2023年第11期77卷 1949-1965页

作者： Xiujuan Wang Yiqi tian Kangfeng Zheng chutong Liu Faculty of Information Technology Beijing University of TechnologyBeijing100124China School of Cyberspace Security Beijing University of Posts and TelecommunicationsBeijing100048China Fan Gongxiu Honors College Beijing University of TechnologyBeijing100124China

Rapid advancement of intelligent transportation systems(ITS)and autonomous driving(AD)have shown the importance of accurate and efficient detection of traffic signs.However,certain drawbacks,such as balancing accuracy and real-time performance,hinder the deployment of traffic sign detection algorithms in ITS and AD domains.In this study,a novel traffic sign detection algorithm was proposed based on the bidirectional Res2Net architecture to achieve an improved balance between accuracy and speed.An enhanced backbone network module,called C2Net,which uses an upgraded bidirectional Res2Net,was introduced to mitigate information loss in the feature extraction process and to achieve information complementarity.Furthermore,a squeeze-and-excitation attention mechanism was incorporated within the channel attention of the architecture to perform channel-level feature correction on the input feature map,which effectively retains valuable features while removing non-essential features.A series of ablation experiments were conducted to validate the efficacy of the proposed methodology.The performance was evaluated using two distinct datasets:the Tsinghua-Tencent 100K and the CSUST Chinese traffic sign detection benchmark 2021.On the TT100K dataset,the method achieves precision,recall,and Map0.5 scores of 83.3%,79.3%,and 84.2%,respectively.Similarly,on the CCTSDB 2021 dataset,the method achieves precision,recall,and Map0.5 scores of 91.49%,73.79%,and 81.03%,respectively.Experimental results revealed that the proposed method had superior performance compared to conventional models,which includes the faster region-based convolutional neural network,single shot multibox detector,and you only look once version 5.

关键词： Target detection traffic sign detection autonomous driving YOLOv5

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乡村治理体系的完善与治理能力现代化——湖北省恩施州“村医村教进两委”基层体制改革研究

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中国农村研究 2017年第1期 124-137页

作者：吴文琦田子耕贺东航刘雨晴苏玉婷洪钰钏瞿楚彤厦门大学马克思主义学院厦门361005 厦门大学公共事务学院厦门361005 厦门大学中国特色社会主义研究中心厦门361005

在国家治理体系和治理能力现代化的背景下,湖北恩施就如何推进山区农村基层治理体系与治理能力的现代化进行了有益探索。恩施州将我国传统的乡贤文化进行再造,将'新乡贤'——村医和村教,引入到村委会和村党支部中,激发农村内生活力,以... 详细信息

在国家治理体系和治理能力现代化的背景下,湖北恩施就如何推进山区农村基层治理体系与治理能力的现代化进行了有益探索。恩施州将我国传统的乡贤文化进行再造,将'新乡贤'——村医和村教,引入到村委会和村党支部中,激发农村内生活力,以此应对乡村日益严重的空心化、老龄化给基层治理带来的挑战。课题组深入访谈42名试点办负责人、基层官员、村医、村教以及村民,通过政策参与的本土化模型对重构的案例进行政策评估,从而分析恩施州选择该政策的内在逻辑,并总结该政策的实践意义和理论价值。

关键词：村医村教村两委基层治理

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