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Potent delivery of an MMP inhibitor to the tumor microenvironment with thermosensitive liposomes for the suppression of metastasis and angiogenesis

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Signal Transduction and Targeted Therapy 2019年第1期4卷 445-453页

作者： Yaqi Lyu Qingqing Xiao lifang yin Lei Yang Wei He School of Pharmacy China Pharmaceutical University210009 NanjingChina Shanghai Dermatology Hospital 200443 ShanghaiChina

Metastasis is a major cause of chemotherapeutic failure and death.Degradation of a specific component of the extracellular matrix(ECM)by matrix metalloproteinases(MMPs)affects the physical barrier of the tumor microenvironment(TME)and induces metastasis.Here,lysolipid-containing thermosensitive liposomes(LTSLs)were prepared to deliver an MMP inhibitor,marimastat(MATT),to the TME to inhibit MMP activity and expression.LTSLs rapidly released their payloads at 42°C.Compared with the saline control,MATT-LTSLs exhibited enhanced accumulation in the tumor and a 20-fold decrease in tumor growth in 4T1 tumor-bearing mice;moreover,MATT-LTSLs reduced MMP-2 and MMP-9 activity by 50%and 43%,respectively,and downregulated MMP-2 and MMP-9 expression in vivo by 30%and 43%,respectively.Most importantly,MATT-LTSL treatment caused a 7-fold decrease in metastatic lung nodules and a 6-fold reduction in microvessels inside the tumor.We believe this study provides an effective approach for the suppression of metastasis,and the use of a cytotoxic agent in combination with MATT is a potential strategy for metastatic cancer treatment.

关键词： metastasis expression. lung

Delivery strategies of amphotericin B for invasive fungal infections

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Acta Pharmaceutica Sinica B 2021年第8期11卷 2585-2604页

作者： Xiaochun Wang Imran Shair Mohammad lifang Fan Zongmin Zhao Md Nurunnabi Marwa A.Sallam Jun Wu Zhongjian Chen lifang yin Wei He Department of Pharmaceutics China Pharmaceutical UniversityNanjing 211198China School of Pharmaceutical Sciences Sun Yat-sen UniversityUniversity TownGuangzhou 510006China Jiangsu Aosaikang Pharmaceutical Co. Ltd.Nanjing 211112China School of Engineering and Applied Sciences Harvard UniversityCambridgeMA 02138USA Department of Pharmaceutical Sciences School of PharmacyUniversity of Texas at El PasoEl PasoTX 79902USA Department of Industrial Pharmacy Faculty of PharmacyAlexandria UniversityAlexandria 21521Egypt Department of Geriatric Cardiology Jiangsu Provincial Key Laboratory of Geriatricsthe First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029China Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China

Invasive fungal infections(IFIs)represent a growing public concern for clinicians to manage in many medical settings,with substantial associated morbidities and mortalities.Among many current therapeutic options for the treatment of IFIs,amphotericin B(AmB)is the most frequently used drug.AmB is considered as a first-line drug in the clinic that has strong antifungal activity and less resistance.In this review,we summarized the most promising research efforts on nanocarriers for AmB delivery and highlighted their efficacy and safety for treating IFIs.We have also discussed the mechanism of actions of AmB,rationale for treating IFIs,and recent advances in formulating AmB for clinical use.Finally,this review discusses some practical considerations and provides recommendations for future studies in applying AmB for combating IFIs.

关键词： Invasive fungal infections Amphotericin B Poor water-solubility Drug delivery Topical administration Nanoparticles Conjugates Toxicity

Cocrystallization-like strategy for the codelivery of hydrophobic and hydrophilic drugs in a single carrier material formulation

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Chinese Chemical Letters 2021年第10期32卷 3071-3075页

作者： Yi Li Chao Teng Helena S.Azevedo lifang yin Wei He School of Pharmacy China Pharmaceutical UniversityNanjing 210009China School of Engineering and Materials Science Institute of BioengineeringQueen Mary University of LondonLondon E14NSUnited Kingdom

Codelivery of drugs by drug carriers is a promising strategy against several diseases such as infections and cancer.However,traditional drug carriers are typically characterized by low drug payload,limiting their treatment efficacy.Using nanocrystals of insoluble drug as carriers,a carrier free platform was developed previously to deliver a second insoluble drug for codelivery.To extend the concept,we hypothesized,herein,that the platform allows for codelivery of hydrophobic and hydrophilic drugs using a cocrystalization-like strategy.To obtain proof-of-concept,paclitaxel(PTX),an insoluble chemotherapeutic agent,and dichloroacetic acid(DCA),a water-soluble inhibitor of pyruvate dehydrogenase kinase,were utilized as model drugs.PTX-DCA hybrid nanocrystals(PTX-DCA NCs)were prepared by antisolvent precipitation and characterized.Their in vitro antitumor activity against cancer cells was evaluated.PTX-DCA NCs prepared from the optimized formulation had a diameter of 160 nm and a rodshape morphology and possessed encapsulated efficacy of approximately 30%for DCA.The use of the hybrid crystals enabled synergy to kill cancer cells,in particular in PTX-resistant cells in a dosedependent pattern.In conclusion,by using a cocrystalization-like strategy,a hydrophilic drug can be formulated into a drug’s nanocrystal for codelivery.

关键词： Hybrid nanocrystal Codelivery Multidrug resistance Paclitaxel Dichloroacetic acid Cocrystallization

Development of fluorinated polyplex nanoemulsions for improved small interfering RNA delivery and cancer therapy

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Nano Research 2018年第7期11卷 3746-3761页

作者： Gang Chen Kaikai Wang Pengkai Wu Yixin Wang Zhanwei Zhou lifang yin Minjie Sun David Oupicky State Key Laboratory of Natural Medicines Departmen t of Pharmaceutics China Pharmaceutical University Nanjing 210009 China Center for Drug Delivery and Nanomedicine Department of Pharmaceutical Sciences University of Nebraska Medical Center Omaha NE 68198 USA

We report the development of a small interfering RNA （siRNA） delivery vector based on cationic perfluorocarbon nanoemulsions. We have prepared perfluorodecalin （PFD） emulsions with a positive surface charge provided by a fluorinated poly（ethylenimine）（F-PEI）. The fluorinated emulsion （F-PEI@PFD） reduced cytotoxicity of F-PEI and demonstrated effective binding with siRNAs to form nanosized emulsion polyplexes. The prepared emulsion polyplexes enhanced cellular uptake and improved endosomal escape of the siRNA. In addition to increased reporter gene silencing in multiple cancer cell lines, when compared with control F-PEI and PEI polyplexes, the siR_NA emulsion polyplexes showed an excellent resistance to serum deactivation and maintained high activity, even in high-serum conditions. The F-PEI@PFD emulsion polyplexes carrying an siRNA to silence the expression of Bcl2 gene induced apoptosis and inhibited tumor growth in a melanoma mouse model in vivo and showed potential for in vivo ultrasound imaging. This study demonstrates the potential of F-PEI@PFD emulsions as a multifunctional theranostic nanoplatform for safe siRNA delivery, with integrated ultrasound imaging functionality.

关键词： polyplexes fluorous interactions small interfering RNA（siRNA） delivery tumor deliver perfluorocarbon emulsion

Cytosolic delivery of the immunological adjuvant PolyⅠ:C and cytotoxic drug crystals via a carrier-free strategy significantly amplifies immune response

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3272-3285页

作者： Xiaoqing Du Yuqi Hou Jia Huang Yan Pang Chenlu Ruan Wei Wu Chenjie Xu Hongwei Zhang lifang yin Wei He Department of Pharmaceutics School of PharmacyChina Pharmaceutical UniversityNanjing 211198China Key Laboratory of Smart Drug Delivery of Ministry of Education of China School of PharmacyFudan UniversityShanghai 201203China Department of Biomedical Engineering City University of Hong KongKowloonHong Kong SARChina Department of Pharmaceutical Sciences School of Pharmacye BostonMCPHS UniversityBostonMA 02115USA

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy.The precise control of the targeting and release of agents is critical in this methodology.This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy.To obtain a proof-of-concept,a co-delivery system was prepared via a drug-delivering-drug(DDD)strategy for cytosolic co-delivery of Poly I:C,a synthetic ds RNA analog to activate RIG-I signaling,and PTX,a commonly used chemotherapeutics,in which pure PTX nanorods were sequentially coated with Poly I:C and mannuronic acid via stimulating the RIG-I signaling axis.The co-delivery system with a diameter of 200 nm enables profound immunogenicity of cancer cells,exhibiting increased secretion of cytokines and chemokines,pronounced immune response in vivo,and significant inhibition of tumor growth.Also,we found that intracellularly sustained release of cytotoxic agents could elicit the immunogenicity of cancer cells.Overall,the intracellular asynchronous release of chemotherapeutics and immunomodulators is a promising strategy to promote the immunogenicity of cancer cells and augment the antitumor immune response.

关键词： Asynchronous release Co-delivery Immunogenicity Cancer cells Immunostimulant Paclitaxel Chemoimmunotherapy

基因介导的精准免疫疗法在急性髓系白血病治疗中的进展

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中国药科大学学报 2024年第1期55卷 53-62页

作者：赵鹏博朱滢尹莉芳辛晓斐中国药科大学药学院药剂系江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心

急性髓系白血病（acute myeloid leukemia, AML）是一种骨髓内造血干细胞的克隆异常，进而导致大量异常分化的髓系细胞在骨髓内聚集而产生的疾病。传统的治疗手段难以治愈AML，嵌合抗原受体T细胞（chimeric antigen receptor Tcell, CA... 详细信息

急性髓系白血病（acute myeloid leukemia, AML）是一种骨髓内造血干细胞的克隆异常，进而导致大量异常分化的髓系细胞在骨髓内聚集而产生的疾病。传统的治疗手段难以治愈AML，嵌合抗原受体T细胞（chimeric antigen receptor Tcell, CAR-T）免疫疗法的成功应用预示着血液肿瘤的治疗进入精准免疫疗法新阶段。然而CAR-T免疫疗法在临床应用中存在诸多问题，例如治疗周期长、价格高昂、产生脱靶效应、发生细胞因子释放综合征等，因此，需要扩展嵌合抗原受体的应用或提出改进措施来提升治疗效果。本文综述了CAR免疫细胞基因工程化改造新策略、原位编辑产生CAR-T的研究进展与应用，同时对体内递送基因药物的新方法进行了简要介绍，旨在为扩展和改进精准免疫疗法在AML中的应用提供新思路和理论依据。

关键词：急性髓系白血病基因编辑嵌合抗原受体原位编辑精准免疫疗法

基于穿透血脑屏障的siRNA纳米递药系统研究进展

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中国药学杂志 2024年第4期59卷 285-295页

作者：苏峰熊峰曹俊如储晓琴何广卫尹莉芳中国药科大学南京211198 安徽中医药大学合肥230012 合肥医工医药股份有限公司合肥230088 安徽医科大学合肥230032

近年来,中枢神经系统(central nervous system,CNS)疾病已经严重威胁了人类的生命健康,血脑屏障(blood-brain barrier,BBB)的存在阻止了大部分药物进入大脑,这使得CNS疾病的治疗成为当今医学和药学领域的重大难题。纳米技术的出现使得... 详细信息

近年来,中枢神经系统(central nervous system,CNS)疾病已经严重威胁了人类的生命健康,血脑屏障(blood-brain barrier,BBB)的存在阻止了大部分药物进入大脑,这使得CNS疾病的治疗成为当今医学和药学领域的重大难题。纳米技术的出现使得药物具有穿透BBB的潜力,小干扰RNA(small interfering RNA,siRNA)药物的快速发展也给CNS疾病患者带来了曙光,但是纳米载体向脑部递药会遇到许多障碍,作为siRNA纳米载体进行脑部递送的条件也非常苛刻。本文主要综述了脂基纳米粒、壳聚糖纳米粒、聚乙烯亚胺纳米粒、树状大分子纳米粒、纳米凝胶、纳米胶束、纳米乳、外泌体、细胞、siRNA缀合物等作为siRNA脑部递药系统的研究进展及优缺点,以期探寻一种合适的siRNA纳米递送系统,用于BBB的穿透。

关键词：血脑屏障小干扰RNA 纳米载体中枢神经系统

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黄体酮混悬注射剂药动学及体内外相关性研究

中国药科大学学报 2024年第2期55卷 217-223页

作者：刘兰岚蔡其霖张汶彦严真尹莉芳中国药科大学药学院药剂系南京210009 江苏省缓释智能制剂及关键功能性辅料开发与评价工程研究中心南京210009

探讨黄体酮混悬注射剂体外释放、体内药动学以及体内外相关性,以自制黄体酮混悬注射液为例,采用桨法和透析袋法测定3种不同粒径(3、5、7μm)的黄体酮混悬注射剂的体外释放曲线;以SD大鼠为实验动物,研究3种粒径黄体酮混悬注射剂的体内药... 详细信息

探讨黄体酮混悬注射剂体外释放、体内药动学以及体内外相关性,以自制黄体酮混悬注射液为例,采用桨法和透析袋法测定3种不同粒径(3、5、7μm)的黄体酮混悬注射剂的体外释放曲线;以SD大鼠为实验动物,研究3种粒径黄体酮混悬注射剂的体内药动学,并将血药浓度-时间曲线经Wagner-Nelson法处理后得到体内累积吸收曲线,与透析袋法所得体外累积释放曲线建立体内外相关性。结果表明,黄体酮混悬注射液采用桨法测定体外释放度时,20 min内均迅速释放85%以上,而采用透析袋法测定时分别在40、84、120 h达85%累积释放度。透析袋法所得体外释放趋势与体内释药趋势基本一致,相关系数大于0.95,具有较强的体内外相关性。本研究为长效混悬注射剂体内外相关性的建立提供参考。

关键词：黄体酮混悬注射剂体外释放药动学体内外相关性

Teaching Reform and Practice of Plant Growth Environment Course in the Context of Application Transformation Development

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Asian Agricultural Research 2017年第7期9卷 76-79页

作者： Yuyu ZHANG Jiani LIU Jingxiang HU Jinzhu HUA Liyuan YAO lifang yin Kunming University/Urban Characteristic Agriculture Engineering Technology Research Center of Yunnan Province/Key Laboratory of Characteristic Biological Resources Development and Utilization in Yunnan Province

Through the personnel training program,revising the syllabus,optimizing teaching contents,reforming teaching methods,strengthening practical teaching links and reforming examination methods,this paper explored the teaching reform and practice of Plant Growth Environment Course,in order to improve the teaching effect,stimulate learning interests of students,and cultivate application type talents meeting social demands.

关键词： Application transformation Plant growth environment Teaching reform