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Elaborately engineering of lipid nanoparticle for targeting delivery of siRNA and suppressing acute liver injury

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Chinese Chemical Letters 2024年第2期35卷 323-328页

作者： Qiu Wang qikun jiang Dan Li Zimeng Yang Lin Gao Fan Liu Chang Li Yao Feng Zhonggui He Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Kangya of Ningxia Pharmaceutical Co.Ltd. Yinchuan 750000China

Small interfering RNA(siRNA)-based gene silencing has been considered as a potential therapy modality against inflammatory ***,the effective delivery of siRNA to desired destination still remains challenging due to poor stability,high molecular weight and negative ***,ionizable lipid nanoparticle(LNP)has been extensively used as vector for effective delivery of ***,we report a mannose-modified LNP(M-MC_(3) LNP@TNFα)loading tumor necrosis factorα(TNFα)siRNA for targeting liver macrophages,achieving effectively inhibit acute liver *** M-MC_(3) LNP@TNFαnot only increases the internalization of LNP by macrophages,but also enhances the gene silencing efficiency of TNFαin ***,the M-MC_(3) LNP@TNFαexhibits higher accumulation in liver of healthy mice than that of MC_(3) LNP@TNFα(un-modified LNP)owing to the targeting effect of *** expected,the M-MC_(3) LNP@TNFαsignificantly suppresses the expression of TNFαand ameliorates liver damage in acute liver injury *** a LNP targeting siRNA delivery holds great potential for the treatment of diseases associated with liver in the future.

关键词： Lipid nanoparticle Targeting siRNA delivery Acute liver injury Gene silencing Tumor necrosis factorα

Emerging non-antibody‒drug conjugates (non-ADCs) therapeutics of toxins for cancer treatment

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Acta Pharmaceutica Sinica B 2024年第4期14卷 1542-1559页

作者： Xiaolan Xu Jiaming Zhang Tao Wang Jing Li Yukang Rong Yanfang Wang Chenxia Bai Qing Yan Xiaohua Ran Yingli Wang Tianhong Zhang Jin Sun qikun jiang Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China School of Education University of NottinghamNottingham NG72RDUK Department of Pharmacy Linyi People's HospitalShandong UniversityLinyi 276000China State Key Laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100871China

The non-selective cytotoxicity of toxins limits the clinical relevance of the *** recent years,toxins have been widely used as warheads for antibody-drug conjugates(ADCs)due to their eff-cient killing activity against various cancer *** ADCs confer certain targeting properties to the toxins,low drug loading capacity,possible immunogenicity,and other drawbacks also limit the po-tential application of ***,non-ADC delivery strategies for toxins have been extensively *** further understand the application of toxins in anti-tumor,this paper provided an over-view of prodrugs,nanodrug delivery systems,and biomimetic drug delivery *** addition,toxins and their combination strategies with other therapies were ***,the prospect and challenge of toxins in cancertreatmentwerealso summarized.

关键词： Toxins Non-antibody-drug conjugates Delivery strategies Prodrugs Nano drug delivery systems Biomimetic drugdelivery systems Combination strategies Cancer treatment

Arginine-peptide complex-based assemblies to combat tumor hypoxia for enhanced photodynamic therapeutic effect

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Nano Research 2022年第6期15卷 5183-5192页

作者： Yanxian Hou Yafei Kuang qikun jiang Shuang Zhou jiang Yu Zhonggui He Jin Sun Shenyang Pharmaceutical University No.103Wenhua RoadShenyang 110016China

Tumor hypoxia is one of the major factors restricting the photodynamic therapy(PDT)*** address this problem,we designed an arginine-peptide complex,namely Fluorenylmethoxycarbonyl-Leucine-Leucine-Leucine-Arginine-OH(Fmoc-L_(3)-Arg),which is able to co-assemble with 5,10,15,20-Tetrakis(4-hydroxyphenyl)porphyrin(THPP)into stable nanoparticles(NPs)with uniform and spherical *** THPP/Fomc-L_(3)-Arg NPs were ultra-sensitive to tumorous acidic and oxidative conditions,and could rapidly release photosensitizers in tumor ***,the co-loaded Fmoc-L_(3)-Arg could efficiently generate nitric oxide(NO),inhibiting mitochondrial cellular respiration and increasing oxygen in tumor cells to support the profound improvement of reactive oxygen species(ROS)yield and PDT *** intravenous injection,the THPP/Fomc-L_(3)-Arg NPs greatly accumulated at tumor tissue and significantly inhibited tumor growth upon *** conclusion,such an arginine-peptide complex-based nanoassembly addresses the inevitable problem of hypoxia-induced tumor resistance to PDT.

关键词： arginine co-assembly nitric oxide tumor hypoxia photodynamic efficacy

Preparation and characterization of solidified oleanolic acid–phospholipid complex aiming to improve the dissolution of oleanolic acid

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Asian Journal of Pharmaceutical Sciences 2016年第2期11卷 241-247页

作者： Xiaoxu Yang qikun jiang Ping Du Juanhang Zhao Tianhong Zhang School of Pharmacy Shenyang Pharmaceutical University

The purpose of this study was to prepare the oleanolic acid–phospholipid complex (OAPC) and then solidify it employing fumed silica by simple solvent evaporation technique to improve dissolution rate of oleanolic acid and oleanolic acid–phospholipid complex. The process of OA-PC was optimized and the type and proportion of fumed silica were studied by dissolution text. The structures of the phospholipid complex and solidified powder were also characterized by differential scanning calorimetry, X-ray diffraction, and scanning electron microscope. In the dissolution tests, OA from solidified powder was further released compared with that from pure OA and OA-PC in different kinds of dissolution media. These results suggest that the method of preparing solidified powder of oleanolic acid–phospholipid complex is suitable for enhancing the dissolution rate of OA and OA-PC.

关键词： Oleanolic acid Phospholipid complex Fumed silica Dissolution

Emerging nanomedicine and prodrug delivery strategies for the treatment of inflammatory bowel disease

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Chinese Chemical Letters 2022年第10期33卷 4449-4460页

作者： Mengchi Sun Weiyue Ban Hao Ling Xiang Yu Zhonggui He qikun jiang Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Huzhou Central Hospital Affiliated Huzhou HospitalZhejiang University School of MedicineAffiliated Central Hospital Huzhou UniversityHuzhou 110016China

Inflammatory bowel disease(IBD)is a chronic and recurrent disease of the gastrointestinal tract,mainly including Crohn's disease(CD)and ulcerative colitis(UC).However,current approaches against IBD do not precisely deliver drugs to the inflammatory site,which leads to life-long medication and serious side effects that can adversely impact patients’*** is necessary to construct optimal drug delivery systems(DDSs)that can target drugs to the region of inflammation,thereby improve therapeutic efficacy and reduce side *** the burgeoning development of nanotechnology-based nanomedicines(NMs)and prodrug strategy,remarkable progresses in the treatment of IBD have been made in recent ***,the latest advances are outlined at the intersection of IBD treatment and nanotherapeutics as well as prodrug ***,the pathophysiological microenvironment of inflammatory sites of IBD is introduced in order to rationally design potential NMs and ***,the necessity of NMs for the IBD therapy is elaborated,and the representative nanotherapeutics via passive targeted and active targeted NMs developed to treat the IBD are ***,the emerging prodrug-based therapeutics are summarized,including 5-aminosalicylic acid-,amino acid-,and carbohydrate-conjugated ***,the design considerations and perspectives of these NMs and prodrugs-driven IBD therapeutics in the clinical translation are spotlighted.

关键词： Inflammatory bowel disease(IBD) Nanotechnology-based nanomedicines(NMs) Prodrug strategy Pathophysiological microenvirnoment Passive targeted and active targeted NMs

Self-adaptive non-covalent albumin-binding near-infrared probe conjugates enabling precise sentinel lymph node metastasis illumination and primary tumor imaging

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Nano Research 2023年第2期16卷 3010-3020页

作者： Qiu Wang qikun jiang Dan Li Chang Li Yao Feng Zimeng Yang Zhonggui He Cong Luo Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Kangya of Ningxia Pharmaceutical Co. LtdYinchuan 750000China

Tumor sentinel lymph node(SLN)metastasis plays a vital role in tumor staging and therapeutic decision-making ***,precise diagnosis of primary tumors and lymphatic metastases is still hindered by low imaging resolution and poor photostability of fluorescent ***,we report three novel IR820-fatty acid(FA)conjugates(IR-OA,IR-LA,and IR-PA)for precise lymphatic metastasis illumination and primary tumor *** IR-FA conjugates are able to non-covalently bound to albumin in vivo,and the fluorescence quantum yield is significantly enhanced after incubation with bovine serum albumin(BSA)in ***,the BSA-IR-FA conjugates display large Stokes shift(>120 nm),dramatically improving in vivo imaging *** them,IR-PA demonstrates distinct advantage over IR-OA,IR-LA,and IR-maleimide(MAL)(fluorescent probe previously reported by our group)in terms of fluorescence quantum yield,photostability,and imaging *** a result,IR-PA exhibits satisfactory imaging results with high fluorescence intensity and imaging resolution in sentinel lymph node metastasis illumination and primary tumor *** findings provide a self-adaptive albumin-binding near-infrared probe conjugate for accurate diagnosis of primary tumors and lymphatic metastases.

关键词： near-infrared probe conjugates non-covalent albumin-binding fluorescence imaging sentinel lymph node metastasis illumination primary tumor diagnosis

Recent progress of hypoxia-modulated multifunctional nanomedicines to enhance photodynamic therapy:opportunities,challenges, and future development

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1382-1396页

作者： Yixin Sun Dongyang Zhao Gang Wang Yang Wang Linlin Cao Jin Sun qikun jiang Zhonggui He Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China School of Pharmacy Guangxi University of Chinese MedicineNanning 530200China Department of Pharmaceutics the Second Hospital of Dalian Medical UniversityDalian 116023China

Hypoxia, a salient feature of most solid tumors, confers invasiveness and resistance to the tumor cells. Oxygen-consumption photodynamic therapy(PDT) suffers from the undesirable impediment of local hypoxia in tumors. Moreover, PDT could further worsen hypoxia. Therefore, developing effective strategies for manipulating hypoxia and improving the effectiveness of PDT has been a focus on antitumor treatment. In this review, the mechanism and relationship of tumor hypoxia and PDT are ***, we highlight recent trends in the field of nanomedicines to modulate hypoxia for enhancing PDT, such as oxygen supply systems, down-regulation of oxygen consumption and hypoxia ***, the opportunities and challenges are put forward to facilitate the development and clinical transformation of PDT.

关键词： medicines Oxygen challenges

Structurally defined tandem-responsive nanoassemblies composed of dipeptide-based photosensitive derivatives and hypoxia-activated camptothecin prodrugs against primary and metastatic breast tumors

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Acta Pharmaceutica Sinica B 2022年第2期12卷 952-966页

作者： Mengchi Sun Hailun jiang Tian Liu Xiao Tan qikun jiang Bingjun Sun Yulong Zheng Gang Wang Yang Wang Maosheng Cheng Zhonggui He Jin Sun Wuya College of Innovation Shenyang Pharmaceutical UniversityShenyang 110016China Key Laboratory of Structure-Based Drug Design and Discovery Shenyang Pharmaceutical UniversityMinistry of EducationShenyang 110016China School of Materials Science and Engineering Ocean University of ChinaQingdao 266100China College of Pharmacy Guangxi University of Chinese MedicineNanning 530200China

Substantial progress in the use of chemo-photodynamic nano-drug delivery systems(nanoDDS) for the treatment of the malignant breast cancer has been achieved. The inability to customize precise nanostructures, however, has limited the therapeutic efficacy of the prepared nano-DDS to date. Here,we report a structurally defined tandem-responsive chemo-photosensitive co-nanoassembly to eliminate primary breast tumor and prevent lung metastasis. This both-in-one co-nanoassembly is prepared by assembling a biocompatible photosensitive derivative(pheophorbide-diphenylalanine peptide, PPADA) with a hypoxia-activated camptothecin(CPT) prodrug [(4-nitrophenyl) formate camptothecin, NCPT]. According to computational simulations, the co-assembly nanostructure is not the classical core-shell type, but consists of many small microphase regions. Upon exposure to a 660 nm laser,PPA-DA induce high levels of ROS production to effectively achieve the apoptosis of normoxic cancer cells. Subsequently, the hypoxia-activated N-CPT and CPT spatially penetrate deep into the hypoxic region of the tumor and suppress hypoxia-induced tumor metastasis. Benefiting from the rational design of the chemo-photodynamic both-in-one nano-DDS, these nanomedicines exhibit a promising potential in the inhibition of difficult-to-treat breast tumor metastasis in patients with breast cancer.

关键词： Chemo-photodynamic Tandem-responsive Both-in-one co-nanoassembly Computational simulations Camptothecin Pyropheophorbide Reactive oxygen species Breast tumor metastasis

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 ***,potential application of MCT1 to facilitate the oral delivery is still *** 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 ***,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 *** 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 *** 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