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Hyaluronic acid-based dual-responsive Nanomicelles mediated mutually synergistic photothermal and molecular targeting therapies

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Nano Research 2022年第7期15卷 6361-6371页

作者： Liangliang Cai Ronghua Ni Xiaofei Ma Rongrong Huang Zhiyuan Tang Jinqiu Xu Yong Han Yuehua Guo Zhifeng Gu Department of Pharmacy Affiliated Hospital of Nantong UniversityNantong 226001China Department of Radiation Oncology Affiliated Hospital of Nantong UniversityNantong 226001China Research Center of Clinical Medicine Affiliated Hospital of Nantong UniversityNantong 226001China Department of Rheumatology Affiliated Hospital of Nantong UniversityNantong 226001China

Precise clinical treatment of triple-negative breast cancer(TNBC)is an obstacle in clinic.Nanotechnology-assisted photothermal therapy(PTT)is a superior treatment modality for TNBC in terms of precision.However,thermoresistance arising from PTT and insufficient drug release from nanocarriers decrease the efficacy of PTT.AT13387 is a novel HSP90 inhibitor that can weaken thermoresistance and undergoing clinic II phase study,showing satisfactory antitumour activity through molecularly targeted therapy(MTT).Whereas,it has poor solubility.Hence hyaluronic acid and stearic acid were connected by hydrazone bonds and disulfide bonds,forming an amphipathic copolymer that could self-assembled into Nanomicelles,followed by encapsulating Cypate and AT13387.These Nanomicelles exhibited great features,including achieving mutually synergistic PTT/MTT for overcoming thermoresistance and promoting translocation of drugs,increasing the solubility of Cypate and AT13387,showing a pH/redox dual response that contributes to drug release,and having the ability of active targeting.Thus,the Nanomicelles developed in this study may be a promising strategy for the precise treatment of TNBC.

关键词： hyaluronic acid Nanomicelles dual responsive photothermal therapy molecular targeting therapy

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Targeted delivery of hyaluronic acid Nanomicelles to hepatic stellate cells in hepatic fibrosis rats

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Acta Pharmaceutica Sinica B 2020年第4期10卷 693-710页

作者： Wenhao Li Chuchu Zhou Yao Fu Tijia Chen Xing Liu Zhirong Zhang Tao Gong Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610064China

Hepatic fibrosis is one kind of liver diseases with a high mortality rate and incidence.The activation and proliferation of hepatic stellate cells(HSCs)is the most fundamental reason of hepatic fibrosis.There are no specific and effective drug delivery carriers for the treatment of hepatic fibrosis at present.We found that when hepatic fibrosis occurs,the expression of CD44 receptors on the surface of HSCs is significantly increased.Based on this finding,we designed silibinin-loaded hyaluronic acid(SLB-HA)micelles to achieve the treatment of hepatic fibrosis.Meanwhile,we constructed liver fibrosis rat model using Sprague-Dawley rats.We demonstrated that HA micelles had specific uptake to HSCs in vitro while avoiding the distribution in normal liver cells and the phagocytosis of macrophages.Importantly,HA micelles showed a significant liver targeting effect in vivo,especially in fibrotic liver which highly expressed CD44 receptors.In addition,SLB-HA micelles could selectively kill activated HSCs,having an excellent anti-hepatic fibrosis effect in vivo and a significant sustained release effect,and also had a good biological safety and biocompatibility.Overall,HA micelles represented a novel nanomicelle system which showed great potentiality in anti-hepatic fibrosis drugs delivery.

关键词： Nanomicelles Hyaluronic acid Hepatic stellate cells Hepatic fibrosis Silibinin

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Reduction-sensitive Nanomicelles:Delivery celastrol for retinoblastoma cells effective apoptosis

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Chinese Chemical Letters 2021年第3期32卷 1046-1050页

作者： Zhihua Guo Liuqi Shi Huayang Feng Fan Yang Zhanrong Li Junjie Zhang Lin Jin Jingguo Li Henan Eye Hospital Henan Provincial People’s HospitalZhengzhou University People’s HospitalZhengzhou 450003China School of Materials Science and Engineering Zhengzhou UniversityZhengzhou 450001China

Celastrol,a Chinese herbal medicine,has exhibited anticancer activity in many types of cancer cells.However,the further clinical application of celastrol is restricted by its poor water solubility and serious side effects.Furthermore,the apoptosis mechanism of tumor cells induced by celastrol has not been exhausted yet.In this study,we developed a reduction sensitive polymeric vector for tumor-targeted celastrol delivery.And our researches indicated that the celastrol could be delivered by reductionsensitive nanomedicine(RSNMs)with a controlled release strategy.Meanwhile,the cell uptake results indicated that excellent reduction-sensitive behavior of RSNMs could effectively accelerate celastrol into the human retinoblastoma(RB)cell.The cell cytotoxicity assay demonstrated that celastrol inhibited proliferation of human RB Y79 cells growth in a dose-dependent manner.Furthermore,the results of flow cytometry and terminal dUTP nick-end labeling(TUNEL)staining showed that celastrol induced apoptosis of the RB Y79 cells,and revealed a time-dependent increase in apoptosis induction of RB Y79 cells.The results of western blotting showed that celastrol induced the apoptosis of human RB Y79 cells involving the activation of caspase-3 and caspase-9.In conclusion,our results revealed that RSNMs may be utilized as a novel therapy for retinoblastoma.

关键词： Reduction-sensitive Nanomicelles Retinoblastoma Celastrol Cell apoptosis

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One-step self-assembled Nanomicelles for improving the oral bioavailability of nimodipine

One-step self-assembled nanomicelles for improving the oral ...

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2018年第十二届中国药物制剂大会

作者：罗静雯 Zhi-Rong Zhang Tao Gong Yao Fu Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology West China School of Pharmacy Sichuan University

Our study aimed to develop a self-assembled nanomicelle for oral administration of nimodipine(NIM) with poor water solubility. The NIM-loaded self-assembled Nanomicelles were prepared according to the one-step self-assembled technique. Briefly, NIM and Solutol HS15 were added in the flask by gently stirring at 60°C for 30 minutes. Using Solutol HS15, the NIM loaded self-assembled Nanomicelles displayed a near spherical morphology with a narrow size distribution of 12.57 ± 0.21 nm(PDI = 0.071 ± 0.011). Compared with Nimotop(NIM tablets), the intestinal absorption of NIM from NIM nanomicelle in rats was improved by 3.13-and 2.25-fold in duodenum and jejunum at 1 h after oral administration. The cellular transport of NIM nanomicelle in Caco-2 cell monolayers was significantly enhanced compared to Nimotop?. Regarding the transport pathways, clathrin, lipid raft/caveolae and macropinocytosis mediated the cell uptake of NIM Nanomicelles, while P-glycoprotein and endoplasmic reticulum/Golgi complex(ER/Golgi) pathways were involved in the exocytosis. Pharmacokinetic study showed that the AUC of NIM Nanomicelles was 3.72-fold that of Nimotop? via oral administration in rats. Moreover, the NIM concentration in brain from NIM nanomicelle was dramatically improved. Therefore, Solutol HS15 based self-assembled Nanomicelles represent a promising delivery system to enhance the oral bioavailability of NIM.

关键词： Nanomicelles Self-assembly Nimodipine Oral bioavailability Transport mechanism

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Hyaluronic acid-based levofloxacin Nanomicelles for nitric oxide-triggered drug delivery to treat bacterial infections

Hyaluronic acid-based levofloxacin nanomicelles for nitric o...

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中国化学会第三届全国糖化学会议

作者： Chunbo Lu Yao Xiao Yinyin Liu Feifei Sun Yuanhao Qiu Haibo Mu Jinyou Duan College of Chemistry ＆ Pharmacy Shaanxi Key Laboratory of Natural Products ＆ Chemical BiologyNorthwest A＆F University

Antibiotics are powerful weapons to fight against bacterial infections,while most of them lack of selective targeting towards pathological site which could restrict their antibacterial efficacy.To overcome this challenge,an antimicrobial levofloxacin（LF）was conjugated onto hyaluronic acid（HA） moieties via an o-phenylenediamine linker to prepare a NO-sensitive nanosystem（HA-NO-LF） in this study.The HA-NO-LF Nanomicelles could enter host cells via a CD44 mediated endocytosis and release drug gradually upon exposure to endogenous NO.Furthermore,the more promising therapeutic effect of the Nanomicelles in ameliorating inflammatory levels was observed in a mouse pneumonia model than that of LF.These results suggest that the HA-NO-LF Nanomicelles may exert potent curative effect in infectious diseases.

关键词： Hyaluronic acid NO-sensitivity Nanomicelles Drug release

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A self-assembling prodrug nanosystem to enhance metabolic stability and anticancer activity of gemcitabine

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Chinese Chemical Letters 2022年第5期33卷 2481-2485页

作者： Mei Cong Guangling Xu Shaoyou Yang Jing Zhang Wenzheng Zhang Dinesh Dhumal Erik Laurini Kaiyue Zhang Yi Xia Sabrina Pricl Ling Peng Weidong Zhao School of Pharmacy Xinxiang Medical UniversityXinxiang 453003China Henan Key Laboratory of Immunology and Targeted Drugs School of Laboratory MedicineXinxiang Medical UniversityXinxiang 453003China Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine School of Laboratory MedicineXinxiang Medical UniversityXinxiang 453003China Aix-Marseille Université CNRSCenter Interdisciplinaire de Nanoscience de MarseilleUMR 7325Equipe Labellisépar La LigueMarseille 13288France Chongqing Key Laboratory of Natural Product Synthesis and Drug Research School of Pharmaceutical SciencesChongqing UniversityChongqing 401331China Molecular Biology and Nanotechnology Laboratory Department of Engineering and ArchitectureUniversity of TriesteTrieste 34127Italy Department of General Biophysics Faculty of Biology and Environmental ProtectionUniversity of LodzLodz 90-236Poland

Self-assembly is a powerful approach in molecular engineering for biomedical applications,in particu-lar for creating self-assembling prodrugs.Here,we report a self-assembling prodrug of the anticancer drug gemcitabine(Gem)based on amphiphilic dendrimer approach.The prodrug reported in this study demonstrates high drug loading(40%)and robust ability to self-assemble into small Nanomicelles,which increase the metabolic stability of Gem and enable entry into cells via endocytosis,hence bypassing transport-mediated uptake.In addition,this prodrug nanosystem exhibited an effective pH-and enzyme-responsive release of Gem,resulting in enhanced anticancer activity and reduced toxicity.Harboring ad-vantageous features of both prodrug-and nanotechnology-based drug delivery,this self-assembling Gem prodrug nanosystem constitutes a promising anticancer candidate.This study also offers new perspectives of the amphiphilic dendrimer nanoplatforms for the development of self-assembling prodrugs.

关键词： Self-assembling prodrug Gemcitabine Amphiphilic dendrimer Anticancer candidate Nanomicelles

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