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Near-infrared light(NIR)-responsive nanoliposomes combining photodynamic therapy and chemotherapy for breast tumor control

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Chinese Chemical Letters 2022年第4期33卷 1923-1926页

作者： Guangzhao Lu Xiqing Gao He Zhang Yeye Zhang Yuan Yu Zhiguo Sun Wei Li Wei Wu Ying Lu Hao Zou department of Pharmaceutical Sciences School of PharmacyNaval Medical UniversityShanghai 200433China department of pharmacy Zhongshan HospitalFudan UniversityShanghai 200032China Laboratory of Nano Biomedicine&International Joint Cancer Institute Naval Medical UniversityShanghai 200433China Key Laboratory of Smart Drug Delivery of MOE School of PharmacyFudan UniversityShanghai 200032China

Light-responsive carriers have been used for the controlled release of antitumor drugs in recent ***, most light-responsive vectors require high-energy ultraviolet or visible light to achieve local drug release, and ultraviolet light would cause cellular damage. Near-infrared light has a deeper tissuepenetration depths and minimal harm to tissues, but it is difficult to cleave the chemical bond *** aim of this study is to develop a novel near-infrared light-responsive carrier for local release of antitumor drugs. Unsaturated phospholipids can be oxidized by singlet oxygen to achieve liposomal drug release, and singlet oxygen can be produced by photosensitizer under light irradiation. A new near-infrared light-responsive nanoliposome was designed that imparts light-triggered local drug release. Nanoliposomes, which were composed of matrix phospholipids and unsaturated phospholipids, were prepared by ammonium sulfate gradient method, and loaded with antitumor drug doxorubicin(DOX) and photosensitizer 1,4,8,11,15,18,22,25-octabutoxypalladium phthalocyanine. Under near-infrared light, photosensitizers could produce singlet oxygen and damage tumor cells by photodynamic therapy. Simultaneously, the unsaturated phospholipids were oxidized by singlet oxygen and result in DOX release, causing sustained cell damage by chemotherapy. Near-infrared light-responsive nanoliposomes exhibit enhanced anticancer activity owing to combined treatment of photodynamic therapy and chemotherapy. A new platform is thus offered for designing effective intracellular drug-release systems, holding great promise for future cancer therapy.

关键词： Near-infrared light Unsaturated phospholipids Nanoliposomes Photosensitizer Singlet oxygen

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Inhibition of post-trabeculectomy fibrosis via topically instilled antisense oligonucleotide complexes co-loaded with fluorouracil

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1754-1768页

作者： Kuan Jiang Junyi Chen Lingyu Tai Chang Liu Xishan Chen Gang Wei Weiyue Lu Weisan Pan Key Laboratory of Smart Drug Delivery Ministry of EducationDepartment of PharmaceuticsSchool of PharmacyFudan UniversityShanghai 201203China department of Ophthalmology Eye&ENT HospitalFudan UniversityShanghai 200031China school of pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China The Institutes of Integrative Medicine of fudan university Shanghai 200040China Shanghai Engineering Research Center of Immunotherapeutics Shanghai 201203China

Trabeculectomy is the mainstay of surgical glaucoma treatment,while the success rate was unsatistying due to postoperative scarring of the filtering *** countermeasures for scar prevention are intraoperative intervention or repeated subconjunctival ***,we designed a codelivery system capable of transporting fluorouracil and anti-TGF-β2 oligonucleotide to synergistically inhibit fibroblast proliferation via topical *** co-delivery system was built based on a cationic dendrimer core(PAMAM),which encapsulated fluorouracil within hydrophobic cavity and condensed oligonucleotide with surface amino groups,and was further modified with hyaluronic acid and cell-penetrating peptide *** co-delivery system was self-assembled into nanoscale complexes with increased cellular uptake and enabled efficient inhibition on proliferation of fibroblast *** vivo studies on rabbit trabeculectomy models further confirmed the anti-fibrosis efficiency of the complexes,which prolonged survival time of filtering blebs and maintained their height and extent during wound healing process,exhibiting an equivalent effect on scar prevention compared to intraoperative infiltration with *** observation by immunohistochemistry staining and quantitative analysis by Western blotting both suggested that TGF-β2 expression was inhibited by the co-delivery *** study provided a potential approach promising to guarantee success rate of trabeculectomy and prolong survival time of filtering blebs.

关键词： Trabeculectomy Fibrosis prevention Gene delivery Penetratin Fluorouracil

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The Role of CARD9 in Metabolic Diseases

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Current Medical Science 2020年第2期40卷 199-204页

作者： Cheng TIAN Ya-li TUO Yi LU Chuan-rui XU Ming XIANG department of pharmacology School of PharmacyTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China

Caspase recruitment domain containing protein 9(CARD9)is an adaptor protein that plays a critical role in pattern recognition receptors(PRRs)-mediated activation of NF-kB and mitogen-activated protein kinase(MAPK).This elicits initiation of the pro・inflammatory cytokines and leads to inflammatory responses,which has been recognized as a critical contributor to chronic *** researches demonstrate that CARD9 is strongly associated with metabolic diseases,such as obesity,insulin resistance,atherosclerosis and so *** this review,we summarize CARD9 signaling pathway and the role of CARD9 in metabolic diseases.

关键词： caspase recruitment domain containing protein 9 pattern recognition receptors metabolic diseases

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Brain tumor-targeted drug delivery strategies

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Acta Pharmaceutica Sinica B 2014年第3期4卷 193-201页

作者： Xiaoli Wei Xishan Chen Man Ying Weiyue Lu department of Pharmaceutics School of PharmacyFudan University&Key Laboratory of Smart Drug Delivery(Fudan University)Ministry of EducationShanghai 201203China

Despite the application of aggressive surgery,radiotherapy and chemotherapy in clinics,brain tumors are still a difficult health challenge due to their fast development and poor *** tumor-targeted drug delivery systems,which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue,are a promising new approach to brain tumor *** brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues,potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug *** this review,we briefly describe the physiological characteristics of brain tumors,including blood–brain/brain tumor barriers,the tumor microenvironment,and tumor stem *** also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.

关键词： Barriers targeting Tumor micro environment Tumor cells Systematic targeted drug delivery

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Substance P-modified human serum albumin nanoparticles loaded with paclitaxel for targeted therapy of glioma

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Acta Pharmaceutica Sinica B 2018年第1期8卷 85-96页

作者： Chunhui Ruan Lisha Liu Yifei Lu Yu Zhang Xi He Xinli Chen Yujie Zhang Qinjun Chen Qin Guo Tao Sun Chen Jiang Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Medical NeurobiologyDepartment of Pharmaceutics School of Pharmacy Fudan University

The blood–brain barrier(BBB) and the poor ability of many drugs to cross that barrier greatly limits the efficacy of chemotherapies for glioblastoma multiforme(GBM). The present study exploits albumin as drug delivery vehicle to promote the chemotherapeutic efficacy of paclitaxel(PTX) by improving the stability and targeting efficiency of PTX/albumin nanoparticles(NPs). Here we characterize PTX-loaded human serum albumin(HSA) NPs stabilized with intramolecular disulfide bonds and modified with substance P(SP) peptide as the targeting ligand. The fabricated SP-HSA-PTX NPs exhibited satisfactory drug-loading content(7.89%) and entrapment efficiency(85.7%) with a spherical structure(about 150 nm) and zeta potential of -12.0 mV. The in vitro drug release from SP-HSA-PTX NPs occurred in a redox-responsive manner. Due to the targeting effect of the SP peptide, cellular uptake of SP-HSA-PTX NPs into brain capillary endothelial cells(BCECs) and U87 cells was greatly *** low IC_(50), prolonged survival period and the obvious pro-apoptotic effect shown by TUNEL analysis all demonstrated that the fabricated SP-HSA-PTX NPs showed a satisfactory anti-tumor effect and could serve as a novel strategy for GBM treatment.

关键词： Human serum albumin Paclitaxel Drug delivery Substance P Blood–brain barrier Glioma

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GLUT1-mediated effective anti-miRNA21 pompon for cancer therapy

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Acta Pharmaceutica Sinica B 2019年第4期9卷 832-842页

作者： Qin Guo Chao Li Wenxi Zhou Xinli Chen Yu Zhang Yifei Lu Yujie Zhang Qinjun Chen Donghui Liang Tao Sun Chen Jiang Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Medical Neurobiology Department of Pharmaceutics School of Pharmacy Fudan University

Oncogenic microRNAs are essential components in regulating the gene expression of cancer cells. Especially miR21, which is a major player involved of tumor initiation, progression, invasion and metastasis in several cancers. The delivery of anti-miR21 sequences has significant potential for cancer treatment. Nevertheless, since anti-miR21 sequences are extremely unstable and they need to obtain certain concentration to function, it is intensely difficult to build an effective delivery system for *** purpose of this work is to construct a self-assembled glutathione(GSH)-responsive system with tumor accumulation capacity for effective anti-miR21 delivery and cancer therapy. A novel drug delivery nanosphere carrying millions of anti-miR21 sequences was developed through the rolling circle transcription(RCT) method. GSH-responsive cationic polymer polyethyleneimine(pOEI) was synthesized to protect the nanosphere from degradation by Dicer or other RNase in normal cells and optimize the pompon-like nanoparticle to suitable size. Dehydroascorbic acid(DHA), a targeting molecule, which is a substrate of glucose transporter 1(GLUT 1) and highly expressed on malignant tumor cells, was connected to pOEI through PEG, and then the polymer was used for contracting a RNA nanospheres into nanopompons. The anti-miR21 nanopompons showed its potential for effective cancer therapy.

关键词： MiRNA21 Dehydroascorbic acid Rolling circle transcription Self-assembly RNAi nanoparticle Tumor-targeting Nanomedicine Cancer treatment

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p-Hydroxybenzoic acid (p-HA) modified polymeric micelles for brain-targeted docetaxel delivery

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Chinese Science Bulletin 2013年第21期58卷 2651-2656页

作者： ZHANG ZhiXin WEI XiaoLi ZHANG XiaoYu LU WeiYue department of Pharmaceutics School of Pharmacy Fudan University Key Laboratory of Smart Drug Delivery (fudan university) Ministry of Education & The Chinese People's Liberation Army State Key Laboratory of Molecular Engineering of Polymers (fudan university)

Chemotherapies for brain diseases have been hampered due to the inability of transport of drug across the blood-brain barrier (BBB). In order to overcome the barrier, p-hydroxybenzoic acid (p-HA), a small molecule of benzamide analogue, was used as a ligand for brain-targeted drug delivery. The p-HA was conjugated to PEG-DSPE to form p-HA-PEG-DSPE. Docetaxel-loaded polymeric micelles were prepared by a thin-film hydration method using methoxy-poly(ethylene glycol)-distearoylphosphatidyl- ethanolamine (mPEG 2000 -DSPE) as a carrier and the p-HA-PEG-DSPE as a brain targeted material. The prepared micelles showed spherical with a mean diameter of (18±3) nm. Encapsulation efficiency and drug loading were (83.49±1.3)%, (7.7±1.2)% for un- modified micelles and (80.65±1.6)%, (7.47±1.8)% for p-HA-modified micelles, respectively. In vitro cellular uptake experiments showed that the p-HA-modified micelles increased BCECs cellular uptake by 1.2 times compared to the unmodified micelles. Ex vivo near-infrared fluorescence imaging showed that brain uptake of the p-HA-modified micelles was 1.3-1.8 times higher than that of the unmodified micelles. In vitro cytotoxicity assay against glioblastoma cell U87 MG showed that inhibition rate of the p-HA-modified micelles increased by 1.2 times compared to that of the unmodified micelles and 1.7 times compared to that of DTX. Survival time of nude mice bearing intracranial glioblastoma showed that the lifetime of saline group, Taxotere group, mPEG-DSPE/DTX micelles group and p-HA-PEG-DSPE/DTX micelles group was 22, 27, 32 and 45.8 d, representively, which indicated that anti-glioblastoma activity of DTX could be significantly enhanced by the p-HA-modified polymeric micelles. These results demonstrated that the p-HA-modified micelles could be a promising brain-targeted drug delivery system for hydrophobic drugs against glioblastoma.

关键词：聚合物胶束改性聚合物对羟基苯甲酸多西紫杉醇脑疾病靶向给药系统细胞摄取胶质细胞

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Biomacromolecules as carriers in drug delivery and tissue engineering

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Acta Pharmaceutica Sinica B 2018年第1期8卷 34-50页

作者： Yujie Zhang Tao Sun Chen Jiang Key Laboratory of Smart Drug Delivery Ministry of Education State Key Laboratory of Medical Neurobiology Department of Pharmaceutics School of Pharmacy Fudan University

Natural biomacromolecules have attracted increased attention as carriers in biomedicine in recent years because of their inherent biochemical and biophysical properties including renewability,nontoxicity, biocompatibility, biodegradability, long blood circulation time and targeting ability. Recent advances in our understanding of the biological functions of natural-origin biomacromolecules and the progress in the study of biological drug carriers indicate that such carriers may have advantages over synthetic material-based carriers in terms of half-life, stability, safety and ease of manufacture. In this review, we give a brief introduction to the biochemical properties of the widely used biomacromoleculebased carriers such as albumin, lipoproteins and polysaccharides. Then examples from the clinic and in recent laboratory development are summarized. Finally the current challenges and future prospects of present biological carriers are discussed.

关键词： Biomacromolecule Protein Polysaccharide Drug delivery Tissue engineering

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Role and mechanism of ORM in adipose tissue fibrosis and insulin resistance in obese mice

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中国药理学与毒理学杂志 2019年第10期 786-787页

作者： WANG Peng-yuan QIN Zhen ZHANG Yu FENG Jia-yi HU Bo-han WEI Jie SU Ding-feng SUN Yang LIU Xia department of pharmacology School of Pharmacy Second Military Medical University department of Clinical pharmacy School of Pharmacy Second Military Medical University

OBJECTIVE During the development of obesity, adipose tissue fibrosis occurs as a hallmark of adipose tissue dysfunction, leading to metabolic dysfunction such as insulin resistance. We previously reported adipokine orosomucoid（ORM） could be a negative feedback signal in energy homeostasis, and its level was significantly elevated in response to obese state. Here we aimed to explore the role of ORM in adipose tissue fibrosis and insulin resistance during obesity, and its possible mechanism. METHODS MRI was used to assess the distribution of fat and the fat or lean mass in ORM1 knockout mice. HE staining, masson staining, qPCR, and Western blotting were used to assess the fibrosis status of mice. And we used glucose tolerance test（GTT） and insulin tolerance test（ITT） to evaluate the regulation of blood glucose and insulin sensitivity in mice. Leptin receptor-deficient db/db mice and high fat diet-induced obese mice were used as obese models. 3 T3-L1 cells were used in vitro. RESULTS ORM1-deficient mice exhibited an obese phenotype with adipose tissue fibrosis and insulin resistance. The m RNA and protein levels of the fibrogenic genes encoding Col1a1, Col3a1, Col6a3 and ECM regulators MMP-2, MMP-13, MMP-14 TIMP-1,TIMP-2, and TIMP-3 in ORM1-deficient mice were significantly increased. GTT and ITT showed abnormal glucose tolerance and insulin resistance in ORM1-deficient ***, exogenous administration of ORM attenuated excessive expression of type Ⅵ collagen, MMP-13 and TIMP-1 induced by adipose fibrosis in obese db/db（lep Rdeficient） mice. GTT and ITT showed ORM treatment improved insulin resistance in db/db mice. Moreover,ORM synergized with insulin to activate Akt in adipose tissue of db/db mice. Further studies found that ORM could bind to C-C chemikine receptor 5（CCR5） and ORM improves insulin resistance in high fat diet-induced obese mice, which could be blocked by maraviroc, an antagonist against CCR5. In addition, the effect of ORM in synergy with insul

关键词： ORM adipose tissue fibrosis insulin resistance CCR5

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Facile and diverse logic circuits based on dumbbell DNA-templated fluorescent copper nanoclusters and S1 nuclease detection

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Chinese Chemical Letters 2022年第5期33卷 2711-2714页

作者： Zefeng Gu Anchen Fu Ru Qiu Ru Sun Zhijuan Cao Shanghai Key Laboratory of Bioactive Small Molecules&department of Pharmaceutical Analysis School of PharmacyFudan UniversityShanghai 201203China

DNA-based logic gates promote the development of molecular computing and show enormous potential in the fields of nanotechnology and biotechnology. Dumbbell oligonucleotides(DNA) with poly-thymine(poly-T) loops and a nicked random double strand have been demonstrated to be an efficient template for the formation of fluorescent copper nanoclusters(Cu NCs) in our previous work. Herein, a new platform technology is presented with which to construct molecular logic gates by employing Cu NCs probe as a basic output generator, coupling of functional nucleases as the inputs. Two dumbbell DNAs are used with the difference in stem length(8 bp and 16 bp, respectively). The degradation of DNA templates can be tuned by various nucleic acid enzymes, single-stranded nuclease(S1), double-stranded specific nuclease(DSN), E. coli DNA ligase, exonucleases Ⅰ and Ⅲ. Briefly, S1 can digest both DNA templates, while the cleavage ability of DSN will be resistant by the short stem of SS-DNA(short-stem DNA). Exonuclease Ⅰ and Ⅲ can degrade these two nicked DNA templates, which are inhibited due to the ligation of E. coli DNA ligase. With this novel strategy, a set of logic gates is successfully constructed at the molecular level,including “YES”, “PASS 0”, “OR”, “INHIBIT”, which take the advantages of no label, easy operation, fast speed, high efficiency and low cost. Furthermore, S1 nuclease, as the biomarker of numerous carcinogens,is selectively detected in the range of 0.05–50 U/m L with the detection limit of 0.005 U/m L(1×10^(−6)U)based on this platform.

关键词： Logic gates Dumbbell DNA templates Poly-thymine loops Copper nanoclusters Nucleic acid enzymes

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