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co-delivery of luteolin and TGF-β1 plasmids with ROS-responsive virus-inspired nanoparticles for microenvironment regulation and chemo-gene therapy of intervertebral disc degeneration

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Nano Research 2022年第9期15卷 8214-8227页

作者： Yifan Ding Huan Wang Yunyun Wang Long Li Jiahui Ding Caiyan Yuan Tao Xu Haoran Xu Hui Xie Ning Zhu Xin Hu Huang Fang Songwei Tan Department of Orthopedic Surgery Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China School of Pharmacy Tongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China Department of Cardiology the Fifth Hospital in WuhanWuhan 430030China Department of Radiology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030China college of Biotechnology and Pharmaceutical Engineering Nanjing Tech UniversityNanjing 211800China State Key Laboratory of Materials-Oriented Chemical Engineering Nanjing Tech UniversityNanjing 211800China college of Materials Science and Engineering Nanjing Tech UniversityNanjing 211800China

Intervertebral disc degeneration(IDD)is closely related to inflammation and imbalance of synthesis/catabolism of extracellular matrix(ECM)in intervertebral disc(IVD).considering this,luteolin(LUT),a kind of natural flavonoid with good anti-inflammatory effect and TGF-β1(a gene that promotes the regeneration of ECM)plasmid was co-loaded and co-delivered to nucleus pulposus cells(NPCs).Reactive oxygen species(ROS)responsive cationic copolymer,poly(β-amino ester)-poly(ε-caprolactone)(PBC),with high plasmid DNA(pDNA)compression affinity was *** can self-assemble into nano-sized polyplexes(pDNA@PBC)with virus-inspired structure and function through which it can transfect pDNA into NPCs with very high efficiency and negligible *** was encapsulated in the hydrophobic core of pDNA@*** co-delivery system,LUT-pTGFβ1@PBC,could enhance the cellular uptake of NPCs and manifest excellent sustained drug release in *** time quantitative polymerase chain reaction(RT-qPCR)and Western blot experiments reveal that the co-delivery system could inhibit inflammation in NPCs and restore the balance of anabolism and catabolism in vitro by activating TGF/SMAD3 and inhibiting NFkB/***,LUT-pTGF-β1@PBC retards IDD in vivo as detected by radiological and histological methods with good biosafety in ***-pTGF-β1@PBC may be a promising option for the treatment of IDD.

关键词： intervertebral disc degeneration poly(β-amino ester) luteolin TGF-β1 co-delivery

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co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

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Chinese Chemical Letters 2022年第5期33卷 2507-2511页

作者： Yunchu Zhang Tingting Li Yuzhu Hu Jing Chen Yihong He Xiang Gao Yan Zhang Department of Thoracic Oncology Cancer CenterState Key Laboratory of BiotherapyWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical *** this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and cyclo(ArgGly-Asp-D-Phe-Lys)(c RGD) polypeptide modified PEG-PLA(c RGD-PEG-PLA) copolymers were used for the co-delivery of curcumin(CUR) and DOX(CUR-DOX/c RGD-M). The particle size of the self-assembled drugloaded nanomicelle approximately was 27.4 nm and the zeta potential was -2.7mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma(LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/c RGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/c RGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

关键词： Doxorubicin Curcumin Lung cancer Nanomicelle co-delivery

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Efficient and targeted drug/siRNA co-delivery mediated by reversibly crosslinked polymersomes toward anti-inflammatory treatment of ulcerative colitis (UC)

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Nano Research 2019年第3期12卷 659-667页

作者： Xin Xu Weijing Yang Qiujun Liang Yanan Shi Wenxin Zhang Xiao Wang Fenghua Meng Zhiyuan Zhong Lichen Yin Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices Institute of Functional Nano and Soft Materials (FUNSOM) the Collaborative Innovation Center of Suzhou Nano Science and Technology Soochow University Suzhou 215123 China Biomedical Polymers Laboratory and Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application College of Chemistry Chemical Engineering and Materials Science Soochow University Suzhou 215123 China

co-delivery of anti-inflammatory siRNA and hydrophilic drug provides a promising approach for the treatment of ulcerative colitis (UC). However, lack of a suitable and efficient co-delivery carrier poses critical challenge against their utilization. We herein developed macrophage-targeting, reversibly crossli nked polymersomes (TKPR-RCP) based on the TKPR-modified, poly(ethyle ne glycol)-b-poly(trimethylene carbonate-codithiolane trimethylene carbonate)-b-polyethylenimine (PEG-P(TMC-DTC)-PEI) triblock copolymer, which could efficiently encapsulate TNF-α siRNA and dexamethasone sodium phosphate (DSP) in their hydrophilic core. The cationic PEI segments provided additional electrostatic interactions with cargo molecules to promote the encapsulatiion, and disulfide crosslinking of the polymersome membrane endowed the TKPR-RCP with high colloidal stability. Because the cationic PEI was embedded in the hydrophilic core, the polymersomes displayed neutral surface charge and thus possessed high serum stability. The TKPR-RCP co-encapsulating TNF-α siRNA and DSP could be efficiently internalized by macrophages (~98%) and undergo redox-responsive membrane de-crosslinking to accelerate cargo release in the cytoplasm, thus inducing efficient gene silencing and anti-inflammatory effect .Intravenous injectio n of the co-delivery TKPR-RCP mediated pote nt and cooperative anti-inflammatory effect in inflamed colons of UC mice, and significantly prevented animals from colonic injury. This study therefore provides a promising approach for the co-delivery of hydrophilic drug/siRNA toward the treatment of inflammatory bowel diseases.

关键词： ulcerative colitis (UC) anti-inflammatory therapy polymersomes reversible crosslinking siRNA/drug co-delivery macrophage targeting

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Preparation and anti-tumor application of hyaluronic acid-based material for disulfide and copper ions co-delivery

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Science China(Technological Sciences) 2021年第9期64卷 2023-2032页

作者： PANG Long ZHONG Wei WANG QiuBo FENG HaoHui DONG HaoNan WANG Song coNG HaiLin SHEN YouQing YU Bing Institute of Biomedical Materials and Engineering College of Chemistry and Chemical EngineeringCollege of Materials Science and EngineeringAffiliated Hospital of Qingdao UniversityQingdao UniversityQingdao 266071China State Key Laboratory of Bio-Fibers and Eco-Textiles Qingdao UniversityQingdao 266071China Key Laboratory of Biomass Chemical Engineering of Ministry of Education Center for BionanoengineeringDepartment of Chemical and Biological EngineeringZhejiang UniversityHangzhou310027China

Disulfide(DSF) has been proved good anti-tumor effect and even better with coadministration of Cu^(2+). In this work, we report the use of hyaluronic acid(HA) based materials to construct vectors for the delivery of both DSF and Cu^(2+). HA was firstly modified with polyethylene glycol monomethyl ether(mPEG) and polycaprolactone(PCL) to synthesize an amphiphilic polymer(HA-PEG-PCL). DSF could be loaded in the hydrophobic core and Cu^(2+) could be cooperated to the negative hydrophilic segment. The Cu^(2+) also played a role as crosslinking agent, which prevented DSF leakage prematurely, avoiding the bad side effects to normal tissues. The interaction between HA and CD44 improved the distribution of nanodrugs in tumor cells. When the nanodrugs were delivered to the cancer cell, the acidic micro-environment would separate the Cu^(2+) from the surface, leading to the disintegration of the micelles, promoting the release of DSF from the micelle core. The results of in vitro and in vivo experiments showed that the DSF and Cu^(2+) co-delivery vector constructed in this work could enhance the antitumor effect and have low biological toxicity.

关键词： hyaluronic acid disulfide Cu^(2+) cancer co-delivery

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DRUG AND PLASMID DNA co-delivery NANOCARRIERS BASED ON ABC-TYPE POLYPEPTIDE HYBRID MIKTOARM STAR coPOLYMERS

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Chinese Journal of Polymer Science 2013年第6期31卷 924-937页

作者： Tao Liu Yan-feng Zhang 刘世勇 CAS Key Laboratory of Soft Matter Chemistry Department of Polymer Science and Engineering University of Science and Technology of China

We report on the fabrication of self-assembled micelles from ABC-type miktoarm star polypeptide hybrid copolymers consisting of poly（ethylene oxide）, poly（L-lysine）, and poly（e-caprolactone） arms, PEO（-b-PLL）-b-PCL, and their functional applications as co-delivery nanocarriers of chemotherapeutic drugs and plasmid DNA. Miktoarm star copolymer precursors, PEO（-b-PZLL）-b-PCL, were synthesized at first via the combination of consecutive ＂click＂ reactions and ring-opening polymerizations （ROP）, where PZLL is poly（e-benzyloxycarbonyl-L-lysine）. Subsequently, the deprotection of PZLL arm afforded amphiphilic miktoarm star copolymers, PEO（-b-PLL）-b-PCL. In aqueous media at pH 7.4, PEO（-b-PLL）-b-PCL self-assembles into micelles consisting of PCL cores and hydrophilic PEO/PLL hybrid coronas. The hydrophobic micellar cores can effectively encapsulate model hydrophobic anticancer drug, paclitaxel; whereas positively charged PLL arms within mixed micellar corona are capable of forming electrostatic polyplexes with negatively charged plasmid DNA （pDNA） at N/P ratios higher than ca. 2. Thus, PEO（-b-PLL）-b-PCL micelles can act as co-delivery nanovehicles for both chemotherapeutic drugs and genes. Furthermore, polyplexes of pDNA with paclitaxel-loaded PEO（-b- PLL）-b-PCL micelles exhibited improved transfection efficiency compared to that of pDNA/blank micelles. We expect that the reported strategy of varying chain topologies for the fabrication of co-delivery polymeric nanocarriers can be further applied to integrate with other advantageous functions such as targeting, imaging, and diagnostics.

关键词： Miktoarm star copolymers Gene delivery co-delivery Polypeptide Self-assembly

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A novel tumor-targeting treatment strategy uses energy restriction via co-delivery of albendazole and nanosilver

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Nano Research 2018年第9期11卷 4507-4523页

作者： Jianming Liang Ruixiang Li Yuwei He Chengli Ling Qi Wang Yongzhuo Huang Jing Qin Weigen Lu Jianxin Wang Department of Pharmaceutics School of Pharmacy Fudan University & Key Laboratory of Smart Drug Delivery Ministry of Education Shanghai 201203 China Institute of Clinical Pharmacology Guangzhou University of Traditional Chinese Medicine Guangzhou 510006 China Shanghai Institute of Materia Medica Chinese Academy of Sciences 501 Haike Rd. Shanghai201203 China Shanghailnstitute of Pharmaceuticallndustry China State Institute of Pharmaceutical Industry 285 Gebaini Rd. Shanghai201203 China School of Pharmacy Chengdu University of Traditional Chinese Medicine No 1166 Liu TaiAvenue Wenjiang District Chengdu 610072 China

Although nanotechnology has been rapidly developed and applied in tumor targeting, the outcome of chemotherapy remains greatly restricted by the toxicity of cytotoxic drugs in normal tissues and cells. Therefore, the development of alternative delivery systems, with few side effects in normal cells, has attracted increasing attention. Energy restriction is a novel and promising approach to cancer treatment, which can restrict tumor growth via inhibition of cellular energy metabolism. In this study, a novel tumor targeting system, based on folate-conjugated bovine serum albumin （BSA）, was developed to co-deliver albendazole and nanosilver simultaneously, to restrain the energy metabolism of tumor cells. This nanosystem showed stronger anti-tumor efficacy than those using nanoparticles without folic acid modification, nanosilver, or albendazole, both in vitro and in vivo. This nanosystem depleted cellular ATP via direct inhibition of glycolytic enzymes and mitochondrial damage, resulting in inhibition of proliferation, cell-cycle arrest, and apoptosis of tumor cells. The enhanced anti-tumor activity contributed to the tumor-targeting ability of this system, resulting in specific energy inhibition in tumor cells. Toxicity evaluation was performed to confirm the safety of this system. This nanosystem provides an efficient and safe strate~ for tumor therapy.

关键词： albendazole nano silver co-delivery tumor targeting energy metabolism

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A Three-drug co-delivery System Based on Reduction-sensitive Polymeric Prodrug to Effectively Reverse Multi-drug Resistance

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Chemical Research in Chinese Universities 2017年第3期33卷 484-491页

作者： XU Jiaqi YI Xiaoqing ZHAO Dan YUAN Gongdao ZHUO Renxi LI Feng Key Laboratory of Biomedical Polymers Ministry of Education College of Chemistry and Molecular Sciences Wuhan University Wuhan 430072 P. R. China

In the present study, we prepared a multi-drug delivery system based on reduction-sensitive paclitaxel （PTX） polymeric prodrug（PEG-b-PMPMC-g-PTX, PMP） polymersomes to co-deliver PTX, doxorubicin hydrochlo- ride（***1） and the P-glycoprotein（P-gp） inhibitor Tariquidar（TQR） to effectively reverse drug resistance by inhibiting the expression of P-gp and improving the accumulation of the encapsulated anticancer drugs. The PTX was linked to the backbone by reduction-sensitive disulphide, making the polymersomes prone to collapse in the reductive environment and to release the drugs. Transmission electron microscope（TEM） was used to confirm the morphology of polymeric assemblies. Moreover, the rupture process of polymersomes was verified by dynamic light scattering （DLS）. The results of confocal laser scanning microscopy（CLSM） and flow cytometry indicate that the PMP/***/TQR three-drug-loaded polymersomes show the strongest fluorescence intensity for DOX-HC1 compared with PMP/DOX-HC1 polymersomes and free DOX-HCl in drug-resistant MCF-7/ADR cells. More importantly, the PMP/***/TQR multi-drug co-delivery system shows a greater growth-inhibitory effect on tumour cells than the other two samples, including PMP/***1 nanoparticles without the TQR component and free DOX-HCl, when co-incubated with either nonresistant HeLa cells or drug-resistant MCF-7/ADR cells. This growth-inhibitory effect was especially evident in drug-resistant cells. These results imply that the co-delivery of PTX, DOX-HCl and TQR based on reduction-sensitive polymeric prodrug may be promising for overcoming multi-drug resistance in tumour treatments.

关键词： Multi-drug resistance co-delivery Polymersome Multi-drug resistance co-delivery Polymersome

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Galactose-modified enzymatic synthesis of poly(amino-co-ester)micelles for co-delivery miR122 and sorafenib to inhibit hepatocellular carcinoma development

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Chinese Chemical Letters 2020年第5期31卷 1173-1177页

作者： Jianhua Xie Yao Lu Baiqing Yu Jun Wu Jie Liu School of Biomedical Engineering Sun Yat-sen UniversityGuangzhou 510006China

Nanomaterials as drug carriers hold promise for the treatment of carcinomas,but integrating multiple functions into a single vector is *** this study,we aim to develop efficie nt materials as vectors for co-delivery of microRNA-122(miR-122)and sorafenib(SRF).We successfully synthesized amphiphilic galactose-modified PEGylated poly(ami no-co-ester)(Gal-PEG-PPMS)copolymers consisted of hydrophilic Gal-PEG5 k chain segments and hydrophobic poly(ω-pentadecalactone-co-N-methyldiethyleneamine-co-sebacic acid)chain segments,which self-assembled to form cationic micelles at pH *** results showed that the micelles could encapsulate SRF and bind miR122 simultaneously,increase cellular uptake ***,the micelles showed favorable transfection efficiency in enhancing miR122 expression level,the migration and invasion ability of hepatocellular carcinoma(HCC)cells we re significantly inhibited after being tra nsfected with miR122-loaded *** importantly,the co-delivery micelles decreased cell activities of HepG2 cells,which was more effective than miR122 or SRF loaded micelles ***,Gal-PEG-PPMS nanoparticles are promising multifunctional carriers for miR122 and SRF co-delivery system to treat HCC.

关键词： Micelles miR122 Sorafenib Hepatocellular carcinoma co-delivery

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Nanocarrier-mediated co-delivery of chemotherapeutic drugs and gene agents for cancer treatment

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Acta Pharmaceutica Sinica B 2015年第3期5卷 169-175页

作者： Lin Kang Zhonggao Gao Wei Huang Mingji Jin Qiming Wang State Key Laboratory of Bioactive Substance and Function of Natural Medicines Beijing City Key Laboratory of Drug Delivery Technology and Novel FormulationsInstitute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College

The efficacy of chemotherapeutic drug in cancer treatment is often hampered by drug resistance of tumor cells,which is usually caused by abnormal gene *** interference mediated by si RNA and mi RNA can selectively knock down the carcinogenic genes by targeting specific m ***,combining chemotherapeutic drugs with gene agents could be a promising strategy for cancer *** to poor stability and solubility associated with gene agents and drugs,suitable protective carriers are needed and have been widely researched for the *** this review,we summarize the most commonly used nanocarriers for co-delivery of chemotherapeutic drugs and gene agents,as well as the advances in co-delivery systems.

关键词： Nanocarrier co-delivery Chemotherapeutic drug Gene Liposome Micelle Dendrimer Supramolecular system

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Targeted co-delivery of daunorubicin and cytarabine based on the hyaluronic acid prodrug modified liposomes

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Chinese Chemical Letters 2022年第10期33卷 4600-4604页

作者： George Frimpong Boafo Yejiao Shi Qingqing Xiao Kosheli Thapar Magar Makhloufi Zoulikha Xuyang Xing Chao Teng Emmanuel Brobbey Xiaotong Li Xiaohong Jiang Xiaochun Wang Yi Yang Samuel Kesse Wei He Shanghai Skin Disease Hospital Tongji University School of MedicineShanghai 200443China Department of Pharmaceutics School of PharmacyChina Pharmaceutical UniversityNanjing 211198China Institute of Translation Medicine Shanghai UniversityShanghai 200444China

Breast cancer is the most prevalent cancer in women,and it was hard to prevent or diagnose at an early ***,it is imperative to develop advanced therapeutics for effective ***,a targeted daunorubicin(DNR)and cytarabine(ara-C)co-delivery system was developed by modifying the ara-C loaded liposomes(LIP-ara-C)with the hyaluronic acid-DNR(HA-DNR)*** co-assembled hybrid nanoparticles(HA-DNR/LIP-ara-C HNPs)exhibited good serum and storage stability with an average diameter of approximately 100 *** specifically binding to the CD44 receptors that overexpressed on cancer cells,these HNPs could be uptake via endocytosis and accumulate intracellularly,in which an optimized DNR and ara-C combination at a molar ratio of 1:5 could generate enhanced synergistic effects with reduced dose-related toxicity on cancer cells.

关键词： Breast cancer Daunorubicin Cytarabine co-delivery Liposomes

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