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Edaravone-loaded poly(amino acid) nanogel inhibits ferroptosis for neuroprotection in cerebral ischemia injury

Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 89-101页

作者： Yunhan Zhang Zhulin Zou Shuang Liu Fangfang Chen Minglu Li Haoyang Zou Haiyan Liu Jianxun Ding Key Laboratory of Pathobiology Ministry of Education Department of AnatomyCollege of Basic Medical SciencesJilin UniversityChangchun 130061China Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China Department of Gastrointestinal Colorectaland Anal SurgeryChina-Japan Union Hospital of Jilin UniversityChangchun 130033China

Neurological injury caused by ischemic stroke is a major cause of permanent disability and death. The currently available neuroprotective drugs fail to achieve desired therapeutic efficacy mainly due to short circulation half-life and poor blood−brain barrier (BBB) permeability. For that, an edaravone-loaded pH/glutathione (pH/GSH) dual-responsive poly(amino acid) nanogel (NG/EDA) was developed to improve the neuroprotection of EDA. The nanogel was triggered by acidic and EDA-induced high-level GSH microenvironments, which enabled the selective and sustained release of EDA at the site of ischemic injury. NG/EDA exhibited a uniform sub-spherical morphology with a mean hydrodynamic diameter of 112.3 ± 8.2 nm. NG/EDA efficiently accumulated at the cerebral ischemic injury site of permanent middle cerebral artery occlusion (pMCAO) mice, showing an efficient BBB crossing feature. Notably, NG/EDA with 50 µM EDA significantly increased neuron survival (29.3%) following oxygen and glucose deprivation by inhibiting ferroptosis. In addition, administering NG/EDA for 7 d significantly reduced infarct volume to 22.2% ± 7.2% and decreased neurobehavioral scores from 9.0 ± 0.6 to 2.0 ± 0.8. Such a pH/GSH dual-responsive nanoplatform might provide a unique and promising modality for neuroprotection in ischemic stroke and other central nervous system diseases.

关键词： Poly(amino acid)nanogel controlled drug delivery Inhibition of ferroptosis Neuroprotection Cerebral ischenia injury therapy

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Targeted nanostrategies eliminate pre-metastatic niche of cancer

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Nano Research 2024年第6期17卷 5358-5373页

作者： Juan Wang Ning Zhang Xiuping Ding Chengrui Fu Xiaodong Li Baosheng Li Jianxun Ding Tianmeng Sun Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education Institute of ImmunologyThe First HospitalJilin University1 Xinmin StreetChangchun 130061China Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of Sciences5625 Renmin StreetChangchun 130022China Department of Radiation Oncology Shandong Cancer Hospital and InstituteShandong First Medical University and Shandong Academy of Medical Sciences440 Jiyan RoadJinan 250117China Department of orthopaedics The Second Hospital of Shandong UniversityShandong University247 Beiyuan StreetJinan 250033China State Key Laboratory of Molecular Engineering of Polymers Fudan University220 Handan RoadShanghai 200433China

Establishing a pre-metastatic niche(PMN)in secondary organs is a prerequisite for cancer metastases.Despite advances in cancer therapy,the efficient inhibition of PMN formation remains a clinical challenge.Recent advances in understanding the specific characteristics of PMN and advances in nanotechnology have provided hope for manipulating their microenvironments.A series of nanostrategies have been designed to eliminate the PMN,including the removal of pro-metastatic exosomes from the bloodstream for excretion via the intestines,the targeting and scavenging of myeloid-derived suppressor cells,fibroblasts,and critical extracellular matrix components,and the elimination of circulating tumor cells prior to colonization in distant organs.This review summarizes the underlying mechanisms of PMN formation,highlights the anti-PMN efficacy of currently reported nanostrategies,and underlines the unresolved questions.

关键词： nanoparticle controlled drug delivery pre-metastatic niche elimination metastasis suppression cancer therapy

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BIODEGRADABLE POLYMERS WITH A PHOSPHORYL-CONTAINING BACKBONE:TISSUE ENGINEERING AND controlled drug delivery APPLICATIONS

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Chinese Journal of Polymer Science 1995年第4期13卷 289-314页

作者： Kam W.Leong 毛海泉卓仁禧 Department of Biomedical Engineering School of Medicine The Johns Hopkins University Baltimore MD 21205 USA Department of Chemistry Wuhan University Wuhan 430072

This review provides a glimpse of the potential of the biodegradable phos-phoryl-containing polymers in medical applications. Undoubtedly these polymerspossess unique properties that are yet to be fully understood. Many areas warrantfurther investigation and much optimization remains to be done. The fascinatingchemistry of phosphorus poses interesting hurdles but at the same time leavesample room for polymer scientists to exercise their creativity in designinginteresting biomaterials. As the mutual understanding between basic and clinicalscientists on the need of medical devices and the capabilities of these newbiomaterials expands, imaginative application of new biomaterials to other medi-cal applications can be expected.

关键词： biodegradable polymers phosphoryl-containing backbone controlled drug delivery

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Poly(β-cyclodextrin)-mediated Polylactide-cholesterol Stereocomplex Micelles for controlled drug delivery

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Chinese Journal of Polymer Science 2017年第6期35卷 693-693,694-699页

作者： Xiang-ru Feng 丁建勋 Ruxandra Gref Xue-si Chen Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied Chemistry Chinese Academy of Sciences Institute of Molecular Sciences CNRS Université Paris-Sud Université Paris Saclay

A series of host-guest interaction-adjusted polylactide stereocomplex micelles was prepared via the self-assembly of 4-armed poly（ethylene glycol）-block-poly（L-lactide/D-lactide）-cholesterol （4-armed PEG-b-PLLA/PDLA-CHOL） and poly（β-cyclodextrin）（PCD） with the molar ratios of CHOL/β-CD at 1：0.5, 1 ：l, and 1：2 in an aqueous environment. The hydrodynamic diameters of the micelles ranged from 84.1 nm to 107 nm depending on the molar ratio of CHOL/β-CD. It was shown that the micelle with the largest proportion of PCD possessed excellent abilities in drug release, cell internalization as well as proliferation inhibitory effect toward human A549 lung cancer cells. The results demonstrated that the stereocomplex and host-guest interactions-mediated PLA micelles exhibited great potential in sustained drug delivery.

关键词： Polylactide Stereocomplex micelle Poly（β-cyclodextrin） Host-guest interaction controlled drug delivery

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Bioinspired Andrias davidianus-Derived wound dressings for localized drug-elution

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Bioactive Materials 2022年第9期7卷 482-494页

作者： Xiang Liu Xiang Mao Guo Ye Menghong Wang Ke Xue Yan Zhang Hongmei Zhang Xiaoqiao Ning Man Zhao Jinlin Song Yu Shrike Zhang Ximu Zhang Chongqing Key Laboratory of Oral Disease and Biomedical Sciences and Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education and Stomatological Hospital Chongqing Medical UniversityChongqing401174China State Key Laboratory of Ultrasound in Medicine and Engineering and Chongqing Key Laboratory of Biomedical Engineering College of Biomedical EngineeringChongqing Medical UniversityChongqing400016China Department of Stomatology The Third Affiliated HospitalChongqing Medical UniversityChongqing401120China Department of Plastic and Reconstructive Surgery Shanghai Ninth People’s HospitalShanghai Jiao Tong University School of Medicine639 Zhi Zao Ju RdShanghai200011China Department of Pharmacy The 958th Hospital of PLAChongqing404100China Division of Engineering in Medicine Department of MedicineBrigham and Women’s HospitalHarvard Medical SchoolCambridgeMA02139USA Department of Plastic and reconstructive surgery Hainan Western Central HospitalHaiNan571700China

Local drug delivery has received increasing attention in recent years.However,the therapeutic efficacy of local delivery of drugs is still limited under certain scenarios,such as in the oral cavity or in wound beds after resection of tumors.In this study,we introduce a bioinspired adhesive hydrogel derived from the skin secretions of Andrias davidianus(SSAD)as a wound dressing for localized drug elution.The hydrogel was loaded with aminoguanidine or doxorubicin,and its controlled drug release and healing-promoting properties were verified in a diabetic rat palatal mucosal defect model and a C57BL/6 mouse melanoma-bearing model,respectively.The results showed that SSAD hydrogels with different pore sizes could release drugs in a controllable manner and accelerate wound healing.Transcriptome analyses of the palatal mucosa suggested that SSAD could significantly upregulate pathways linked to cell adhesion and extracellular matrix deposition and had the ability to recruit keratinocyte stem cells to defect sites.Taken together,these findings indicate that property-controllable SSAD hydrogels could be a promising biofunctional wound dressing for local drug delivery and promotion of wound healing.

关键词： Andrias davidianus Hydrogel drug loading controlled drug delivery Stem cell recruitment Wound healing

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Sustained delivery of rhMG53 promotes diabetic wound healing and hair follicle development

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Bioactive Materials 2022年第12期7卷 104-115页

作者： Hong Niu Haichang Li Ya Guan Xin Zhou Zhongguang Li Serana Li Zhao Peng Chen Tao Tan Hua Zhu Valerie Bergdall Xuehong Xu Jianjie Ma Jianjun Guan Department of Mechanical Engineering and Materials Science Washington University in St.LouisSt.LouisMO63130USA Institute of Materials Science and Engineering Washington University in St.LouisSt.LouisMO63130USA Department of Surgery Davis Heart and Lung Research InstituteThe Ohio State UniversityColumbusOH43210USA Laboratory of Cell Genetics and Developmental Biology Shaanxi Normal University College of Life SciencesXi’an710062China Department of Veterinary Preventive Medicine University Laboratory Animals ResourcesThe Ohio State UniversityColumbusOH43210USA

MG53 is an essential component of the cell membrane repair machinery,participating in the healing of dermal wounds.Here we develop a novel delivery system using recombinant human MG53(rhMG53)protein and a reactive oxygen species(ROS)-scavenging gel to treat diabetic wounds.Mice with ablation of MG53 display defective hair follicle structure,and topical application of rhMG53 can promote hair growth in the mg53􀀀/􀀀mice.Cell lineage tracing studies reveal a physiological function of MG53 in modulating the proliferation of hair follicle stem cells(HFSCs).We find that rhMG53 protects HFSCs from oxidative stress-induced apoptosis and stimulates differentiation of HSFCs into keratinocytes.The cytoprotective function of MG53 is mediated by STATs and MAPK signaling in HFSCs.The thermosensitive ROS-scavenging gel encapsulated with rhMG53 allows for sustained release of rhMG53 and promotes healing of chronic cutaneous wounds and hair follicle development in the db/db mice.These findings support the potential therapeutic value of using rhMG53 in combination with ROS-scavenging gel to treat diabetic wounds.

关键词： Diabetic wound healing hair follicle stem cell MG53 ROS-Scavenging hydrogel controlled drug delivery

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Graphene-incorporated hyaluronic acid-based hydrogel as a controlled Senexin A delivery system

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Biomaterials Translational 2022年第2期3卷 152-161页

作者： Panita Maturavongsadit Weiwei Wu Jingyu Fan Igor B.Roninson Taixing Cui Qian Wang Department of Chemistry and Biochemistry University of South CarolinaColumbiaSCUSA Department of Cell Biology and Anatomy School of Medicine Columbia University of South CarolinaColumbiaSCUSA Department of drug Discovery&Biomedical Sciences College of PharmacyUniversity of South CarolinaColumbiaSCUSA

Perivascular delivery of therapeutic agents against established aetiologies for occlusive vascular remodelling has great therapeutic potential for vein graft failure.However,none of the perivascular drug delivery systems tested experimentally have been translated into clinical practice.In this study,we established a novel strategy to locally and sustainably deliver the cyclin-dependent kinase 8/19 inhibitor Senexin A(SenA),an emerging drug candidate to treat occlusive vascular disease,using graphene oxide-hybridised hyaluronic acid-based hydrogels.We demonstrated an approach to accommodate SenA in hyaluronic acid-based hydrogels through utilising graphene oxide nanosheets allowing for non-covalent interaction with SenA.The resulting hydrogels produced sustained delivery of SenA over 21 days with tunable release kinetics.In vitro assays also demonstrated that the hydrogels were biocompatible.This novel graphene oxide-incorporated hyaluronic acid hydrogel offers an optimistic outlook as a perivascular drug delivery system for treating occlusive vascular diseases,such as vein graft failure.

关键词： controlled drug delivery graphene oxide hyaluronic acid-based hydrogel Senexin A

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Biointerface engineering nanoplatforms for cancer-targeted drug delivery

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Asian Journal of Pharmaceutical Sciences 2020年第4期15卷 397-415页

作者： Huaiyu Zhang Shujun Dong Zhongmin Li Xiangru Feng Weiguo Xu Catrina Mae STulinao Yang Jiang Jianxun Ding Department of Gastrointestinal Colorectal and Anal Surgery China-Japan Union Hospital of Jilin UniversityChangchun 130033China Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China VIP Integrated Department School and Hospital of StomatologyJilin UniversityChangchun 130021China Far Eastern University-Nicanor Reyes Medical Foundation Quezon City 1118Philippines

Over the past decade,nanoparticle-based therapeutic modalities have become promising strategies in cancer therapy.Selective delivery of anticancer drugs to the lesion sites is critical for elimination of the tumor and an improved prognosis.Innovative design and advanced biointerface engineering have promoted the development of various nanocarriers for optimized drug delivery.Keeping in mind the biological framework of the tumormicroenvironment,biomembrane-camouflaged nanoplatforms have been a research focus,reflecting their superiority in cancer targeting.In this review,we summarize the development of various biomimetic cell membrane-camouflaged nanoplatforms for cancertargeted drug delivery,which are classified according to the membranes fromdifferent cells.The challenges and opportunities of the advanced biointerface engineering drug delivery nanosystems in cancer therapy are discussed.

关键词： Cell membrane-camouflaged nanoplatform Biofunctionalization Tumor microenvironment controlled drug delivery Targeted cancer therapy

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Ultrasound-triggered noninvasive regulation of blood glucose levels using microgels integrated with insulin nanocapsules

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Nano Research 2017年第4期10卷 1393-1402页

作者： Jin Di Jicheng Yu Qun Wang Shanshan Yao Yanqi Ye Matthew Pless Yong Zhu Yun Jing Zhen Gu Joint Department of Biomedical Engineering University of North Carolina at Chapel Hill and North Carolina State University Raleigh NC27695 USA Center for Nanotechnology in drug delivery and Division of Molecular Pharmaceutics UNC Eshelman School of Pharmacy University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA Department of Chemical and Biological Engineering Iowa State University Ames IA 50011 USA Department of Mechanical and Aerospace Engineering North Carolina State University Raleigh NC 27695 USA Department of Medicine University of North Carolina at Chapel Hill Chapel Hill NC 27599 USA

Diabetes is a serious public health problem affecting 422 million people worldwide. Traditional diabetes management often requires multiple daily insulin injections, associated with pain and inadequate glycemia control. Herein, we have developed an ultrasound-triggered insulin delivery system capable of pulsatile insulin release that can provide both long-term sustained and fast on-demand responses. In this system, insulin-loaded poly（lactic-co-glycolic acid）（PLGA） nanocapsules are encapsulated within chitosan microgels. The encapsulated insulin in nanocapsules can passively diffuse from the nanoparticle but remain restricted within the microgel. Upon ultrasound treatment, the stored insulin in microgels can be rapidly released to regulate blood glucose levels. In a chemically-induced type I diabetic mouse model, we demonstrated that this system, when activated by 30 s ultrasound administration, could effectively achieve glycemic control for up to one week in a noninvasive, localized, and pulsatile manner.

关键词： controlled drug delivery focused ultrasound diabetes nanocapsule microgel

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Cystine proportion regulates fate of polypeptide nanogel as nanocarrier for chemotherapeutics

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Science China Chemistry 2021年第2期64卷 293-301页

作者： Xiangru Feng Weiguo Xu Xiaoru Xu Gao Li Jianxun Ding Xuesi Chen Key Laboratory of Polymer Ecomaterials Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun130022China School of Applied Chemistry and Engineering University of Science and Technology of ChinaHefei230026China College of Acumox and Tuina Changchun University of Chinese MedicineChangchun130022China

The physicochemical characteristics of nanoparticles are closely related to their drug delivery performances in vitro and in vivo.A well-designed nanocarrier can prolong the drug half-life in the blood circulation,upregulate the drug accumulation at the target site,and enhance the treatment efficacy.To elucidate the impact of physicochemical properties on the fate of nanogel as a nanocarrier of chemotherapeutics,three methoxy poly(ethylene glycol)-poly(L-phenylalanine-co-L-cystine)(mPEG-P(LP-coLC))nanogels with different L-cystine proportions were developed,namely mPEG-P(LP10-co-LC5)(NG10-5),mPEG-P(LP10-coLC10)(NG10-10),and mPEG-P(LP10-co-LC15)(NG10-15).The three nanogels shared similar surface charge and reductionresponsive behavior,but they had distinct diameters and different drug release profiles.Among them,NG10-5,which has the smallest diameter,was preferentially internalized by tumor cells in vitro and showed rapid migration to the tumor site in vivo.Using doxorubicin(DOX)as a model chemotherapeutic agent,NG10-5/DOX had the most prolonged blood circulation period and highest tumor accumulation after intravenous administration.NG10-5/DOX also had the most potent antitumor effect of all three drug-loaded nanogels.Accordingly,adjusting physicochemical characteristics by changing the amino acid composition might improve the therapeutic efficacies of nanogels and enhance their potential for clinical application.

关键词： polypeptide nanogel cystine proportion fate of nanocarrier controlled drug delivery cancer therapy

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