2024/08/06 更新

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写真a

リー ジユンジエ
LI JUNJIE
LI JUNJIE
所属
先導物質化学研究所 ソフトマテリアル部門 准教授
職名
准教授
連絡先
メールアドレス
電話番号
928026238
外部リンク

学位

  • PhD

受賞

  • 日韓バイオマテリアル学会若手研究者交流AWARD

    2023年7月   Japanese and Korean Biomaterials Societies Young Scientist Exchange Program Award

  • CASNNベストポスター賞、中国アメリカン・ナノメディシン・ナノテクノロジー学会年次大会

    2019年8月   CASNN Best Poster Award, Chinese American Society of Nanomedicine and Nanobiotechnology 2019 Annual Conference

  • 日本学術振興会特別研究員

    2017年8月   JSPS Postdoctoral Fellowship

  • 中国科学技術大学優秀卒業生

    2017年6月   Outstanding graduate of University of Science and Technology of China

  • 中国科学技術大学大学院生国家奨学金

    2013年10月   National Scholarship for Graduate Student in University of Science and Technology of China

論文

  • Leveraging Adrenergic Receptor Blockade for Enhanced Nonalcoholic Fatty Liver Disease Treatment via a Biomimetic Nanoplatform

    2024年5月

  • Editorial: Delivery systems in biologics-based therapeutics

    Anjaneyulu Dirisala, Junjie Li, Daniel Gonzalez-Carter, Zheng Wang

    FRONTIERS IN BIOENGINEERING AND BIOTECHNOLOGY   11   2023年8月

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    記述言語:英語  

    DOI: 10.3389/fbioe.2023.1274210

  • Stealth and pseudo-stealth nanocarriers 招待 査読

    Panyue Wen, Wendong Ke, Anjaneyulu Dirisala, Kazuko Toh, Masaru Tanaka, Junjie Li

    Advanced Drug Delivery Reviews   114895 - 114895   2023年5月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.addr.2023.114895

  • Targeted nanomedicine in cisplatin-based cancer therapeutics

    Yu Han, Panyue Wen, Junjie Li, Kazunori Kataoka

    Journal of Controlled Release   345   709 - 720   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Since its license in 1978, cisplatin has proved to be one of the most successful chemotherapeutic agents in the world. However, two acute challenges facing cisplatin, resistance and toxicity, have resulted in a bottleneck of clinical application. Targeted nanomedicine shows great promise in delivering cisplatin for maximizing efficacy while minimizing off-target toxicity. This article surveyed the recent progress and challenges of targeted nanomedicine in managing resistance and toxicity of cisplatin in both fundamental and clinical aspects. Particularly, we focused on three major mechanisms counteracting cisplatin sensitivity (decreased intracellular accumulation, increased cisplatin deactivation, and enhanced DNA repair/translesion synthesis) and correspondingly highlighted a few representative approaches to increase cisplatin sensitivity through improving the intracellular concentration of cisplatin and implementing combination therapy. Moreover, the requirements for future advancements in cisplatin delivery systems are rendered with emphasis on (i) understanding of nano-bio interaction and post-accumulation biological effects instead of overwhelmingly improving tumor accumulation, (ii) development of stimuli-responsive and/or actively-targeted nanomedicines, (iii) optimization of combination therapy, (iv) novel combinations targeting tumor microenvironment and immunotherapy. We postulate that cisplatin-based nanomedicines will continuously advance and potentially revolutionize oncological treatment.

    DOI: 10.1016/j.jconrel.2022.03.049

  • Effective mRNA Protection by Poly(L‐Ornithine) Synergizes with Endosomal Escape Functionality of a Charge‐Conversion Polymer Toward Maximizing mRNA Introduction Efficiency 査読

    Anjaneyulu Dirisala, Satoshi Uchida, Junjie Li, Joachim F. R. Van Guyse, Kotaro Hayashi, Sai V. C. Vummaleti, Sarandeep Kaur, Yuki Mochida, Shigeto Fukushima, Kazunori Kataoka

    Macromolecular Rapid Communications   2100754 - 2100754   2022年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/marc.202100754

  • Tumor-dilated polymersome nanofactories for enhanced enzyme prodrug chemo-immunotherapy

    Abd Al-Wali Mohammed M. Japir, Wendong Ke, Junjie Li, Jean Felix Mukerabigwi, Alhadi Ibrahim, Yuheng Wang, Xiang Li, Qinghao Zhou, Fathelrahman Mohammed, Zhishen Ge

    Journal of Controlled Release   339   418 - 429   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jconrel.2021.10.015

  • Hypoxia-responsive block copolymer polyprodrugs for complementary photodynamic-chemotherapy

    Qinghao Zhou, Fathelrahman Mohammed, Yuheng Wang, Jingbo Wang, Nannan Lu, Junjie Li, Zhishen Ge

    Journal of Controlled Release   339   130 - 142   2021年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1016/j.jconrel.2021.09.023

  • Enzymatically Transformable Polymersome‐Based Nanotherapeutics to Eliminate Minimal Relapsable Cancer

    Junjie Li, Zhishen Ge, Kazuko Toh, Xueying Liu, Anjaneyulu Dirisala, Wendong Ke, Panyue Wen, Hang Zhou, Zheng Wang, Shiyan Xiao, Joachim F. R. Van Guyse, Theofilus A. Tockary, Jinbing Xie, Daniel Gonzalez‐Carter, Hiroaki Kinoh, Satoshi Uchida, Yasutaka Anraku, Kazunori Kataoka

    Advanced Materials   33 ( 49 )   2105254 - 2105254   2021年10月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/adma.202105254

  • Chemo-physical Strategies to Advance the in Vivo Functionality of Targeted Nanomedicine: The Next Generation

    Junjie Li, Kazunori Kataoka

    Journal of the American Chemical Society   143 ( 2 )   538 - 559   2021年1月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/jacs.0c09029

  • Self‐Boosting Catalytic Nanoreactors Integrated with Triggerable Crosslinking Membrane Networks for Initiation of Immunogenic Cell Death by Pyroptosis 査読

    Junjie Li, Yasutaka Anraku, Kazunori Kataoka

    Angewandte Chemie International Edition   59 ( 32 )   13526 - 13530   2020年8月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/anie.202004180

  • Self‐Boosting Catalytic Nanoreactors Integrated with Triggerable Crosslinking Membrane Networks for Initiation of Immunogenic Cell Death by Pyroptosis 査読

    Junjie Li, Yasutaka Anraku, Kazunori Kataoka

    Angewandte Chemie   132 ( 32 )   13628 - 13632   2020年8月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1002/ange.202004180

  • Transient stealth coating of liver sinusoidal wall by anchoring two-armed PEG for retargeting nanomedicines 査読 国際誌

    Anjaneyulu Dirisala, Satoshi Uchida, Kazuko Toh, Junjie Li, Shigehito Osawa, Theofilus A. Tockary, Xueying Liu, Saed Abbasi, Kotaro Hayashi, Yuki Mochida, Shigeto Fukushima, Hiroaki Kinoh, Kensuke Osada, Kazunori Kataoka

    Science Advances   6 ( 26 )   eabb8133 - eabb8133   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A major critical issue in systemically administered nanomedicines is nonspecific clearance by the liver sinusoidal endothelium, causing a substantial decrease in the delivery efficiency of nanomedicines into the target tissues. Here, we addressed this issue by in situ stealth coating of liver sinusoids using linear or two-armed poly(ethylene glycol) (PEG)–conjugated oligo(<sc>l</sc>-lysine) (OligoLys). PEG-OligoLys selectively attached to liver sinusoids for PEG coating, leaving the endothelium of other tissues uncoated and, thus, accessible to the nanomedicines. Furthermore, OligoLys having a two-armed PEG configuration was ultimately cleared from sinusoidal walls to the bile, while OligoLys with linear PEG persisted in the sinusoidal walls, possibly causing prolonged disturbance of liver physiological functions. Such transient and selective stealth coating of liver sinusoids by two-arm-PEG-OligoLys was effective in preventing the sinusoidal clearance of nonviral and viral gene vectors, representatives of synthetic and nature-derived nanomedicines, respectively, thereby boosting their gene transfection efficiency in the target tissues.

    DOI: 10.1126/sciadv.abb8133

  • Dual-Sensitive Nanomicelles Enhancing Systemic Delivery of Therapeutically Active Antibodies Specifically into the Brain 査読

    Jinbing Xie, Daniel Gonzalez-Carter, Theofilus A. Tockary, Noriko Nakamura, Yonger Xue, Makoto Nakakido, Hiroki Akiba, Anjaneyulu Dirisala, Xueying Liu, Kazuko Toh, Tao Yang, Zengtao Wang, Shigeto Fukushima, Junjie Li, Sabina Quader, Kouhei Tsumoto, Takanori Yokota, Yasutaka Anraku, Kazunori Kataoka

    ACS Nano   14 ( 6 )   6729 - 6742   2020年5月

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    記述言語:その他   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1021/acsnano.9b09991

  • Therapeutic Polymersome Nanoreactors with Tumor-Specific Activable Cascade Reactions for Cooperative Cancer Therapy 査読

    リージェンジェ

    13 ( 2 )   2357 - 2369   2019年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Therapeutic Polymersome Nanoreactors with Tumor-Specific Activable Cascade Reactions for Cooperative Cancer Therapy
    Therapeutic nanoreactors are of increasing interest in precise cancer therapy, which have been explored to in situ produce therapeutic compounds from inert prodrugs or intrinsic molecules at the target sites. However, engineering a nanoreactor with tumor activable cascade reactions for efficient cooperative cancer therapy remains a great challenge. Herein, we demonstrate a polymersome nanoreactor with tumor acidity-responsive membrane permeability to activate cascade reactions for orchestrated cooperative cancer treatment. The nanoreactors are constructed from responsive polyprodrug polymersomes incorporating ultrasmall iron oxide nanoparticles and glucose oxidase in the membranes and inner aqueous cavities, respectively. The cascade reactions including glucose consumption to generate H2O2, accelerated iron ion release, Fenton reaction between H2O2 and iron ion to produce hydroxyl radicals (center dot OH), and center dot OH-triggered rapid release of parent drugs can be specifically activated by the tumor acidity-responsive membrane permeability. During this process, the orchestrated cooperative cancer therapy including starving therapy, chemodynamic therapy, and chemotherapy is realized for high-efficiency tumor suppression by the in situ consumed and produced compounds. The nanoreactor design with tumor-activable cascade reactions represents an insightful paradigm for precise cooperative cancer therapy.

    DOI: 10.1021/acsnano.8b09082

  • Sustained and Bioresponsive Two‐Stage Delivery of Therapeutic miRNA via Polyplex Micelle‐Loaded Injectable Hydrogels for Inhibition of Intervertebral Disc Fibrosis 査読

    リージェンジェ

    Advanced Healthcare Materials   7   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sustained and Bioresponsive Two‐Stage Delivery of Therapeutic miRNA via Polyplex Micelle‐Loaded Injectable Hydrogels for Inhibition of Intervertebral Disc Fibrosis

    DOI: 10.1002/adhm.201800623

  • Precise tuning of disulfide crosslinking in mRNA polyplex micelles for optimizing extracellular and intracellular nuclease tolerability 査読

    リージェンジェ

    Journal of drug targeting   2018年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Precise tuning of disulfide crosslinking in mRNA polyplex micelles for optimizing extracellular and intracellular nuclease tolerability

    DOI: 10.1080/1061186x.2018.1550646

  • Intracellular glutathione-depleting polymeric micelles for cisplatin prodrug delivery to overcome cisplatin resistance of cancers 査読

    リージェンジェ

    Journal of Controlled Release   273   30 - 39   2018年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Intracellular glutathione-depleting polymeric micelles for cisplatin prodrug delivery to overcome cisplatin resistance of cancers

    DOI: 10.1016/j.jconrel.2018.01.019

  • Therapeutic Vesicular Nanoreactors with Tumor-Specific Activation and Self-Destruction for Synergistic Tumor Ablation 査読

    Junjie Li, Anjaneyulu Dirisala, Zhishen Ge, Yuheng Wang, Wei Yin, Wendong Ke, Kazuko Toh, Jinbing Xie, Yu Matsumoto, Yasutaka Anraku, Kensuke Osada, Kazunori Kataoka

    ANGEWANDTE CHEMIE-INTERNATIONAL EDITION   56 ( 45 )   14025 - 14030   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the in vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H2O2) production by the catalysis of GOD in theraNR increases tumor oxidative stress significantly. Meanwhile, high levels of H2O2 induce self-destruction of theraNR releasing quinone methide (QM) to deplete glutathione and suppress the antioxidant ability of cancer cells. Finally, theraNR efficiently kill cancer cells and ablate tumors via the synergistic effect.

    DOI: 10.1002/anie.201706964

  • Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy 査読

    リージェンジェ

    Nano letters   17   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Polymer Prodrug-Based Nanoreactors Activated by Tumor Acidity for Orchestrated Oxidation/Chemotherapy

    DOI: 10.1021/acs.nanolett.7b03531

  • Therapeutic Vesicular Nanoreactors with Tumor‐Specific Activation and Self‐Destruction for Synergistic Tumor Ablation 査読

    リージェンジェ

    Angewandte Chemie International Edition   129   14213 - 14218   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Therapeutic Vesicular Nanoreactors with Tumor‐Specific Activation and Self‐Destruction for Synergistic Tumor Ablation

    DOI: 10.1002/ange.201706964

  • Light‐Triggered Clustered Vesicles with Self‐Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy against Hypoxic Tumor 査読

    リージェンジェ

    Advanced Functional Materials   27 ( 33 )   1702108   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Light-Triggered Clustered Vesicles with Self-Supplied Oxygen and Tissue Penetrability for Photodynamic Therapy against Hypoxic Tumor
    Smart nanocarriers are of particular interest for highly effective photodynamic therapy (PDT) in the field of precision nanomedicine. Nevertheless, a critical challenge still remains in the exploration of potent PDT treatment against hypoxic tumor. Herein, light-triggered clustered polymeric vesicles for photoinduced hypoxic tumor ablation are demonstrated, which are able to deeply penetrate into the tumor and simultaneously afford oxygen supply upon light irradiation. Hydrogen peroxide (H2O2) and poly(amidoamine) dendrimer conjugating chlorin e6/cypate (CC-PAMAM) are coassembled with reactive-oxygen-species-responsive triblock copolymer into the polymeric vesicles. Upon 805 nm irradiation, the vesicles exhibit the light-triggered thermal effect that is able to decompose H2O2 into O-2, which distinctly ensures the alleviation of tumor hypoxia at tumor. Followed by 660 nm irradiation, the vesicles are rapidly destabilized through singlet oxygen-mediated cleavage of copolymer under light irradiation and thus allow the release of photoactive CC-PAMAM from the vesicular chambers, followed by their deep penetration in the poorly permeable tumor. Consequently, the light-triggered vesicles with both self-supplied oxygen and deep tissue penetrability achieve the total ablation of hypoxic hypopermeable pancreatic tumor through photodynamic damage. These findings represent a general and smart nanoplatform for effective photoinduced treatment against hypoxic tumor.

    DOI: 10.1002/adfm.201702108

  • Integrated Nanoparticles To Synergistically Elevate Tumor Oxidative Stress and Suppress Antioxidative Capability for Amplified Oxidation Therapy 査読

    リージェンジェ

    ACS applied materials & interfaces   9 ( 35 )   29538 - 29546   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Integrated Nanoparticles To Synergistically Elevate Tumor Oxidative Stress and Suppress Antioxidative Capability for Amplified Oxidation Therapy

    DOI: 10.1021/acsami.7b08347

  • Smart Asymmetric Vesicles with Triggered Availability of Inner Cell-Penetrating Shells for Specific Intracellular Drug Delivery 査読

    Junjie Li, Shiyan Xiao, Yixuan Xu, Shuai Zuo, Zengshi Zha, Wendong Ke, Chuanxin He, Zhishen Ge

    ACS APPLIED MATERIALS & INTERFACES   9 ( 21 )   17727 - 17735   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Smart nanocarriers attract considerable interest in the filed of precision nanomedicine. Dynamic control of the interaction between nano carriers and cells offers the feasibility that in situ activates cellular internalization at the targeting sites. Herein, we demonstrate a novel class of enzyme-responsive asymmetric polymeric vesicles self-assembled from matrix metalloproteinase (MMP)-cleavable peptide-linked triblock copolymer, poly(ethylene glycol)-GPLGVIZG-b-poly(epsilon-caprolactone)-b-poly(3-guanidinopropyl methacrylamide) (PEG-GPLGVRG-PCL-PGPMA), in which the cell-penetrating PGPMA segments asymmetrically distribute in the outer and inner shells with fractions of 9&#37; and 91&#37;, respectively. Upon treatment with MMP-2, to cleave the stealthy PEG Shell, the vesicles undergo morphological transformation into fused multicavity vesicles and small nanoparticles, accompanied by redistribution of PGPMA segments with 76&#37; exposed to the outside. The vesicles after dePEGylation show significantly increased cellular internalization efficiency (similar to 10 times) as compared to the original ones due to the triggered availability of cell-penetrating shells. The vesicles loading hydrophobic anticancer drug paclitaxel (PTX) in the membrane exhibit significantly enhanced cytotoxicity against MMP-overexpressing HT1080 cells and multicellular spheroids. The proposed vesicular system can serve as a smart nanoplatform for in situ activating intracellular drug delivery in MMP-enriched tumors.

    DOI: 10.1021/acsami.7b02808

  • Facile Preparation and Radiotherapy Application of an Amphiphilic Block Copolymer Radiosensitizer 査読

    Kaijie Zhao, Wendong Ke, Wei Yin, Junjie Li, Ming Qiang, Zhishen Ge

    ACS MACRO LETTERS   6 ( 5 )   556 - 560   2017年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Radiosensitizer plays an important role in the cancer radiotherapy for efficient killing of hypoxic cancer cells at a low radiation dose. However, the commercially available small molecular radiosensitizers show low efficiency due to poor bioavailability in tumor tissues. In this report, we develop a novel amphiphilic block copolymer radiosensitizer, metronidazole-conjugated poly(ethylene glycol)-b-poly(gamma-propargyl-L-glutamate) (PEG-b-P(PLG-g-MN)), which can be self assembled into core shell micelles (MN-Micelle) with an optimal size of similar to 60 nm in aqueous solution. In vitro cytotoxicity evaluation indicated that MN-Micelle sensitized the hypoxic cancer cells more efficiently under radiation with the sensitization enhancement ratio (SER) of 1.62 as compared with that of commercially available sodium glycididazole (GS; SER = 1.17) at the metronidazole-equivalent concentration of 180 mu g/mL. Upon intravenous injection of MN-Micelle into the tumor-bearing mice, high tumor deposition was achieved, which finally suppressed tumor growth completely after electron beam radiation at a low radiation dose of 4 Gy. MN-Micelle with outstanding performance as an in vivo radiosensitizer holds great potentials for translation into radiotherapy application.

    DOI: 10.1021/acsmacrolett.7b00196

  • Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin 査読

    リージェンジェ

    Biomacromolecules   17 ( 10 )   3268 - 3276   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Modular Design and Facile Synthesis of Enzyme-Responsive Peptide-Linked Block Copolymers for Efficient Delivery of Doxorubicin

    DOI: 10.1021/acs.biomac.6b00997

  • Finely Tuned Thermo‐Responsive Block Copolymer Micelles for Photothermal Effect‐Triggered Efficient Cellular Internalization 査読

    リージェンジェ

    Macromolecular bioscience   16 ( 9 )   1265 - 1272   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Finely Tuned Thermo-Responsive Block Copolymer Micelles for Photothermal Effect-Triggered Efficient Cellular Internalization
    Although biodegradable amphiphilic block copolymer micelles have been widely applied in the clinical applications as drug delivery nanocarriers, low-efficiency cellular internalization frequently reduces therapeutic efficacy of the loaded drugs. Here, photothermal effect-promoted cellular internalization of finely tuned thermo-responsive amphiphilic biodegradable block copolymer nanocarriers via noninvasive stimuli of near-infrared (NIR) light irradiation is demonstrated. Amphiphilic block copolymers, poly(epsilon-caprolactone)-block-poly(N-isopropylacrylamide-co-N,N-dimethylacrylamide) (PCL-b-P(NIPAM-co-DMA)), are prepared with finely tuned compositions of P(NIPAM-co-DMA) for desirable lower critical solution temperature of the block copolymer micelles in aqueous solution. The block copolymers are then used to co-encapsulate doxorubicin and indocyanine green, which show high encapsulation efficiency and significant photothermal effect upon exposure to NIR light irradiation. The photo thermal effect-induced collapse and hydrophilic-to-hydrophobic transition of P(NIPAM-co-DMA) shells significantly enhance the interactions between drug-loaded micelles and cell membranes, which dramatically promote the cellular internalization of the micelles and therapeutic efficacy of loaded anticancer drugs.

    DOI: 10.1002/mabi.201600119

  • Dual Stimuli-Responsive Polymer Prodrugs Quantitatively Loaded by Nanoparticles for Enhanced Cellular Internalization and Triggered Drug Release 査読

    Mingming Huang, Kaijie Zhao, Lei Wang, Shanqing Lin, Junjie Li, Jingbo Chen, Chengai Zhao, Zhishen Ge

    ACS APPLIED MATERIALS & INTERFACES   8 ( 18 )   11226 - 11236   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Direct encapsulation of hydrophobic drugs into amphiphilic block copolymer micelles is frequently subjected to low drug loading efficiency (DLE) and loading content (DLC), as well as lower micellar stability and uncontrollable drug release. In this report, we prepare the copolymer prodrugs (PPEMA-co-PCPTM) via reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(piperidin-1-yl)ethyl methacrylate (PEMA) and reduction-responsive CPT monomer (CPTM), which were quantitatively encapsulated into poly(ethylene glycol)-block-poly(epsilon-caprolactone) (PEG-b-PCL) micelles. The polymer prodrug-loaded nanoparticles showed high stability for a long time in aqueous solution or blood serum and even maintain similar size after a lyophilization-dissolution cycle. The tumoral pH (similar to 6.8)-responsive properties of PPEMA segments endow the micellar cores with triggered transition from neutral to positively charged and swellable properties. The PEG-b-PCL nanoparticles loading polymer prodrugs (PPEMA-b-PCPTM) eliminated burst drug release. Simultaneously, CPT drug release can be triggered by reductive agents and solution pH. At pH 6.8, efficient cellular internalization was achieved due to positively charged cores of the nanoparticles. As compared with nanoparticles loading PCPTM, higher cytotoxicity was observed by the nanoparticles loading PPEMA-b-PCPTM at pH 6.8. Further multicellular tumor spheroid (MCTs) penetration and growth suppression studies demonstrated that high-efficiency penetration capability and significant size shrinkage of MCTs were achieved after treatment by PPEMA-b-PCPTM-loaded nanoparticles at pH 6.8. Therefore, the responsive polymer prodrug encapsulation strategy represents an effective method to overcome the disadvantages of common hydrophobic drug encapsulation approaches by amphiphilic block copolymer micelles and simultaneously endows the nanoparticles with responsive drug release behaviors as well as enhanced cellular internalization and tumor penetration capability.

    DOI: 10.1021/acsami.5b12227

  • Self-sufficing H2O2-responsive nanocarriers through tumor-specific H2O2 production for synergistic oxidation-chemotherapy 査読

    Junjie Li, Wendong Ke, Lei Wang, Mingming Huang, Wei Yin, Ping Zhang, Qixian Chen, Zhishen Ge

    JOURNAL OF CONTROLLED RELEASE   225   64 - 74   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    One of distinct features in tumor tissues is the elevated concentration of reactive oxygen species (ROS) during tumor immortality, proliferation and metastasis. However, ROS-responsive materials are rarely utilized in the field of in vivo tumoral ROS-responsive applications due to the fact that the intrinsic ROS level in the tumors could not escalate to an adequate level that the developed materials can possibly respond. Herein, palmitoyl ascorbate (PA) as a prooxidant for hydrogen peroxide (H2O2) production in tumor tissue is strategically compiled into a H2O2-responsive camptothecin (CPT) polymer prodrug micelle, which endowed the nanocarriers with self-sufficing H2O2 stimuli in tumor tissues. Molecular oncology manifests the hallmarks of tumoral physiology with deteriorating propensity in eliminating hazardous ROS. H2O2 production was demonstrated to specifically sustain in tumors, which not only induced tumor cell apoptosis by elevated oxidation stress but also served as autochthonous H2O2 resource to trigger CPT release for chemotherapy. Excess H2O2 and released CPT could penetrate into cells efficiently, which showed synergistic cytotoxicity toward cancer cells. Systemic therapeutic trial revealed potent tumor suppression of the proposed formulation via synergistic oxidation-chemotherapy. This report represents a novel nanomedicine platform combining up-regulation of tumoral H2O2 level and self-sufficing H2O2-responsive drug release to achieve novel synergistic oxidation-chemotherapy. (C) 2016 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.jconrel.2016.01.029

  • Endogenous Stimuli‐Sensitive Multistage Polymeric Micelleplex Anticancer Drug Delivery System for Efficient Tumor Penetration and Cellular Internalization 査読

    リージェンジェ

    Advanced healthcare materials   4 ( 15 )   2206 - 2219   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Endogenous Stimuli-Sensitive Multistage Polymeric Micelleplex Anticancer Drug Delivery System for Efficient Tumor Penetration and Cellular Internalization
    To efficiently deliver anticancer drugs to the entire tumor tissue and cancer cells, an endogenous stimuli-sensitive multistage polymeric micelle-plex drug delivery system is developed via electrostatic complexation between poly(ethylene glycol)-block-poly[(N'-dimethylmaleoyl-2-aminoethyl)aspartamide]-block-poly(epsilon-caprolactone) (PEG-b-PAsp(EDA-DM)-b-PCL) triblock copolymer micelles and cisplatin prodrug (Pt(IV))-conjugated cationic poly(amidoamine) dendrimers (PAMAM-Pt(IV)). The micelleplexes maintain structural stability at pH 7.4 ensuring long blood circulation and high tumor accumulation level, while they exhibit triggered release of secondary PAMAM.Pt( IV) dendrimer nanocarriers at tumoral acidity (approximate to pH 6.8) due to acid-labile charge-reversal properties of PAsp(EDA-DM) component under mildly acidic condition. The released PAMAM delivery nanocarriers with small size and slightly positive charges exhibit significantly deep tumor tissue penetration and efficient cellular internalization, followed by release of active cisplatin anticancer drug in intracellular reducing medium. In vivo investigation reveals that the Pt(IV)-loading micelleplexes significantly suppress tumor growth via intravenous injection due to synergistic effect of long circulation in bloodstream, high tumor accumulation, deep tumor tissue penetration, and efficient cellular internalization. Thus, the micelleplexes with stimuli-responsive multistage release feature show great potentials for better therapeutic efficacy of cancer especially through enhanced tumor penetration and cellular internalization.

    DOI: 10.1002/adhm.201500379

  • A Near‐Infrared Photothermal Effect‐Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin‐Loaded Polymeric Micelles Mediated by Reversible Diels–Alder Reaction 査読

    リージェンジェ

    Macromolecular rapid communications   36 ( 20 )   1841 - 1849   2015年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    A Near-Infrared Photothermal Effect-Responsive Drug Delivery System Based on Indocyanine Green and Doxorubicin-Loaded Polymeric Micelles Mediated by Reversible Diels-Alder Reaction
    Near-infrared light (NIR) possesses great advantages for light-responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR-responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)-loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)-block-poly(furfuryl methacrylate) (POEGMA-b-PFMA), are synthesized by sequential reversible addition-fragmentation chain-transfer (RAFT) polymerization, followed by modification with N-octyl maleimide through Diels-Alder (DA) reaction to produce POEGMA-b-POMFMA. The self-assembly of POEGMA-b-POMFMA by nanoprecipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase-induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR-triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation.

    DOI: 10.1002/marc.201500337

  • Endosomal-escape polymers based on multicomponent reaction-synthesized monomers integrating alkyl and imidazolyl moieties for efficient gene delivery 査読

    リージェンジェ

    ACS Macro Letters   4 ( 10 )   1123 - 1127   2015年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Endosomal-escape polymers based on multicomponent reaction-synthesized monomers integrating alkyl and imidazolyl moieties for efficient gene delivery

    DOI: 10.1021/acsmacrolett.5b00615

  • Ternary polyplex micelles with PEG shells and intermediate barrier to complexed DNA cores for efficient systemic gene delivery 査読

    Junjie Li, Qixian Chen, Zengshi Zha, Hui Li, Kazuko Toh, Anjaneyulu Dirisala, Yu Matsumoto, Kensuke Osada, Kazunori Kataoka, Zhishen Ge

    JOURNAL OF CONTROLLED RELEASE   209   77 - 87   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Simultaneous achievement of prolonged retention in blood circulation and efficient gene transfection activity in target tissues has always been a major challenge hindering in vivo applications of nonviral gene vectors via systemic administration. Herein, we constructed novel rod-shaped ternary polyplex micelles (TPMs) via complexation between the mixed block copolymers of poly(ethylene glycol)-b-poly{N'-[N-(2-aminoethyl)-2-aminoethyl] aspartamide} (PEG-b-PAsp(DET)) and poly(N-isopropylacrylamide)-b-PAsp(DET) (PNIPAM-b-PAsp (DET)) and plasmid DNA (pDNA) at room temperature, exhibiting distinct temperature-responsive formation of a hydrophobic intermediate layer between PEG shells and pDNA cores through facile temperature increase from room temperature to body temperature (similar to 37 degrees C). As compared with binary polyplex micelles of PEG-b-PAsp(DET) (BPMs), TPMs were confirmed to condense pDNA into a more compact structure, which achieved enhanced tolerability to nuclease digestion and strong counter polyanion exchange. In vitro gene transfection results demonstrated TPMs exhibiting enhanced gene transfection efficiency due to efficient cellular uptake and endosomal escape. Moreover, in vivo performance evaluation after intravenous injection confirmed that TPMs achieved significantly prolonged blood circulation, high tumor accumulation, and promoted gene expression in tumor tissue. Moreover, TPMs loading therapeutic pDNA encoding an anti-angiogenic protein remarkably suppressed tumor growth following intravenous injection into H22 tumor-bearing mice. These results suggest TPMs with PEG shells and facilely engineered intermediate barrier to inner complexed pDNA have great potentials as systemic nonviral gene vectors for cancer gene therapy. (C) 2015 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.jconrel.2015.04.024

  • Gene therapy for nucleus pulposus regeneration by heme oxygenase-1 plasmid DNA carried by mixed polyplex micelles with thermo-responsive heterogeneous coronas 査読

    Ganjun Feng, Hongying Chen, Junjie Li, Qiang Huang, Melanie J. Gupte, Hao Liu, Yueming Song, Zhishen Ge

    BIOMATERIALS   52   1 - 13   2015年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Safe and high-efficiency gene therapy for nucleus pulposus (NP) regeneration was urgently desired to treat disc degeneration-associated diseases. In this work, an efficient nonviral cationic block copolymer gene delivery system was used to deliver therapeutic plasmid DNA (pDNA), which was prepared via complexation between the mixed cationic block copolymers, poly(ethylene glycol)-block-poly{N-[N-(2-aminoethyl)-2-aminoehtyl]aspartamide) IPEG-b-PAsp(DET)] and poly(N-isopropylacrylamide)-block-PAsp(DET) [PNIPAM-b-PAsp(DET)], and pDNA at 25 degrees C. The mixed polyplex micelles (MPMs) containing heterogeneous coronas with hydrophobic and hydrophilic microdomains coexisting could be obtained upon heating from 25 to 37 degrees C, which showed high tolerability against nuclease and strong resistance towards protein adsorption. The gene transfection efficiency of MPMs in NP cells was significantly higher than that of regular polyplex micelles prepared from sole block copolymer of PEG-b-PAsp(DET) (SPMs) in in vitro and in vivo evaluation due to the synergistic effect of improved colloidal stability and low cytotoxicity. High expression of heme oxygenase-1 (HO-1) in NP cells transfected by MPMs loading HO-1 pDNA significantly decreased the expression activity of matrix metalloproteinases 3 (MMP-3) and cyclooxygenase-2 (COX-2) induced by interleukin-1 beta (IL-1 beta), and simultaneously increased the NP phenotype-associated genes such as aggrecan, type II collagen, and SOX-9. Moreover, the therapeutic effects of MPMs loading pDNA were tested to treat disc degeneration induced by stab injury. The results demonstrated that administration of HO-1 pDNA carried by MPMs in rat tail discs apparently reduced inflammatory responses induced by need stab and increased glycosaminoglycan (GAG) content, finally achieving better therapeutic efficacy as compared with SPMs. Consequently, MPMs loading HO-1 pDNA were demonstrated to be potential as a safe and high-efficiency nonviral gene delivery system for retarding or regenerating the degenerative discs. (C) 2015 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.biomaterials.2015.02.024

  • Polyplex Micelles with Thermoresponsive Heterogeneous Coronas for Prolonged Blood Retention and Promoted Gene Transfection 査読

    Yang Li, Junjie Li, Biao Chen, Qixian Chen, Guoying Zhang, Shiyong Liu, Zhishen Ge

    BIOMACROMOLECULES   15 ( 8 )   2914 - 2923   2014年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adequate retention in blood circulation is a prerequisite for construction of gene delivery carriers for systemic applications. The stability of gene carriers in the bloodstream requires them to effectively resist protein adsorption and maintain small size in the bloodstream avoiding dissociation, aggregation, and nuclease digestion under salty and proteinous medium. Herein, a mixture of two block catiomers consisting of the same cationic block, poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PAsp(DET)), but varying shell-forming blocks, poly[2-(2-methoxyethoxy) ethyl methacrylate] (PMEO(2)MA), and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), was used to complex with plasmid DNA (pDNA) to fabricate polyplex micelles with mixed shells (MPMs) at 20 degrees C. The thermoresponsive property of PMEO(2)MA allows distinct phase transition from hydrophilic to hydrophobic by increasing incubation temperature from 20 to 37 degrees C, which results in a distinct heterogeneous corona containing hydrophilic and hydrophobic regions at the surface of the MPMs. Subsequent study verified that this transition promoted further condensation of pDNA, thereby giving rise to improved complex and colloidal stability. The proposed system has shown remarkable stability in salty and proteinous solution and superior tolerance to nuclease degradation. As compared with polyplex micelles formed from single POEGMA-b-PAsp(DET) block copolymer, in vivo circulation experiments in the bloodstream further confirmed that the retention time of MPMs was prolonged significantly. Moreover, the proposed system exhibited remarkably high cell transfection activity especially at low N/P ratios and negligible cytotoxicity and thus portends promising utility for systemic gene therapy applications.

    DOI: 10.1021/bm500532x

▼全件表示

書籍等出版物

  • Thermo-responsive polyplex micelles with PEG shells and PNIPAM layer to protect DNA cores for systemic gene therapy

    リージェンジェ(担当:単著)

    Humana Press, New York, NY 

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    記述言語:英語  

    https://link.springer.com/protocol/10.1007/978-1-4939-3718-9_17

講演・口頭発表等

  • Enzyme-responsive asymmetric polymersomes with triggered apoptosis-mimicking flip-flop of cell-penetrating inner shells 国際会議

    リージェンジェ

    4th Symposium on Innovative Polymers for Controlled Delivery (SIPCD 2016)  2016年9月 

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    記述言語:英語  

    国名:その他  

    Enzyme-responsive asymmetric polymersomes with triggered apoptosis-mimicking flip-flop of cell-penetrating inner shells

  • Novel stimuli-responsive block copolymers as nonviral gene delivery vectors for efficiently overcoming physiologic barriers 国際会議

    リージェンジェ

    the 1st International Conference on Nanomedicine (ChinaNanomedicine 2015, Hangzhou, China)  2016年2月 

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    記述言語:英語  

    国名:その他  

    Novel stimuli-responsive block copolymers as nonviral gene delivery vectors for efficiently overcoming physiologic barriers

MISC

  • Enzyme-responsive asymmetric polymersomes with triggered apoptosis-mimicking flip-flop of cell-penetrating inner shells

    Junjie Li, Zhishen Ge

    JOURNAL OF CONTROLLED RELEASE   2017年8月

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    記述言語:英語  

    DOI: 10.1016/j.jconrel.2017.03.380

  • Novel stimuli-responsive block copolymers as nonviral gene delivery vectors for efficiently overcoming physiologic barriers

    Zhishen Ge, Junjie Li, Yang Li

    NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE   2016年2月

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    記述言語:英語  

    DOI: 10.1016/j.nano.2015.12.238

共同研究・競争的資金等の研究課題

  • Development of Reversible Double-Layer Polymer Modification Technology to Break the Safety/Efficacy Trade-Off of Delivering Enzyme

    研究課題/領域番号:23H03740  2023年 - 2025年

    日本学術振興会  科学研究費助成事業  基盤研究(B)

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    担当区分:研究代表者  資金種別:科研費

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