Jian Deng

Collaborative Innovation Center of Chemical Science and Engineering Tianjin

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Yanjun Zhao

Tianjin University

Zheng Wang

Tianjin University

Fang Liu

Tianjin University

Aiping Fan

Tianjin University

Peipei Dai

Collaborative Innovation Center of Chemical Science and Engineering Tianjin

Di Lu

Guangzhou Medical University

Min Gao

Jiangnan University

Jundong Zhu

Army Medical University

Yang An

Jilin University

Xuan Meng

Tianjin University of Science and Technology

Cooperative Institutions

Tianjin University

Collaborative Innovation Center of Chemical Science and Engineering Tianjin

Tianjin Institute of Pharmaceutical Research (China)

Nankai University

The University of Texas Health Science Center at San Antonio

Chinese Academy of Sciences

Tianjin University of Science and Technology

Chinese Academy of Medical Sciences & Peking Union Medical College

Peking University

Huazhong University of Science and Technology

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Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery

ACS Applied Materials & Interfaces (2018)

Juanjuan Li Xuan Meng Jian Deng Di Lu Xin Zhang

Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 ± 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 ± 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy.

10.1021/acsami.8b06299

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Citations (86)

Triggered All-Active Metal Organic Framework: Ferroptosis Machinery Contributes to the Apoptotic Photodynamic Antitumor Therapy

Nano Letters (2019)

Xuan Meng Jian Deng Fang Liu Tao Guo Mengying Liu

Nanoscale photodynamic therapy (PDT) is an appealing antitumor modality for which apoptosis is the major mechanism of toxicity induction. It was postulated that the highly reactive singlet oxygen in PDT could deplete glutathione (GSH) and activate ferroptosis, the extent to which could be further manipulated by a redox-responsive nanocarrier. To validate this, a disulfide-bearing imidazole ligand coordinated with zinc to form an all-active metal organic framework (MOF) nanocarrier where a photosensitizer (chlorin e6/Ce6) was encapsulated. Regardless of light irradiation, the Ce6-loaded nanocarrier caused the depletion of intracellular GSH via the disulfide–thiol exchange reaction in a murine mammary carcinoma cell line (4T1). The GSH depletion further caused the inactivation of glutathione peroxide 4 (GPX4) and the enhancement of cytotoxicity that was alleviated by ferroptosis inhibitors. The superior in vivo antitumor efficacy of the all-active nanocarrier was corroborated in a 4T1 tumor-bearing mice model regarding tumor growth suppression and animal survival rate. The coadministration of an iron chelator weakened the antitumor potency of the nanocarrier due to ferroptosis inhibition, which was supported by the fact of tumor growth upsurge and the recovered GPX4 activity. The current work highlights the contribution of ferroptotic machinery to antitumor PDT via an activatable, adaptable, all-active MOF nanocarrier.

Nanocarriers

10.1021/acs.nanolett.9b02904

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Electron-Accepting Micelles Deplete Reduced Nicotinamide Adenine Dinucleotide Phosphate and Impair Two Antioxidant Cascades for Ferroptosis-Induced Tumor Eradication

ACS Nano (2020)

Xuliang Guo Fang Liu Jian Deng Peipei Dai Yan Qin

Ferroptotic antitumor therapy has been compromised by various intracellular antioxidants, particularly glutathione and thioredoxin. Both are cofactors of glutathione peroxide 4 (GPX4) that act against oxidative stress via catalyzing the reduction of lipid peroxides. It was postulated that tailored polymer micelles could enhance ferroptotic antitumor efficacy via diminishing glutathione and thioredoxin under hypoxia. The aim was to engineer hypoxia-responsive micelles for selective enhancement of ferroptotic cell death in solid tumor. The polymer contains hydrophilic poly(ethylene glycol) (PEG) that is linked by azobenzene linker with nitroimidazole-conjugated polypeptide. The tailored polymer could self-assemble into nanoscale micelles to encapsulate RAS-selective lethal small molecule 3, a covalent GPX4 inhibitor. Under hypoxia, the azobenzene moiety enabled PEG shedding and enhanced micelles uptake in 4T1 cells. Likewise, the nitroimidazole moiety was reduced by the overexpressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient depletion of NADPH. This impaired both the glutathione and thioredoxin redox cycle, leading to diminished intracellular glutathione and thioredoxin. The selective potency of ferroptotic micelles in depleting NADPH, glutathione and thioredoxin was further verified in vivo in the 4T1 tumor xenograft mice model. This work highlights the role of hypoxia-responsive polymers in enhancing the potency of ferroptotic inducers against solid tumors without additional side effects to healthy organs.

10.1021/acsnano.0c00764

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Citations (158)

NAD+-dependent Deacetylase SIRT3 Regulates Mitochondrial Protein Synthesis by Deacetylation of the Ribosomal Protein MRPL10

Journal of Biological Chemistry (2009)

Yongjie Yang Hüseyin Çimen Min-Joon Han Tong Shi Jian Deng

A member of the sirtuin family of NAD(+)-dependent deacetylases, SIRT3, is located in mammalian mitochondria and is important for regulation of mitochondrial metabolism, cell survival, and longevity. In this study, MRPL10 (mitochondrial ribosomal protein L10) was identified as the major acetylated protein in the mitochondrial ribosome. Ribosome-associated SIRT3 was found to be responsible for deacetylation of MRPL10 in an NAD(+)-dependent manner. We mapped the acetylated Lys residues by tandem mass spectrometry and determined the role of these residues in acetylation of MRPL10 by site-directed mutagenesis. Furthermore, we observed that the increased acetylation of MRPL10 led to an increase in translational activity of mitochondrial ribosomes in Sirt3(-/-) mice. In a similar manner, ectopic expression and knockdown of SIRT3 in C2C12 cells resulted in the suppression and enhancement of mitochondrial protein synthesis, respectively. Our findings constitute the first evidence for the regulation of mitochondrial protein synthesis by the reversible acetylation of the mitochondrial ribosome and characterize MRPL10 as a novel substrate of the NAD(+)-dependent deacetylase, SIRT3.

SIRT3

Mitochondrial ribosome

Ribosomal protein

10.1074/jbc.m109.053421

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Citations (158)

Software architecture evaluation model of the utility management system

Xiaoting Zhang Jian Deng

We build the Utility Management System software architecture evaluation model for reducing the risk of software system. we got t the Utility Management System software architecture needs, Combined with the Quality Attribute Workshop method and the PALM method, from the main function, external cross-linking relationship and development trend, so as to build five evaluation dimensions of software architecture, including modularity, technology maturity, competition processing, independence, reliability. Then grading each evaluation dimension to get the Utility Management System software architecture evaluation model. The model can realize the risk identification of early development of the Utility Management System software system through the comprehensive evaluation of five dimensions of software architecture, so as to help improve the quality of software system and reduce the cost of the whole life cycle of the system.

Resource-oriented architecture

10.1117/12.2686872

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Boosting the Ferroptotic Antitumor Efficacy via Site-Specific Amplification of Tailored Lipid Peroxidation

ACS Applied Materials & Interfaces (2019)

Yang An Jundong Zhu Fang Liu Jian Deng Xuan Meng

Ferroptosis is an iron-dependent cell death pathway that can eradicate certain apoptosis-insensitive cancer cells. The ferroptosis-inducing molecules are tailored lipid peroxides whose efficacy is compromised in hypoxic solid tumor and lack of tumor selectivity. It has been demonstrated that ascorbate (Asc) in pharmacological concentrations can selectively kill cancer cells via accumulating hydrogen peroxide (H2O2) only in tumor extracellular fluids. It was hypothesized that Asc-induced, selective enrichment of H2O2 in tumor coupled with Fe3+ codelivery could simultaneously address the above two problems via boosting the levels of hydroxyl radicals and oxygen in the tumor site to ease peroxidation initiation and propagation, respectively. The aim of this work was to synergize the action of Asc with lipid-coated calcium phosphate (CaP) hybrid nanocarrier that can concurrently load polar Fe3+ and nonpolar RSL3, a ferroptosis inducer with the mechanism of inhibiting lipid peroxide repair enzyme (GPX4). The hybrid nanocarriers showed accelerated cargo release at acidic conditions (pH 5.0). The combinational approach (Asc plus nanocarrier) produced significantly elevated levels of hydroxyl radicals, lipid peroxides, and depleted glutathione under hypoxia, which was accompanied with the strong cytotoxicity (IC50 = 1.2 ± 0.2 μM) in the model 4 T1 cells. In the 4 T1 tumor-bearing xenograft mouse model, the intravenous nanocarrier delivery plus intraperitoneal Asc administration resulted in a superior antitumor performance in terms of tumor suppression, which did not produce supplementary adverse effects to the healthy organs. This work provides a novel approach to enhance the potency of ferroptotic nanomedicine against solid tumors without inducing additional side effects.

Nanocarriers

Tumor Hypoxia

10.1021/acsami.9b10954

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Citations (81)

Stereoselective Stabilization of Polymeric Vitamin E Conjugate Micelles

Biomacromolecules (2017)

Min Gao Jian Deng Huiying Chu Yu Tang Zheng Wang

Vitamin E (α-tocopherol; TPGS) micelle is a robust nanocarrier in delivering hydrophobic active pharmaceutical ingredients, but it is suffering from poor stability that is essential in terms of pharmaceutical and biomedical applications. Taking advantage of the chirality of vitamin E, this work reports the stereoselective stabilization of polymer-vitamin E conjugate micelles. Vitamin E was covalently linked to multivalent methoxy poly(ethylene glycol)-co-poly(glutamic acid), generating amphiphilic conjugates that could self-assemble into micelles. Eight types of micelles were produced via tailored combination of polymer backbone and side chain with different chirality. The particle size and critical micelle concentration analysis demonstrated a correlation between conjugate chirality and micelle stability. The most stable micelles were obtained when poly(glutamic acid) and vitamin E both are dextrorotatory, because of the high degree of α-helix revealed by both circular dichroism spectroscopy and molecular dynamics simulation. This phenomenon was further verified by the fluorescence resonance energy transfer (FRET) analysis in HepG2 cells. The current work not only provides a method to enhance the stability of vitamin E micelles, but also adds an additional facile tool in regulating the stability of polymer conjugate micelles without changing the conjugate composition.

Conjugate

Nanocarriers

Chirality

10.1021/acs.biomac.7b01409

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Citations (40)

Hierarchical theranostic nanomedicine: MRI contrast agents as a physical vehicle anchor for high drug loading and triggered on-demand delivery

Journal of Materials Chemistry B (2018)

Guangqin Liu Jian Deng Fang Liu Zheng Wang Dan Peer

The loading of drugs and imaging agents in theranostic nanomedicines by a physical approach is usually poor (<5%), which limits their therapeutic effect and translation potential. We report a hierachical hybrid nanocarrier made of a manganese phosphate core, an outermost lipid shell, and an electrostatically deposited campothecin phosphonate interfacial middle layer. The hydrophobic interactions between camptothecin and lipid layers maintained the integrity and stability of the hybrid nanocarrier. Such a nanoplatform could surprisingly load camptothecin over 15% (w/w) with decent serum stability. The nanocarrier displayed pH-dependent cargo release profiles due to particle collapse under acidic conditions under which the r1 relaxivity of magnetic resonance imaging (MRI) was 25.2 mM-1 s-1 (pH 5.0). The nanocarrier could efficiently transport camptothecin into 4T1 cells with a half maximal inhibitory concentration of 5.4 ± 0.3 μM. Both in vivo MRI and fluorescence imaging analysis revealed that the nanocarrier could competently deliver the cargo to the tumor site. The anticancer efficacy of camptothecin-loaded nanocarrier was proved using the same 4T1 tumor-bearing mice model coupled with the histological and apoptosis analysis. This work not only presented a novel drug encapsulation approach, but also provided a new theranostic hybrid nanoplatform which could realize MRI-guided delivery of hydrophobic agents.

Nanocarriers

Camptothecin

MRI contrast agent

10.1039/c8tb00135a

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Citations (13)

Self-immolative micellar drug delivery: The linker matters

Nano Research (2018)

Xuan Meng Min Gao Jian Deng Di Lu Aiping Fan

Linker

Conjugate

HeLa

10.1007/s12274-018-2134-5

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Citations (30)

Energy‐Free, Singlet Oxygen‐Based Chemodynamic Therapy for Selective Tumor Treatment without Dark Toxicity

Advanced Healthcare Materials (2019)

Yanrui Chen Jian Deng Fang Liu Peipei Dai Yang An

Abstract Traditional singlet oxygen‐based antitumor therapies have been burdened with the necessity of external energy (e.g., light and ultrasound) and harmful dark toxicity. Ascorbate at the pharmacological concentration could accumulate hydrogen peroxide only in the tumor site. It is postulated that the concurrent delivery of ascorbate and nanoparticulate hypochlorous ion (ClO − ) could produce singlet oxygen at the tumor site as an energy‐free, tumor‐specific therapy. The ClO − is loaded in a hybrid core–shell nanocarrier consisting of a zeolitic imidazolate framework and amphiphilic poloxamer 188. Intracellular singlet oxygen production is verified in 4T1 cells by the cooperation between hybrid nanocarriers and ascorbate, which induces significant apoptotic cell death. Upon intravenous nanocarriers delivery plus intraperitoneal ascorbate administration to xenograft mice, the in vivo antitumor efficacy of this cooperative nanomedicine is demonstrated without noticeable side‐effects. This work demonstrates a proof‐of‐concept of singlet oxygen‐based chemodynamic therapy for selective tumor eradication, which produces a novel trigger‐free, singlet oxygen‐based cancer therapy without the side effects of traditional photodynamic and sonodynamic therapy.

Sonodynamic therapy

Nanocarriers

Rose bengal

10.1002/adhm.201900366

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Citations (63)