55 results on '"Keman Cheng"'
Search Results
2. Modular-designed engineered bacteria for precision tumor immunotherapy via spatiotemporal manipulation by magnetic field
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Xiaotu Ma, Xiaolong Liang, Yao Li, Qingqing Feng, Keman Cheng, Nana Ma, Fei Zhu, Xinjing Guo, Yale Yue, Guangna Liu, Tianjiao Zhang, Jie Liang, Lei Ren, Xiao Zhao, and Guangjun Nie
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Science - Abstract
Abstract Micro-nano biorobots based on bacteria have demonstrated great potential for tumor diagnosis and treatment. The bacterial gene expression and drug release should be spatiotemporally controlled to avoid drug release in healthy tissues and undesired toxicity. Herein, we describe an alternating magnetic field-manipulated tumor-homing bacteria developed by genetically modifying engineered Escherichia coli with Fe3O4@lipid nanocomposites. After accumulating in orthotopic colon tumors in female mice, the paramagnetic Fe3O4 nanoparticles enable the engineered bacteria to receive and convert magnetic signals into heat, thereby initiating expression of lysis proteins under the control of a heat-sensitive promoter. The engineered bacteria then lyse, releasing its anti-CD47 nanobody cargo, that is pre-expressed and within the bacteria. The robust immunogenicity of bacterial lysate cooperates with anti-CD47 nanobody to activate both innate and adaptive immune responses, generating robust antitumor effects against not only orthotopic colon tumors but also distal tumors in female mice. The magnetically engineered bacteria also enable the constant magnetic field-controlled motion for enhanced tumor targeting and increased therapeutic efficacy. Thus, the gene expression and drug release behavior of tumor-homing bacteria can be spatiotemporally manipulated in vivo by a magnetic field, achieving tumor-specific CD47 blockage and precision tumor immunotherapy.
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- 2023
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3. Personalized cancer vaccines from bacteria-derived outer membrane vesicles with antibody-mediated persistent uptake by dendritic cells
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Jie Liang, Keman Cheng, Yao Li, Jiaqi Xu, Yiwei Chen, Nana Ma, Qingqing Feng, Fei Zhu, Xiaotu Ma, Tianjiao Zhang, Yale Yue, Guangna Liu, Xinjing Guo, Zhiqiang Chen, Xinwei Wang, Ruifang Zhao, Ying Zhao, Jian Shi, Xiao Zhao, and Guangjun Nie
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Tumor vaccine ,Outer membrane vesicles ,Antibody modification ,Antigen display ,Dendritic cell uptake ,Myeloid derived suppressor cells ,Science (General) ,Q1-390 - Abstract
Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen, thus efficiently facilitating antitumor adaptive immunity. Bacteria-derived outer membrane vesicles (OMVs) are an excellent candidate due to their abundance of pathogen associated molecular patterns. However, during the uptake of OMVs by dendritic cells (DCs), the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage, a phenomenon we refer to as “maturation-induced uptake obstruction” (MUO). Herein we decorated OMV with the DC-targeting αDEC205 antibody (OMV-DEC), which endowed the nanovaccine with an uptake mechanism termed as “not restricted to maturation via antibody modifying” (Normandy), thereby overcoming the MUO phenomenon. We also proved the applicability of this nanovaccine in identifying the human tumor neoantigens through rapid antigen display. In summary, this engineered OMV represents a powerful nanocarrier for personalized cancer vaccines, and this antibody modification strategy provides a reference to remodel the DC uptake pattern in nanocarrier design.
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- 2022
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4. Lipid‐Peptide‐mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer
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Qinglin Li, Lizhuo Zhang, Jiayan Lang, Zhuo Tan, Qingqing Feng, Fei Zhu, Guangna Liu, Zhangguo Ying, Xuefei Yu, He Feng, Heqing Yi, Qingliang Wen, Tiefeng Jin, Keman Cheng, Xiao Zhao, and Minghua Ge
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anaplastic thyroid carcinoma ,lipid‐peptide‐mRNA nanoparticles ,mRNA delivery ,sodium iodide transporter ,Science - Abstract
Abstract Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid‐peptide‐mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase‐free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10‐fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (131I) accumulation in the tumor, thereby significantly inhibiting tumor growth. Overall, this work designs three arginine‐rich peptide nanoparticles, contributing to the choice of liposome cores for gene delivery. LPm NP can serve as a promising adjunctive therapy for patients with ATC by restoring iodine affinity and enhancing the therapeutic efficacy of radioactive iodine.
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- 2023
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5. Author Correction: Modular-designed engineered bacteria for precision tumor immunotherapy via spatiotemporal manipulation by magnetic field
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Xiaotu Ma, Xiaolong Liang, Yao Li, Qingqing Feng, Keman Cheng, Nana Ma, Fei Zhu, Xinjing Guo, Yale Yue, Guangna Liu, Tianjiao Zhang, Jie Liang, Lei Ren, Xiao Zhao, and Guangjun Nie
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Science - Published
- 2023
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6. Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology
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Keman Cheng, Ruifang Zhao, Yao Li, Yingqiu Qi, Yazhou Wang, Yinlong Zhang, Hao Qin, Yuting Qin, Long Chen, Chen Li, Jie Liang, Yujing Li, Jiaqi Xu, Xuexiang Han, Gregory J. Anderson, Jian Shi, Lei Ren, Xiao Zhao, and Guangjun Nie
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Science - Abstract
Outer membrane vesicles (OMVs), non-replicative particles secreted by Gram-negative bacteria, are known for their immunostimulatory and adjuvant properties. Here, by employing a Plug-and-Display technology, the authors engineer OMVs to display tumor antigens on the surface, a platform that promotes anti-tumor immune responses in preclinical cancer models.
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- 2021
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7. Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis
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Nana Ma, Zhiqiang Chen, Guangna Liu, Yale Yue, Yao Li, Keman Cheng, Xiaotu Ma, Qingqing Feng, Jie Liang, Tianjiao Zhang, Xiaoyu Gao, Xinwei Wang, Xinjing Guo, Fei Zhu, Guangjun Nie, and Xiao Zhao
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General Engineering ,General Physics and Astronomy ,General Materials Science - Abstract
In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a "Plug-and-Display" delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency. However, we found that the presence of a subcutaneous xenograft seriously hampered the efficiency of NanoVac to eliminate lung metastases, with the subcutaneous xenograft mimicking the primary tumor burden in clinical practice. The primary tumor secreted significant amounts of granulocyte colony-stimulating factor (G-CSF) and altered the epigenetic features of granulocyte monocyte precursor cells (GMPs) in the bone marrow, thus disrupting systemic immunity, particularly the function of APCs, and ultimately resulting in NanoVac failure to affect metastases. These changes in the systemic immune macroenvironment were plastic, and debulking surgery of primary tumor resection reversed the dysfunction of APCs and failure of NanoVac. These results demonstrate that, in addition to the formulation design of the tumor nanovaccines themselves, the systemic immune macroenvironment incapacitated by tumor development is another key factor that cannot be ignored to affect the efficiency of tumor nanovaccines, and the combination of primary tumor resection with NanoVac is a promising radical treatment for widely metastatic tumors.
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- 2022
8. Cell‐Reprogramming‐Inspired Dynamically Responsive Hydrogel Boosts the Induction of Pluripotency via Phase‐Separated Biomolecular Condensates
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Fei Zhu, Na Yan, Xukun Lu, Junchao Xu, Haiyan Gu, Jie Liang, Keman Cheng, Xiaona Wang, Xiaotu Ma, Nana Ma, Xiao Zhao, Chunying Chen, and Guangjun Nie
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Mechanics of Materials ,Mechanical Engineering ,General Materials Science - Published
- 2023
9. Antigen-bearing outer membrane vesicles as tumour vaccines produced in situ by ingested genetically engineered bacteria
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Yale Yue, Jiaqi Xu, Yao Li, Keman Cheng, Qingqing Feng, Xiaotu Ma, Nana Ma, Tianjiao Zhang, Xinwei Wang, Xiao Zhao, and Guangjun Nie
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Mice ,Antigens, Neoplasm ,Cell Membrane ,Escherichia coli ,Biomedical Engineering ,Animals ,Medicine (miscellaneous) ,Bioengineering ,Arabinose ,Cancer Vaccines ,Computer Science Applications ,Biotechnology - Abstract
The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria. In mice, oral administration of arabinose and the genetically engineered E. coli led to the production of OMVs that crossed the intestinal epithelium into the lamina propria, where they stimulated dendritic cell maturation. In a mouse model of pulmonary metastatic melanoma and in mice bearing subcutaneous colon tumours, the antigen-bearing OMVs inhibited tumour growth and protected the animals against tumour re-challenge. The in situ production of OMVs by genetically modified commensal bacteria for the delivery of stimulatory molecules could be leveraged for the development of other oral vaccines and therapeutics.
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- 2022
10. Redox-Responsive Functional Iron Oxide Nanocrystals for Magnetic Resonance Imaging-Guided Tumor Hyperthermia Therapy and Heat-Mediated Immune Activation
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Yao Li, Xiaotu Ma, Xiaoli Liu, Yale Yue, Keman Cheng, Qiang Zhang, Guangjun Nie, Xiao Zhao, and Lei Ren
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General Materials Science - Published
- 2022
11. Antigen-Capturing Oncolytic Adenoviruses Along with IDO Blockade for Improved Tumor Immunotherapy
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Chen Xu, Keman Cheng, Xinwei Wang, Jingjing Liu, Jie Liang, Guangna Liu, Yichao Lu, Ming Tang, Bingfei Qian, Liting Chen, Zhenguo Cheng, Zhenning Wang, Xiao Zhao, and Funan Liu
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- 2023
12. Injectable Immunotherapeutic Hydrogel Containing RNA-Loaded Lipid Nanoparticles Reshapes Tumor Microenvironment for Pancreatic Cancer Therapy
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Chao Gao, Keman Cheng, Yao Li, Ruining Gong, Xiao Zhao, Guangjun Nie, and He Ren
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Mechanical Engineering ,Bioengineering ,Hydrogels ,General Chemistry ,Condensed Matter Physics ,Pancreatic Neoplasms ,Interferon Regulatory Factors ,Tumor Microenvironment ,Humans ,Nanoparticles ,Immunologic Factors ,General Materials Science ,Immunotherapy ,RNA, Small Interfering - Abstract
Pancreatic cancer immunotherapy is becoming a promising strategy for improving the survival rate of postsurgical patients. However, the low response rate to immunotherapy suggests a low number of antigen-specific T cells and a high number of immunosuppressive tumor-associated macrophages in the pancreatic tumor microenvironment. Herein, we developed an
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- 2022
13. Nanoscale Organization of TRAIL Trimers using DNA Origami to Promote Clustering of Death Receptor and Cancer Cell Apoptosis
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Nana Ma, Keman Cheng, Qingqing Feng, Guangna Liu, Jie Liang, Xiaotu Ma, Zhiqiang Chen, Yichao Lu, Xinwei Wang, Wei He, Hu Xu, Shan Wu, Jiajia Zou, Quanwei Shi, Guangjun Nie, and Xiao Zhao
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Biomaterials ,General Materials Science ,General Chemistry ,Biotechnology - Published
- 2023
14. Site‐Specific Modification of Virus‐Like Particles for Exogenous Tumor Antigen Display and Minimizing Preexisting Immunity
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Keman Cheng, Nana Ma, Jie Liang, Xiaotu Ma, Qingqing Feng, Guangna Liu, Chen Xu, Ming Tang, Lizhuo Zhang, Xiaoyu Gao, Jiaqi Xu, Chufan Wang, Fei Zhu, Xinwei Wang, Xiang Li, Xiao Zhao, and Guangjun Nie
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Biomaterials ,General Materials Science ,General Chemistry ,Biotechnology - Published
- 2023
15. Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy via Immune Activation and Checkpoint Inhibition
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Gregory J. Anderson, Lei Ren, Yinlong Zhang, Yujing Li, Keman Cheng, Jiaqi Xu, Ruifang Zhao, Yao Li, Xiao Zhao, Junchao Xu, Guangna Liu, Kaiyue Zhang, Yazhou Wang, Jian Shi, and Guangjun Nie
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Tumor microenvironment ,Bacterial outer membrane vesicles ,Chemistry ,T cell ,medicine.medical_treatment ,General Engineering ,General Physics and Astronomy ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,01 natural sciences ,Immune checkpoint ,0104 chemical sciences ,Cell biology ,medicine.anatomical_structure ,Immune system ,Ectodomain ,Cancer immunotherapy ,medicine ,General Materials Science ,0210 nano-technology ,Bacterial outer membrane - Abstract
Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may hamper T cell function and limit immunotherapeutic effectiveness. Here, we report the development of genetically engineered OMVs whose surface has been modified by insertion of the ectodomain of programmed death 1 (PD1). This genetic modification does not affect the ability of OMVs to trigger immune activation. More importantly, the engineered OMV-PD1 can bind to PD-L1 on the tumor cell surface and facilitate its internalization and reduction, thereby protecting T cells from the PD1/PD-L1 immune inhibitory axis. Through the combined effects of immune activation and checkpoint suppression, the engineered OMVs drive the accumulation of effector T cells in the tumor, which, in turn, leads to a greater impairment of tumor growth, compared with not only native OMVs but also the commonly used PD-L1 antibody. In conclusion, this work demonstrates the potential of bioengineered OMVs as effective immunotherapeutic agents that can comprehensively regulate the tumor immune microenvironment to effect markedly increased anti-tumor efficacy.
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- 2020
16. Dual-Antigen-Loaded Hepatitis B Virus Core Antigen Virus-like Particles Stimulate Efficient Immunotherapy Against Melanoma
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Huan Min, Shefang Ye, Yaming Zhou, Jun Yang, Yao Li, Tao Du, C.P. Wang, Lei Ren, Keman Cheng, Xi Zhou, Lihuang Li, Yingqiu Qi, Qiang Zhang, Yazhou Wang, and Shengli Bi
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0301 basic medicine ,Materials science ,Innate immune system ,viruses ,medicine.medical_treatment ,virus diseases ,Dendritic cell ,Immunotherapy ,Virus ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Immune system ,Antigen ,Cancer immunotherapy ,030220 oncology & carcinogenesis ,Cancer research ,medicine ,Cytotoxic T cell ,General Materials Science - Abstract
Tumor cells are rich in antigens, which provide a reliable antigen library for the design of personalized vaccines. However, an effective tumor vaccine vector that can efficiently deliver antigens to lymphoid organs to stimulate strong CD8+ cytotoxic T-lymphocyte immune response is still lacking. Here we designed a dual-antigen delivery system based on hepatitis B virus core antigen virus-like particles (HBc VLPs). We first confirmed that different antigen-loaded HBc VLP monomers could be assembled into nanoparticles (hybrid VLPs). Hybrid VLPs could slightly enhance bone marrow-derived dendritic cell maturation in vitro. Strikingly, hybrid VLPs could generate antigen-specific antitumor immunity and innate immunity in vivo which could significantly inhibit tumor growth or metastatic formation in a subcutaneous tumor or lung metastatic tumor model, respectively. Moreover, dual-epitope vaccination generated enhanced T-cell responses that potently inhibited tumor growth and metastatic formation. Together, this study provides a new powerful concept for cancer immunotherapy and suggests a novel design for VLP-based personalized nanomedicine.
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- 2020
17. Modularly Designed Peptide Nanoprodrug Augments Antitumor Immunity of PD-L1 Checkpoint Blockade by Targeting Indoleamine 2,3-Dioxygenase
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Lei Ren, Ying Xu, Xiao Zhao, Yazhou Wang, Guangjun Nie, Yiye Li, Yinlong Zhang, Gregory J. Anderson, Huan Min, Keman Cheng, Ruifang Zhao, and Xuexiang Han
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medicine.medical_treatment ,Immune checkpoint inhibitors ,Peptide ,010402 general chemistry ,01 natural sciences ,Biochemistry ,B7-H1 Antigen ,Catalysis ,Colloid and Surface Chemistry ,PD-L1 ,Tumor Microenvironment ,medicine ,Humans ,Indoleamine-Pyrrole 2,3,-Dioxygenase ,Prodrugs ,Indoleamine 2,3-dioxygenase ,chemistry.chemical_classification ,Tumor microenvironment ,Antitumor immunity ,biology ,Chemistry ,General Chemistry ,Immunotherapy ,0104 chemical sciences ,Blockade ,Drug Design ,Cancer research ,biology.protein ,Nanoparticles ,Oligopeptides - Abstract
The limited efficacy of single-agent immune checkpoint inhibitors in treating tumors has prompted investigations on their combination partners. Here, a tumor-homing indoleamine 2,3-dioxygenase (IDO) nanoinhibitor is reported to selectively inhibit immunosuppressive IDO pathway in the tumor microenvironment. It is self-assembled from a modularly designed peptide-drug conjugate containing a hydrophilic targeting motif (arginyl-glycyl-aspartic acid; RGD), two protonatable histidines, and an ester bond-linked hydrophobic IDO inhibitor, which exhibits pH-responsive disassembly and esterase-catalyzed drug release. Markedly, it achieved potent and persistent inhibition of intratumoral IDO activity with a reduced systemic toxicity, which greatly enhanced the therapeutic efficacy of programmed cell death-ligand 1 blockade
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- 2020
18. Drug conjugate-based anticancer therapy - Current status and perspectives
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Yuqi Yang, Shuhang Wang, Peiwen Ma, Yale Jiang, Keman Cheng, Yue Yu, Ning Jiang, Huilei Miao, Qiyu Tang, Funan Liu, Yan Zha, and Ning Li
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Cancer Research ,Immunoconjugates ,Drug Delivery Systems ,Pharmaceutical Preparations ,Oncology ,Neoplasms ,Humans ,Antineoplastic Agents - Abstract
Drug conjugates are conjugates comprising a tumor-homing carrier tethered to a cytotoxic agent via a linker that are designed to deliver an ultra-toxic payload directly to the target cancer cells. This strategy has been successfully used to increase the therapeutic efficacy of cytotoxic agents and reduce their toxic side effects. Drug conjugates are being developed worldwide, with the potential to revolutionize current cancer treatment strategies. Antibody-drug conjugates (ADCs) have developed rapidly, and 14 of them have received market approval since the first approval event by the Food and Drug Administration in 2000. However, there are some limitations in the use of antibodies as carriers. Other classes of drug conjugates are emerging, such as targeted drugs conjugated with peptides (peptide-drug conjugates, PDCs) and polymers (polymer-drug conjugates, PolyDCs) with the remaining constructs similar to those of ADCs. These novel drug conjugates are gaining attention because they overcome the limitations of ADCs. This review summarizes the current state and advancements in knowledge regarding the design, constructs, and clinical efficacy of different drug conjugates.
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- 2023
19. Lipid‐Peptide‐mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer
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Qinglin Li, Lizhuo Zhang, Jiayan Lang, Zhuo Tan, Qingqing Feng, Fei Zhu, Guangna Liu, Zhangguo Ying, Xuefei Yu, He Feng, Heqing Yi, Qingliang Wen, Tiefeng Jin, Keman Cheng, Xiao Zhao, and Minghua Ge
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General Chemical Engineering ,General Engineering ,General Physics and Astronomy ,Medicine (miscellaneous) ,General Materials Science ,Biochemistry, Genetics and Molecular Biology (miscellaneous) - Abstract
Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid-peptide-mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids. An amphiphilic chimeric peptide, consisting of nine arginine and hydrophobic segments (6 histidine, C18 or cholesterol), is synthesized for adsorption of mRNA encoding NIS in RNase-free conditions. In vitro studies show that LP(R9H6) m NP is most efficient at delivering mRNA and can increase NIS expression in ATC cells by more than 10-fold. After intratumoral injection of NIS mRNA formulated in optimized LPm NP, NIS expression in subcutaneous ATC tumor tissue increases significantly in nude mice, resulting in more iodine 131 (
- Published
- 2022
20. Engineered Bacterial Outer Membrane Vesicles as Controllable Two‐Way Adaptors to Activate Macrophage Phagocytosis for Improved Tumor Immunotherapy
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Qingqing Feng, Xiaotu Ma, Keman Cheng, Guangna Liu, Yao Li, Yale Yue, Jie Liang, Lizhuo Zhang, Tianjiao Zhang, Xinwei Wang, Xiaoyu Gao, Guangjun Nie, and Xiao Zhao
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Macrophages ,Mechanical Engineering ,CD47 Antigen ,Polyethylene Glycols ,Mice ,Bacterial Outer Membrane ,Phagocytosis ,Mechanics of Materials ,Cell Line, Tumor ,Delayed-Action Preparations ,Tumor Microenvironment ,Animals ,General Materials Science ,Immunotherapy - Abstract
The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however, re-education of macrophages remains a challenge. Bacteria-derived outer membrane vesicles (OMVs) are highly immunogenic nanovesicles that can robustly stimulate macrophages. Here, an OMV-based controllable two-way adaptor is reported, in which a CD47 nanobody (CD47nb) is fused onto OMV surface (OMV-CD47nb), with the outer surface coated with a polyethylene glycol (PEG) layer containing diselenide bonds (PEG/Se) to form PEG/Se@OMV-CD47nb. The PEG/Se layer modification not only mitigates the immunogenicity of OMV-CD47nb, thereby remarkedly increasing the dose that can be administered safely through intravenous injection, but also equips the formulation with radiation-triggered controlled release of OMV-CD47nb. Application of radiation to tumors in mice injected with the nanoformulation results in remodeling of TME. As two-way adaptors, OMV-CD47nb activates TAM phagocytosis of tumor cells via multiple pathways, including induction of M1 polarization and blockade of "don't eat me" signal. Moreover, this activation of TAMs results in the stimulation of T cell-mediated antitumor immunity through effective antigen presentation.
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- 2022
21. Nanoparticle-based medicines in clinical cancer therapy
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Shuhang Wang, Keman Cheng, Kun Chen, Chen Xu, Peiwen Ma, Guohui Dang, Yuqi Yang, Qi Lei, Huiyao Huang, Yue Yu, Yuan Fang, Qiyu Tang, Ning Jiang, Huilei Miao, Funan Liu, Xiao Zhao, and Ning Li
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Biomedical Engineering ,Pharmaceutical Science ,General Materials Science ,Bioengineering ,Biotechnology - Published
- 2022
22. Controlled production of bacterial outer membrane vesicles in intestine by orally administered bacteria as an effective tumor vaccine
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Xiao Zhao, Jiaqi Xu, Nana Ma, Yao Li, Tianjiao Zhang, Xinwei Wang, Guangjun Nie, Keman Cheng, Qingqing Feng, Yale Yue, and Xiaotu Ma
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biology ,Bacterial outer membrane vesicles ,Chemistry ,biology.organism_classification ,Bacteria ,Microbiology - Abstract
Therapeutic tumor vaccines hold great promise for effective tumor immunotherapy, however orally administered tumor vaccines that can stimulate a robust immune response are still limited. The major challenges in oral vaccines are the complex gastrointestinal environment and intestinal epithelial barriers. Numerous intestinal commensal bacteria interact with the host immune cells through the release of outer membrane vesicles (OMVs) which can penetrate the intestinal epithelial barriers. Here, we present an effective tumor vaccine based on the OMVs which are generated by orally administered genetically engineered bacteria in intestine. A tumor antigen was fused with the surface protein ClyA on OMVs, whose expression was controlled by an arabinose-inducible promoter. Through oral administration of the modified bacteria and arabinose, in situ controllable production of OMVs loaded with tumor antigen in the intestine was achieved. The OMV-based tumor vaccine not only overcame the intestinal epithelial barriers to reach the immune cells in the lamina propria, but also stimulated dendritic cell maturation to facilitate a potent antitumor adaptive immunity. The oral bacteria generated OMV-based tumor vaccine significantly inhibited the lung metastatic melanoma and subcutaneous colon cancer in mouse models. Furthermore, a robust immune memory was generated, offering long-term protection against tumor challenge. Our work provides a proof-of-concept for oral bacteria generated OMV-based tumor vaccine that may be further developed and translated into clinical use.
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- 2021
23. Fe3O4-Based Multifunctional Nanospheres for Amplified Magnetic Targeting Photothermal Therapy and Fenton Reaction
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Yanan Sun, Dongtao Ge, Xiuming Zhang, Wei Shi, Huiling Su, Keman Cheng, Ziyang Li, Yuan He, and Huanhuan Wu
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Fenton reaction ,Chemistry ,education ,fungi ,0206 medical engineering ,Biomedical Engineering ,food and beverages ,Cancer ,Nanotechnology ,02 engineering and technology ,Photothermal therapy ,021001 nanoscience & nanotechnology ,medicine.disease ,Polypyrrole ,020601 biomedical engineering ,humanities ,Biomaterials ,chemistry.chemical_compound ,Combined treatment ,medicine ,0210 nano-technology - Abstract
Multifunctional nanoplatforms have attracted the interests of many scientists because they can achieve better therapeutic effect in the combined treatment of cancer. A novel cancer therapeutic stra...
- Published
- 2018
24. Bifunctional Therapeutic Peptide Assembled Nanoparticles Exerting Improved Activities of Tumor Vessel Normalization and Immune Checkpoint Inhibition
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Hamideh Rezavani Alanagh, Keman Cheng, Yingqiu Qi, Chen Li, Zhao Ying, Mona Atabakhshi-Kashi, Zeinab Farhadi Sabet, Guangjun Nie, Fenfen Li, Mohammad Taleb, and Yazhou Wang
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medicine.medical_treatment ,Biomedical Engineering ,Pharmaceutical Science ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Biomaterials ,Immune system ,Cancer immunotherapy ,Neoplasms ,medicine ,Peptide amphiphile ,Tumor Microenvironment ,Cytotoxic T cell ,Humans ,Immune Checkpoint Inhibitors ,Tumor microenvironment ,Chemistry ,Immunotherapy ,021001 nanoscience & nanotechnology ,Immune checkpoint ,0104 chemical sciences ,Drug delivery ,Cancer research ,Nanoparticles ,0210 nano-technology ,Peptides - Abstract
The effectiveness of cancer immunotherapy is impaired by the dysfunctional vasculature of tumors. Created hypoxia zones and limited delivery of cytotoxic immune cells help to have immune resistance in tumor tissue. Structural and functional normalization of abnormal tumor vasculature provide vessels for more perfusion efficiency and drug delivery that result in alleviating the hypoxia in the tumor site and increasing infiltration of antitumor T cells. Taking advantage of peptide amphiphiles, herein, a novel peptide amphiphile nanoparticle composed of an antiangiogenic peptide (FSEC) and an immune checkpoint blocking peptide (D PPA) is designed and characterized. FSEC peptide is known to be involved in vessel normalization of tumors in vivo. D PPA is an inhibitory peptide of the PD-1/PD-L1 immune checkpoint pathway. The peptide amphiphile nanoparticle sets out to test whether simultaneous modulation of tumor vasculature and immune systems in the tumor microenvironment has a synergistic effect on tumor suppression. Increased intratumoral infiltration of immune cells following vascular normalization, and simultaneously blocking the immune checkpoint function of PD-L1 reactivates effective immune responses to the tumors. In summary, the current study provides a new perspective on the regulation of tumor vessel normalization and immunotherapy based on functional peptide nanoparticles as nanomedicine for improved therapeutic purposes.
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- 2021
25. Bioengineered bacteria-derived outer membrane vesicles as a versatile antigen display platform for tumor vaccination via Plug-and-Display technology
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Xiao Zhao, Long Chen, Yujing Li, Xuexiang Han, Yao Li, Hao Qin, Lei Ren, Jian Shi, Yinlong Zhang, Yuting Qin, Guangjun Nie, Gregory J. Anderson, Jiaqi Xu, Yazhou Wang, Chen Li, Jie Liang, Ruifang Zhao, Keman Cheng, and Yingqiu Qi
- Subjects
0301 basic medicine ,Science ,T-Lymphocytes ,General Physics and Astronomy ,Bioengineering ,Cancer Vaccines ,Article ,General Biochemistry, Genetics and Molecular Biology ,Extracellular Vesicles ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Antigen ,Antigens, Neoplasm ,Immunity ,Animals ,Antigen Presentation ,Antigens, Bacterial ,Multidisciplinary ,Innate immune system ,biology ,Chemistry ,Vesicle ,Vaccination ,Dendritic Cells ,General Chemistry ,biology.organism_classification ,Immunity, Innate ,Nanostructures ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Nanotechnology in cancer ,030220 oncology & carcinogenesis ,Female ,Peptides ,Bacterial outer membrane ,Immunologic Memory ,Bacteria ,Bacterial Outer Membrane Proteins - Abstract
An effective tumor vaccine vector that can rapidly display neoantigens is urgently needed. Outer membrane vesicles (OMVs) can strongly activate the innate immune system and are qualified as immunoadjuvants. Here, we describe a versatile OMV-based vaccine platform to elicit a specific anti-tumor immune response via specifically presenting antigens onto OMV surface. We first display tumor antigens on the OMVs surface by fusing with ClyA protein, and then simplify the antigen display process by employing a Plug-and-Display system comprising the tag/catcher protein pairs. OMVs decorated with different protein catchers can simultaneously display multiple, distinct tumor antigens to elicit a synergistic antitumour immune response. In addition, the bioengineered OMVs loaded with different tumor antigens can abrogate lung melanoma metastasis and inhibit subcutaneous colorectal cancer growth. The ability of the bioengineered OMV-based platform to rapidly and simultaneously display antigens may facilitate the development of these agents for personalized tumour vaccines., Outer membrane vesicles (OMVs), non-replicative particles secreted by Gram-negative bacteria, are known for their immunostimulatory and adjuvant properties. Here, by employing a Plug-and-Display technology, the authors engineer OMVs to display tumor antigens on the surface, a platform that promotes anti-tumor immune responses in preclinical cancer models.
- Published
- 2021
26. Fe
- Author
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Huanhuan, Wu, Keman, Cheng, Yuan, He, Ziyang, Li, Huiling, Su, Xiuming, Zhang, Yanan, Sun, Wei, Shi, and Dongtao, Ge
- Abstract
Multifunctional nanoplatforms have attracted the interests of many scientists because they can achieve better therapeutic effect in the combined treatment of cancer. A novel cancer therapeutic strategy which combines an Fe
- Published
- 2021
27. Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy
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Yao, Li, Ruifang, Zhao, Keman, Cheng, Kaiyue, Zhang, Yazhou, Wang, Yinlong, Zhang, Yujing, Li, Guangna, Liu, Junchao, Xu, Jiaqi, Xu, Gregory J, Anderson, Jian, Shi, Lei, Ren, Xiao, Zhao, and Guangjun, Nie
- Abstract
Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may hamper T cell function and limit immunotherapeutic effectiveness. Here, we report the development of genetically engineered OMVs whose surface has been modified by insertion of the ectodomain of programmed death 1 (PD1). This genetic modification does not affect the ability of OMVs to trigger immune activation. More importantly, the engineered OMV-PD1 can bind to PD-L1 on the tumor cell surface and facilitate its internalization and reduction, thereby protecting T cells from the PD1/PD-L1 immune inhibitory axis. Through the combined effects of immune activation and checkpoint suppression, the engineered OMVs drive the accumulation of effector T cells in the tumor, which, in turn, leads to a greater impairment of tumor growth, compared with not only native OMVs but also the commonly used PD-L1 antibody. In conclusion, this work demonstrates the potential of bioengineered OMVs as effective immunotherapeutic agents that can comprehensively regulate the tumor immune microenvironment to effect markedly increased anti-tumor efficacy.
- Published
- 2020
28. Rapid Surface Display of mRNA Antigens by Bacteria‐Derived Outer Membrane Vesicles for a Personalized Tumor Vaccine
- Author
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Yao Li, Xiaotu Ma, Yale Yue, Kaiyue Zhang, Keman Cheng, Qingqing Feng, Nana Ma, Jie Liang, Tianjiao Zhang, Lizhuo Zhang, Zhiqiang Chen, Xinwei Wang, Lei Ren, Xiao Zhao, and Guangjun Nie
- Subjects
Mice ,Bacteria ,Mechanics of Materials ,Mechanical Engineering ,Liposomes ,Animals ,Nanoparticles ,General Materials Science ,RNA, Messenger ,Cancer Vaccines - Abstract
Therapeutic mRNA vaccination is an attractive approach to trigger antitumor immunity. However, the mRNA delivery technology for customized tumor vaccine is still limited. In this work, bacteria-derived outer membrane vesicles (OMVs) are employed as an mRNA delivery platform by genetically engineering with surface decoration of RNA binding protein, L7Ae, and lysosomal escape protein, listeriolysin O (OMV-LL). OMV-LL can rapidly adsorb box C/D sequence-labelled mRNA antigens through L7Ae binding (OMV-LL-mRNA) and deliver them into dendritic cells (DCs), following by the cross-presentation via listeriolysin O-mediated endosomal escape. OMV-LL-mRNA significantly inhibits melanoma progression and elicits 37.5% complete regression in a colon cancer model. OMV-LL-mRNA induces a long-term immune memory and protects the mice from tumor challenge after 60 days. In summary, this platform provides a delivery technology distinct from lipid nanoparticles (LNPs) for personalized mRNA tumor vaccination, and with a "Plug-and-Display" strategy that enables its versatile application in mRNA vaccines.
- Published
- 2022
29. Antigen Capture and Immune Modulation by Bacterial Outer Membrane Vesicles as In Situ Vaccine for Cancer Immunotherapy Post‐Photothermal Therapy
- Author
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Yao Li, Kaiyue Zhang, Yao Wu, Yale Yue, Keman Cheng, Qingqing Feng, Xiaotu Ma, Jie Liang, Nana Ma, Guangna Liu, Guangjun Nie, Lei Ren, and Xiao Zhao
- Subjects
Biomaterials ,Vaccines ,Bacterial Outer Membrane ,Antigens, Neoplasm ,Photothermal Therapy ,Neoplasms ,Immunity ,Tumor Microenvironment ,Humans ,General Materials Science ,Immunotherapy ,General Chemistry ,Biotechnology - Abstract
Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT). 1-MT@OMV-Mal can bind to the released tumor antigens after PTT, and be efficiently recognized and taken up by dendritic cells. Furthermore, in situ injection of 1-MT@OMV-Mal simultaneously overcomes the immune inhibition of IDO on tumor-infiltrating effector T cells, leading to remarkable inhibition on both primary and distant tumors. Together, a promising in situ vaccine based on OMVs to facilitate immune-mediated tumor clearance after PTT through orchestrating antigen capture and immune modulation is presented.
- Published
- 2022
30. Biogenic nanoparticles as immunomodulator for tumor treatment
- Author
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Keman Cheng, Qinglin Kang, and Xiao Zhao
- Subjects
medicine.medical_treatment ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Cell therapy ,Cancer immunotherapy ,Neoplasms ,medicine ,Humans ,Adverse effect ,Drug discovery ,business.industry ,Cancer ,021001 nanoscience & nanotechnology ,medicine.disease ,Microvesicles ,Immune checkpoint ,0104 chemical sciences ,Nanomedicine ,Cancer research ,Nanoparticles ,Immunotherapy ,0210 nano-technology ,business - Abstract
In the past few decades, cancer immunotherapy has developed rapidly. Cancer immunotherapy, either used alone or in combination with a variety of immunotherapies (such as cancer therapeutic vaccines, adoptive cell therapy, or immune checkpoint blocking therapy), is a very attractive class of cancer therapy. However, so far, the clinical effect of most cancer immunotherapy is not satisfactory. It has been widely recognized that nanotechnology can enhance the efficacy of cancer immunotherapy. A variety of biogenic nanoparticles have been developed, which have excellent immunogenicity and modifiability, and can carry tumor therapeutic drugs to achieve combined therapy, so as to improve the effectiveness and durability of antitumor immunity while reducing adverse side effects. In this review, we summarized the key parameters and futures of three kinds of biogenic nanomaterials in cancer immunotherapy; we highlighted the progress of cancer immunotherapy based on outer membrane vesicles, virus-like particles, and exosomes. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.
- Published
- 2020
31. A Graphdiyne Oxide-Based Iron Sponge with Photothermally Enhanced Tumor-Specific Fenton Chemistry
- Author
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Jianshe Hu, Huan Min, Yiye Li, Xuexiang Han, Guangjun Nie, Huibiao Liu, Ying Liu, Keman Cheng, Yingqiu Qi, and Yinlong Zhang
- Subjects
inorganic chemicals ,Materials science ,Cell Survival ,Radical ,Iron ,Oxide ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Hemolysis ,Theranostic Nanomedicine ,Nanocomposites ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,Neoplasms ,Animals ,Humans ,General Materials Science ,Hydrogen peroxide ,chemistry.chemical_classification ,Reactive oxygen species ,Mice, Inbred BALB C ,Nanocomposite ,biology ,Mechanical Engineering ,Polymer ,Hydrogen Peroxide ,Hyperthermia, Induced ,Photothermal therapy ,Phototherapy ,021001 nanoscience & nanotechnology ,biology.organism_classification ,Combinatorial chemistry ,Xenograft Model Antitumor Assays ,Ferrosoferric Oxide ,0104 chemical sciences ,Sponge ,chemistry ,Mechanics of Materials ,Female ,Graphite ,0210 nano-technology ,Reactive Oxygen Species - Abstract
Fenton reaction-mediated oncotherapy is an emerging strategy which uses iron ions to catalytically convert endogenous hydrogen peroxide into hydroxyl radicals, the most reactive oxygen species found in biology, for efficient cancer therapy. However, Fenton reaction efficiency in tumor tissue is typically limited due to restrictive conditions. One strategy to overcome this obstacle is to increase the temperature specifically at the tumor site. Herein, a tumor-targeting iron sponge (TTIS) nanocomposite based on graphdiyne oxide, which has a high affinity for iron is described. TTIS can accumulate in tumor tissue by decoration with a tumor-targeting polymer to enable tumor photoacoustic and magnetic resonance imaging. With its excellent photothermal conversion efficiency (37.5%), TTIS is an efficient photothermal therapy (PTT) agent. Moreover, the heat produced in the process of PTT can accelerate the release of iron ions from TTIS and simultaneously enhance the efficiency of the Fenton reaction, thus achieving a combined PTT and Fenton reaction-mediated cancer therapy. This work introduces a graphdiyne oxide-based iron sponge that exerts an enhanced antitumor effect through PTT and Fenton chemistry.
- Published
- 2020
32. A CRISPR-Cas13a system for efficient and specific therapeutic targeting of mutant KRAS for pancreatic cancer treatment
- Author
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Liang Liu, Jiayan Lang, Guangjun Nie, Xueyan Li, Jian Shi, Yanli Wang, Keman Cheng, Yongwei Wang, and Xiao Zhao
- Subjects
0301 basic medicine ,Cancer Research ,Cell Survival ,medicine.medical_treatment ,Mutant ,Mice, Nude ,Apoptosis ,Biology ,medicine.disease_cause ,Targeted therapy ,Proto-Oncogene Proteins p21(ras) ,Mice ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,RNA, Messenger ,Cell Proliferation ,Trans-activating crRNA ,Gene knockdown ,Oncogene ,Effector ,Oncogenes ,medicine.disease ,Pancreatic Neoplasms ,030104 developmental biology ,Oncology ,Mutation ,Cancer research ,Female ,RNA Interference ,KRAS ,CRISPR-Cas Systems ,Neoplasm Transplantation ,Signal Transduction - Abstract
Mutant KRAS is a known driver oncogene in pancreatic cancer. However, this protein remains an "undruggable" therapeutic target. Inhibiting mutated KRAS expression at the mRNA level is a potentially effective strategy. Recently, a novel CRISPR-Cas effector, Cas13a has been reported to specifically knock down mRNA expression under the guidance of a single CRISPR-RNA in mammalian cells. Here we demonstrate that the CRISPR-Cas13a system can be engineered for targeted therapy of mutant KRAS in pancreatic cancer. In initial screening, we show that the bacterial Cas13a protein and crRNA significantly knock down mutant KRAS mRNA expression, identifying a CRISPR-Cas13a system that can induce up to a 94% knockdown efficiency. Introducing a single mismatch into the crRNA-target duplex enabled the CRISPR-Cas13a system to specifically recognize KRAS-G12D mRNA with no detectable effects on wild-type KRAS mRNA. More importantly, CRISPR-Cas13a-mediated KRAS-G12D mRNA knockdown potently induced apoptosis in vitro and elicited marked tumor shrinkage in mice. Our work describes an optimization strategy for the development of a CRISPR-Cas13a system to affect efficient and specific knockdown of the oncogenic mRNA, establishing the CRISPR-Cas13a system as a flexible, targeted therapeutic tool.
- Published
- 2018
33. Sequentially Responsive Therapeutic Peptide Assembling Nanoparticles for Dual-Targeted Cancer Immunotherapy
- Author
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Tianjiao Ji, Shefang Ye, Ying Zhao, Lei Ren, Gregory J. Anderson, Guangjun Nie, Bin Wang, Xiao Zhao, Yanping Ding, Yinlong Zhang, Keman Cheng, and Huanhuan Wu
- Subjects
medicine.medical_treatment ,Cell ,Mice, Nude ,Bioengineering ,Peptide ,02 engineering and technology ,Isoindoles ,010402 general chemistry ,01 natural sciences ,B7-H1 Antigen ,Mice ,Drug Delivery Systems ,Immune system ,Cancer immunotherapy ,Tumor Microenvironment ,medicine ,Animals ,Cytotoxic T cell ,General Materials Science ,Melanoma ,chemistry.chemical_classification ,Mechanical Engineering ,Imidazoles ,General Chemistry ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,Small molecule ,0104 chemical sciences ,medicine.anatomical_structure ,chemistry ,Delayed-Action Preparations ,Nucleic acid ,Cancer research ,Nanoparticles ,Immunotherapy ,Peptides ,0210 nano-technology - Abstract
Combination therapeutic regimen is becoming a primary direction for current cancer immunotherapy to broad the antitumor response. Functional nanomaterials offer great potential for steady codelivery of various drugs, especially small molecules, therapeutic peptides, and nucleic acids, thereby realizing controllable drug release, increase of drug bioavailability, and reduction of adverse effects. Herein, a therapeutic peptide assembling nanoparticle that can sequentially respond to dual stimuli in the tumor extracellular matrix was designed for tumor-targeted delivery and on-demand release of a short d-peptide antagonist of programmed cell death-ligand 1 (DPPA-1) and an inhibitor of idoleamine 2,3-dioxygenase (NLG919). By concurrent blockade of immune checkpoints and tryptophan metabolism, the nanoformulation increased the level of tumor-infiltrated cytotoxic T cells and in turn effectively inhibited melanoma growth. To achieve this, an amphiphilic peptide, consisting of a functional 3-diethylaminopropyl i...
- Published
- 2018
34. Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment
- Author
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Ying Zhao, Xiuchao Wang, Qing Robert Miao, Hao Qin, Keman Cheng, Guangjun Nie, Jihui Hao, Yongwei Wang, Xuexiang Han, He Ren, Jiayan Lang, Xiaowei Zheng, Wei Sun, Xiao Zhao, Jian Shi, Yu Lin, and Ruifang Zhao
- Subjects
0301 basic medicine ,endocrine system diseases ,Cell ,Biophysics ,Bioengineering ,Deoxycytidine ,Equilibrative Nucleoside Transporter 1 ,Biomaterials ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Pancreatic cancer ,Ribonucleotide Reductases ,medicine ,Animals ,Humans ,Cationic liposome ,Precision Medicine ,RNA, Small Interfering ,Cytotoxicity ,Chemistry ,medicine.disease ,Gemcitabine ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,medicine.anatomical_structure ,Mechanics of Materials ,030220 oncology & carcinogenesis ,Liposomes ,Cancer cell ,Ceramics and Composites ,Cancer research ,Nanomedicine ,Female ,Nanocarriers ,Carcinoma, Pancreatic Ductal ,medicine.drug - Abstract
Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene-silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine.
- Published
- 2018
35. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of HBc VLPs based cancer vaccine
- Author
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Lei Ren, Wenjun Shan, Jun Yang, C.P. Wang, Qiuyan Guo, Xiumin Wang, Qiang Zhang, Yunlong Wang, and Keman Cheng
- Subjects
animal structures ,business.industry ,viruses ,medicine.medical_treatment ,Immunogenicity ,Assisted delivery ,virus diseases ,digestive system diseases ,In vitro ,Tumor antigen ,Vaccination ,Immune system ,Cancer immunotherapy ,medicine ,Cancer research ,General Materials Science ,Cancer vaccine ,business - Abstract
Tumor vaccines have made a significant breakthrough in clinical trials of cancer therapy, but have shown limited efficacy. Herein, we develop a novel tumor vaccine delivery strategy through a biodegradable microneedle patch (MN), which allows sustained release of tumor antigen and induces long term anti-tumor response. A tumor antigen peptide (OVA257–264: SIINFEKL) was fused with hepatitis B core (HBc) protein virus like particles (OVA-HBc VLPs) to increase the immunogenicity of tumor antigen. Mesoporous silica nanoparticles (MSN) were adopted as a vaccine adjuvant for enhancing the function of dendritic cells (DCs). OVA-HBc VLPs and MSN were capsulated into microneedles together [MSN/OVA-HBc@MN]. MSN/OVA-HBc@MN could significantly stimulate DC maturation and increase the presentation of OVA on DCs in vitro. MSN/OVA-HBc@MN can effectively stimulate antigen specific anti-tumor immune response and be used as prophylactic vaccines to effectively inhibit tumor formation. Moreover, the addition of CpG-DNA can enhance the therapeutic effect of MSN/OVA-HBc@MN in distant tumors and long term immune memory effect. Our results thus demonstrate that MSN- CpG/OVA-HBc@MN could be as a potential tumor-specific vaccination platform for tumor therapy.
- Published
- 2021
36. A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer
- Author
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Keman Cheng, He Ren, Guangjun Nie, Yongwei Wang, Xiuchao Wang, Xiao Zhao, Jihui Hao, Shaoli Liu, Ying Zhao, Xiaowei Zheng, Yinlong Zhang, Jian Shi, Xuexiang Han, Chungen Lan, Jiayi Guo, and Lijun Fang
- Subjects
Male ,0301 basic medicine ,Cancer Research ,Time Factors ,Mutant ,Kaplan-Meier Estimate ,Bioinformatics ,medicine.disease_cause ,Antineoplastic Combined Chemotherapy Protocols ,Gene knockdown ,Middle Aged ,Immunohistochemistry ,Verteporfin ,Tumor Burden ,Phenotype ,Oncology ,Female ,RNA Interference ,raf Kinases ,KRAS ,Carcinoma, Pancreatic Ductal ,Signal Transduction ,medicine.drug ,Porphyrins ,Mice, Nude ,Biology ,Transfection ,Disease-Free Survival ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,Cell Line, Tumor ,Pancreatic cancer ,medicine ,Animals ,Humans ,Tumor growth ,Genetic Testing ,Protein Kinase Inhibitors ,Protein kinase B ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Dose-Response Relationship, Drug ,Phenylurea Compounds ,YAP-Signaling Proteins ,Phosphoproteins ,medicine.disease ,Xenograft Model Antitumor Assays ,Pancreatic Neoplasms ,Pyrimidines ,030104 developmental biology ,Tissue Array Analysis ,Mutation ,Cancer research ,Proto-Oncogene Proteins c-akt ,Kras mutation ,Transcription Factors - Abstract
KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment. We found that reduced YAP expression closely correlates with longer relapse-free and overall survival of patients. Stable knockdown of YAP significantly inhibited pancreatic cancer cell proliferation and tumor growth. In addition, LY3009120 exhibited a dramatically enhanced antitumor effect in combination with YAP knockdown. YAP depletion blocks the activation of a parallel AKT signal pathway after LY3009120 treatment. Finally, combination with a YAP inhibitor, verteporfin, significantly enhanced the antitumor efficacy of LY3009120. Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer.
- Published
- 2017
37. Inhibition of platelet function using liposomal nanoparticles blocks tumor metastasis
- Author
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Yiye Li, Hao Qin, Guangjun Nie, Keman Cheng, Greg J. Anderson, Saraswati Sukumar, Yingqiu Qi, Xuexiang Han, Suping Li, Shaoli Liu, Jing Wang, Jiayan Lang, Yinlong Zhang, and Jingyan Wei
- Subjects
0301 basic medicine ,Blood Platelets ,Ticagrelor ,Adenosine ,Cell ,Medicine (miscellaneous) ,Antineoplastic Agents ,Pentapeptide repeat ,Metastasis ,03 medical and health sciences ,Circulating tumor cell ,Cell Line, Tumor ,medicine ,Animals ,Platelet ,Neoplasm Metastasis ,metastatic inhibition ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,Mice, Inbred BALB C ,tumor metastasis ,Chemistry ,Cancer ,Mammary Neoplasms, Experimental ,medicine.disease ,In vitro ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Cancer cell ,Liposomes ,Cancer research ,Nanoparticles ,Tumor associated platelets ,liposomal nanoparticle ,Oligopeptides ,Research Paper - Abstract
Extensive evidence has shown that platelets support tumor metastatic progression by inducing epithelial-mesenchymal transition of cancer cells and by shielding circulating tumor cells from immune-mediated elimination. Therefore, blocking platelet function represents a potential new avenue for therapy focused on eliminating metastasis. Here we show that liposomal nanoparticles bearing the tumor-homing pentapeptide CREKA (Cys-Arg-Glu-Lys-Ala) can deliver a platelet inhibitor, ticagrelor, into tumor tissues to specifically inhibit tumor-associated platelets. The drug-loaded nanoparticles (CREKA-Lipo-T) efficiently blocked the platelet-induced acquisition of an invasive phenotype by tumor cells and inhibited platelet-tumor cell interaction in vitro. Intravenously administered CREKA-Lipo-T effectively targeted tumors within 24 h, and inhibited tumor metastasis without overt side effects. Thus, the CREKA-Lipo formulation provides a simple strategy for the efficient delivery of anti-metastatic drugs and shows considerable promise as a platform for novel cancer therapeutics.
- Published
- 2017
38. A Bioinspired Nanoprobe with Multilevel Responsive T
- Author
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Yao, Li, Xiao, Zhao, Xiaoli, Liu, Keman, Cheng, Xuexiang, Han, Yinlong, Zhang, Huan, Min, Guangna, Liu, Junchao, Xu, Jian, Shi, Hao, Qin, Haiming, Fan, Lei, Ren, and Guangjun, Nie
- Subjects
Fibrin ,Mice, Inbred BALB C ,Transplantation, Heterologous ,Contrast Media ,Breast Neoplasms ,Hydrogen Peroxide ,Signal-To-Noise Ratio ,Ferric Compounds ,Magnetic Resonance Imaging ,Fibronectins ,Mice ,Manganese Compounds ,Cell Line, Tumor ,Animals ,Humans ,Nanoparticles ,Female ,Neoplasm Metastasis ,Oligopeptides - Abstract
Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T
- Published
- 2019
39. Reversing tumor stemness via orally targeted nanoparticles achieves efficient colon cancer treatment
- Author
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Guangjun Nie, Jing Wang, Yinlong Zhang, Guangna Liu, Junchao Xu, Keman Cheng, Yao Li, Yingqiu Qi, Xiao Zhao, Jiaqi Xu, Sheng Qi, Jian Shi, and Meifang Wang
- Subjects
Side effect ,Colorectal cancer ,Biophysics ,Administration, Oral ,Antineoplastic Agents ,Bioengineering ,02 engineering and technology ,Metastasis ,Biomaterials ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,Targeted nanoparticles ,Oral administration ,Cell Line, Tumor ,Proto-Oncogene Proteins ,Hyaluronic acid ,Animals ,Medicine ,030304 developmental biology ,Polycomb Repressive Complex 1 ,Mice, Inbred BALB C ,0303 health sciences ,biology ,business.industry ,CD44 ,021001 nanoscience & nanotechnology ,medicine.disease ,digestive system diseases ,chemistry ,Mechanics of Materials ,Delayed-Action Preparations ,Neoplastic Stem Cells ,Ceramics and Composites ,biology.protein ,Cancer research ,Nanoparticles ,Nanomedicine ,Female ,Neoplasm Recurrence, Local ,Colorectal Neoplasms ,0210 nano-technology ,business - Abstract
The acquisition of stemness in colorectal cancer (CRC) attributed to the recurrence and metastasis in CRC treatment. Therefore, targeting the stemness of CRC forms a basis for the development of novel therapeutic approaches. However, the pain and systemic side effect from long-term of venipuncture injection remain great challenges to neoplastic treatment. Here, we introduce an oral drug delivery system for sustained release of BMI-1 inhibitor (PTC209) that reverse the stemness of CRC to over-come these obstacles. In this system, nanoparticles modified with hyaluronic acid (HA) showed high-affinity to CD44 / CD168 overexpressed-CRC cells, and efficiently targeted to tumor site in a metastatic orthotropic colon cancer mouse model by oral administration. Significantly, the observed tumor growth inhibition is accompanied by decreased expression of stemness markers in the tumor tissues. Furthermore, HA-NPs-PTC209 also significantly prevented metastasis to the gastrointestinal system, while failing to exhibit acute side effects. In summary, we have developed an orally active, easily synthesized nanomedicine that shows promise for the treatment of colon cancer.
- Published
- 2019
40. Tumor-Specific Silencing of Tissue Factor Suppresses Metastasis and Prevents Cancer-Associated Hypercoagulability
- Author
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Tianjiao Ji, Jing Wang, Chunzhi Di, Guangjun Nie, Long Chen, Yinlong Zhang, Keman Cheng, Yingqiu Qi, Ying Zhao, Suping Li, Yongwei Wang, Xiao Zhao, and Shaoli Liu
- Subjects
Small interfering RNA ,Lung Neoplasms ,Mice, Nude ,Bioengineering ,02 engineering and technology ,Metastasis ,Thromboplastin ,Tissue factor ,Circulating tumor cell ,Cell Line, Tumor ,Medicine ,Gene silencing ,Animals ,Humans ,Thrombophilia ,General Materials Science ,Platelet activation ,Gene Silencing ,Neoplasm Metastasis ,RNA, Small Interfering ,Tumor microenvironment ,business.industry ,Mechanical Engineering ,Cancer ,Thrombosis ,General Chemistry ,Neoplasms, Experimental ,021001 nanoscience & nanotechnology ,Condensed Matter Physics ,medicine.disease ,Neoplastic Cells, Circulating ,Neoplasm Proteins ,Gene Expression Regulation, Neoplastic ,Cancer research ,Nanoparticles ,Female ,0210 nano-technology ,business - Abstract
Within tumors, the coagulation-inducing protein tissue factor (TF), a major initiator of blood coagulation, has been shown to play a critical role in the hematogenous metastasis of tumors, due to its effects on tumor hypercoagulability and on the mediation of interactions between platelets and tumor cells. Targeting tumor-associated TF has therefore great therapeutic potential for antimetastasis therapy and preventing thrombotic complication in cancer patients. Herein, we reported a novel peptide-based nanoparticle that targets delivery and release of small interfering RNA (siRNA) into the tumor site to silence the expression of tumor-associated TF. We showed that suppression of TF expression in tumor cells blocks platelet adhesion surrounding tumor cells in vitro. The downregulation of TF expression in intravenously administered tumor cells (i.e., simulated circulating tumor cells [CTCs]) prevented platelet adhesion around CTCs and decreased CTCs survival in the lung. In a breast cancer mouse model, siRNA-containing nanoparticles efficiently attenuated TF expression in the tumor microenvironment and remarkably reduced the amount of lung metastases in both an experimental lung metastasis model and tumor-bearing mice. What's more, this strategy reversed the hypercoagulable state of the tumor bearing mice by decreasing the generation of thrombin-antithrombin complexes (TAT) and activated platelets, both of which are downstream products of TF. Our study describes a promising approach to combat metastasis and prevent cancer-associated thrombosis, which advances TF as a therapeutic target toward clinic applications.
- Published
- 2019
41. Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α Inhibitor Impairs Pancreatic Tumor Growth
- Author
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Gregory J. Anderson, Yiye Li, Guangjun Nie, Xiuchao Wang, Jian Shi, Marzieh Geranpayehvaghei, Jihui Hao, Hao Qin, Xuexiang Han, Keman Cheng, Ying Zhao, Xiao Zhao, He Ren, Xiaowei Zheng, Jiayan Lang, Ruifang Zhao, and Yao Li
- Subjects
General Physics and Astronomy ,Administration, Oral ,Transferrin receptor ,Antineoplastic Agents ,02 engineering and technology ,Deferoxamine ,010402 general chemistry ,Iron Chelating Agents ,01 natural sciences ,Drug Delivery Systems ,Pancreatic tumor ,Pancreatic cancer ,Cell Line, Tumor ,medicine ,Humans ,General Materials Science ,Cell Proliferation ,Liposome ,Chemistry ,General Engineering ,021001 nanoscience & nanotechnology ,medicine.disease ,Hypoxia-Inducible Factor 1, alpha Subunit ,In vitro ,0104 chemical sciences ,Pancreatic Neoplasms ,Cancer cell ,Cancer research ,Nanoparticles ,Drug Screening Assays, Antitumor ,0210 nano-technology ,Intracellular ,medicine.drug - Abstract
Rapidly growing cancer cells exhibit a strong dependence on iron for their survival. Thus, iron-removing drugs, iron chelators, have potential applications in cancer treatment. Deferoxamine (DFO) is an efficient iron chelator, but its short circulation half-life and ability to induce hypoxia-inducible factor 1α (HIF1α) overexpression restricts its use as an antitumor agent. In the present study, we first found that a pattern of iron-related protein expression favoring higher intracellular iron closely correlates with shorter overall and relapse-free survival in pancreatic cancer patients. We subsequently found that a combination of DFO and the HIF1α inhibitor, lificiguat (also named YC1), significantly enhanced the antitumor efficacy of DFO in vitro. We then employed transferrin receptor 1 (TFR1) targeting liposomes to codeliver DFO and YC1 to pancreatic tumors in a mouse model. The encapsulation of DFO prolonged its circulation time, improved its accumulation in tumor tissues via the enhanced permeability and retention (EPR) effect, and facilitated efficient uptake by cancer cells, which express high level of TFR1. After entering the tumor cells, the encapsulated DFO and YC1 were released to elicit a synergistic antitumor effect in subcutaneous and orthotopic pancreatic cancer xenografts. In summary, our work overcame two major obstacles in DFO-based cancer treatment through a simple liposome-based drug delivery system. This nanoencapsulation and targeting paradigm lays the foundation for future application of iron chelation in cancer therapy.
- Published
- 2019
42. Biomimetic Metal-Organic Framework Nanoparticles for Cooperative Combination of Antiangiogenesis and Photodynamic Therapy for Enhanced Efficacy
- Author
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Guangna Liu, Long Chen, Yiye Li, Xuexiang Han, Ying Xu, Guangjun Nie, Huan Min, Yao Li, Junchao Xu, Jing Wang, Na Yang, Keman Cheng, Yingqiu Qi, and Yinlong Zhang
- Subjects
Materials science ,medicine.medical_treatment ,Nanoparticle ,Metal Nanoparticles ,Photodynamic therapy ,Angiogenesis Inhibitors ,Antineoplastic Agents ,02 engineering and technology ,010402 general chemistry ,01 natural sciences ,Antiangiogenesis Therapy ,chemistry.chemical_compound ,Biomimetic Materials ,Neoplasms ,medicine ,Animals ,Humans ,General Materials Science ,Apatinib ,Photosensitizer ,Metal-Organic Frameworks ,Mice, Inbred BALB C ,Photosensitizing Agents ,Delivery vehicle ,Mechanical Engineering ,Kinase insert domain receptor ,Glutathione ,021001 nanoscience & nanotechnology ,Combined Modality Therapy ,0104 chemical sciences ,chemistry ,Photochemotherapy ,Mechanics of Materials ,Cancer research ,0210 nano-technology - Abstract
Photodynamic therapy (PDT) is a promising anticancer treatment and is clinically approved for different types of tumors. However, current PDT suffers several obstacles, including its neutralization by excess glutathione (GSH) in the tumor tissue and its strongly proangiogenic tumor response. In this work, a biomimic, multifunctional nanoparticle-based PDT agent, combining a tumor-targeted photosensitizer with GSH scavenging and antiangiogenesis therapy, is developed. A porphyrinic Zr-metal-organic framework nanoparticle is used simultaneously as the photosensitizer and the delivery vehicle of vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor apatinib. The core nanoparticles are wrapped in MnO2 to consume the intratumoral GSH and then decorated with a tumor cell membrane camouflage. After intravenous administration, the nanoparticles selectively accumulate in tumor through homotypic targeting mediated by the biomimic decoration, and the combination of enhanced PDT and antiangiogenic drug significantly improves their tumor inhibition efficiency. This study provides an integrated solution for mechanism-based enhancement of PDT and demonstrates the encouraging potential for multifunctional nanosystem applicable for tumor therapy.
- Published
- 2018
43. Development of a Cancer Vaccine Using In Vivo Click‐Chemistry‐Mediated Active Lymph Node Accumulation for Improved Immunotherapy
- Author
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Chunzhi Di, Ying Zhao, Ruifang Zhao, Keman Cheng, Yinlong Zhang, Gregory J. Anderson, Yuting Qin, Hao Qin, Yuliang Zhao, Long Chen, Xuexiang Han, Jian Shi, Guangjun Nie, and Jin Zhu
- Subjects
Materials science ,medicine.medical_treatment ,02 engineering and technology ,010402 general chemistry ,Cancer Vaccines ,01 natural sciences ,Mice ,Antigen ,In vivo ,medicine ,Animals ,General Materials Science ,Lymph node ,Mechanical Engineering ,Endothelial Cells ,Cancer ,Immunotherapy ,021001 nanoscience & nanotechnology ,medicine.disease ,0104 chemical sciences ,medicine.anatomical_structure ,Mechanics of Materials ,Cancer research ,Cancer vaccine ,0210 nano-technology ,Adjuvant ,CD8 - Abstract
Due to their ability to elicit a potent immune reaction with low systemic toxicity, cancer vaccines represent a promising strategy for treating tumors. Considerable effort has been directed toward improving the in vivo efficacy of cancer vaccines, with direct lymph node (LN) targeting being the most promising approach. Here, a click-chemistry-based active LN accumulation system (ALAS) is developed by surface modification of lymphatic endothelial cells with an azide group, which provide targets for dibenzocyclooctyne (DBCO)-modified liposomes, to improve the delivery of encapsulated antigen and adjuvant to LNs. When loading with OVA257-264 peptide and poly(I:C), the formulation elicits an enhanced CD8+ T cell response in vivo, resulting in a much more efficient therapeutic effect and prolonged median survival of mice. Compared to treatment with DBCO-conjugated liposomes (DL)-Ag/Ad without the azide targeting, the percent survival of ALAS-vaccine-treated mice improves by 100% over 60 days. Altogether, the findings indicate that the novel ALAS approach is a powerful strategy to deliver vaccine components to LNs for enhanced antitumor immunity.
- Published
- 2021
44. Inducing enhanced immunogenic cell death with nanocarrier-based drug delivery systems for pancreatic cancer therapy
- Author
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Guangjun Nie, Xiuchao Wang, Tianjiao Ji, Yinlong Zhang, Jihui Hao, Ruifang Zhao, Kam W. Leong, Shaoli Liu, Xiao Zhao, Keni Yang, Keman Cheng, He Ren, and Xiao Yang
- Subjects
0301 basic medicine ,Organoplatinum Compounds ,medicine.medical_treatment ,Biophysics ,Antineoplastic Agents ,Bioengineering ,02 engineering and technology ,Biomaterials ,Interferon-gamma ,03 medical and health sciences ,Drug Delivery Systems ,Immune system ,Cancer immunotherapy ,Cell Line, Tumor ,polycyclic compounds ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Inducer ,Doxorubicin ,Pancreas ,Cell Death ,business.industry ,Dendritic Cells ,Immunotherapy ,biochemical phenomena, metabolism, and nutrition ,021001 nanoscience & nanotechnology ,Mice, Inbred C57BL ,Oxaliplatin ,Pancreatic Neoplasms ,030104 developmental biology ,Mechanics of Materials ,Drug delivery ,Immunology ,Ceramics and Composites ,Cancer research ,Nanoparticles ,bacteria ,Immunogenic cell death ,Female ,0210 nano-technology ,business ,T-Lymphocytes, Cytotoxic ,medicine.drug - Abstract
Immunogenic cell death (ICD) occurs when apoptotic tumor cell elicits a specific immune response, which may trigger an anti-tumor effect, via the release of immunostimulatory damage-associated molecular patterns (DAMPs). Hypothesizing that nanomedicines may impact ICD due to their proven advantages in delivery of chemotherapeutics, we encapsulated oxaliplatin (OXA) or gemcitabine (GEM), an ICD and a non-ICD inducer respectively, into the amphiphilic diblock copolymer nanoparticles. Neither GEM nor nanoparticle-encapsulated GEM (NP-GEM) induced ICD, while both OXA and nanoparticle-encapsulated OXA (NP-OXA) induced ICD. Interestingly, NP-OXA treated tumor cells released more DAMPs and induced stronger immune responses of dendritic cells and T lymphocytes than OXA treatment in vitro. Furthermore, OXA and NP-OXA exhibited stronger therapeutic effects in immunocompetent mice than in immunodeficient mice, and the enhancement of therapeutic efficacy was significantly higher in the NP-OXA group than the OXA group. Moreover, NP-OXA treatment induced a higher proportion of tumor infiltrating activated cytotoxic T-lymphocytes than OXA treatment. This general trend of enhanced ICD by nanoparticle delivery was corroborated in evaluating another pair of ICD inducer and non-ICD inducer, doxorubicin and 5-fluorouracil. In conclusion, although nanoparticle encapsulation did not endow a non-ICD inducer with ICD-mediated anti-tumor capacity, treatment with a nanoparticle-encapsulated ICD inducer led to significantly enhanced ICD and consequently improved anti-tumor effects than the free ICD inducer. The proposed nanomedicine approach may impact cancer immunotherapy via the novel cell death mechanism of ICD.
- Published
- 2016
45. Drp1-Dependent Mitochondrial Fission Mediates Toxicity of Positively Charged Graphene in Microglia
- Author
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Yuanqin Jiang, Shefang Ye, Keman Cheng, Zhenqing Hou, Tong Zhou, Yange Wang, Peiyan Yang, and Lei Ren
- Subjects
0301 basic medicine ,Programmed cell death ,Materials science ,Biomedical Engineering ,macromolecular substances ,02 engineering and technology ,Mitochondrion ,law.invention ,Biomaterials ,03 medical and health sciences ,chemistry.chemical_compound ,law ,medicine ,Polyethylenimine ,Microglia ,Graphene ,Autophagy ,technology, industry, and agriculture ,021001 nanoscience & nanotechnology ,030104 developmental biology ,medicine.anatomical_structure ,Biochemistry ,chemistry ,Apoptosis ,Biophysics ,Mitochondrial fission ,0210 nano-technology - Abstract
The unique physicochemical properties of graphene and its derivatives enable their application in the diagnostics and therapy of central nervous system (CNS) diseases. However, the potential impacts of surface properties of functionalized graphene on microglia remain poorly understood. Herein, we used graphene oxides (GO), polyethylene glycol (PEG)- and polyethylenimine (PEI)-functionalized GO, which possess different surface charges, to investigate their effects on microglia by focusing on mitochondrial dynamics. The positively charged GO-PEI was found to promote mitochondrial fission as observed in BV-2 cells with mitochondria labeled by DsRed2-mito, indicating that alterations in mitochondrial dynamics depend on the surface properties of graphene. Concurrent to mitochondrial fragmentation, treatment with positively charged GO-PEI induced an increase in mitochondrial recruitment of dynamin-related protein (Drp1). Additionally, GO-PEI treatment also led to apoptotic and autophagic cell death. However, Drp1 silencing by small interfering RNA (siRNA) could effectively attenuate GO-PEI-induced apoptotic and autophagic cell death, indicating that mitochondrial fragmentation occurs upstream of GO-PEI-mediated toxicity in microglia. Overall, our study indicated that positively charged GO-PEI might cause deleterious influence on the central immune homeostasis by Drp1-dependent mitochondrial fragmentation, and provide the strategies for the rational design of graphene-based materials in neuroscience.
- Published
- 2016
46. Correction to Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α Inhibitor Impairs Pancreatic Tumor Growth
- Author
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Xiaowei Zheng, Jiayan Lang, Yiye Li, Xiuchao Wang, He Ren, Xuexiang Han, Xiao Zhao, Keman Cheng, Jian Shi, Gregory J. Anderson, Guangjun Nie, Marzieh Geranpayehvaghei, Ruifang Zhao, Ying Zhao, Hao Qin, Jihui Hao, and Yao Li
- Subjects
Deferoxamine ,Iron Chelator ,Co delivery ,Pancreatic tumor ,business.industry ,General Engineering ,medicine ,Cancer research ,General Physics and Astronomy ,General Materials Science ,medicine.disease ,business ,medicine.drug - Published
- 2020
47. A Bioinspired Nanoprobe with Multilevel Responsive T 1 ‐Weighted MR Signal‐Amplification Illuminates Ultrasmall Metastases
- Author
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Huan Min, Hao Qin, Xiao Zhao, Lei Ren, Guangjun Nie, Xiaoli Liu, Xuexiang Han, Keman Cheng, Junchao Xu, Guangna Liu, Yinlong Zhang, Jian Shi, Yao Li, and Haiming Fan
- Subjects
Materials science ,medicine.diagnostic_test ,Mechanical Engineering ,Cancer ,Nanoprobe ,Magnetic resonance imaging ,02 engineering and technology ,010402 general chemistry ,021001 nanoscience & nanotechnology ,medicine.disease ,01 natural sciences ,0104 chemical sciences ,Metastasis ,Immunosurveillance ,Nuclear magnetic resonance ,Breast cancer ,Mechanics of Materials ,In vivo ,medicine ,General Materials Science ,0210 nano-technology ,Signal amplification - Abstract
Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T1 -weighted magnetic resonance imaging (MRI) contrast agent, UMFNP-CREKA is reported. By conjugating the ultrasmall manganese ferrite nanoparticles (UMFNPs) with a tumor-targeting penta-peptide CREKA (Cys-Arg-Glu-Lys-Ala), ultrasmall breast cancer metastases are accurately detected. With a behavior similar to neutrophils' immunosurveillance process for eliminating foreign pathogens, UMFNP-CREKA exhibits a chemotactic "targeting-activation" capacity. UMFNP-CREKA is recruited to the margin of tumor metastases by the binding of CREKA with fibrin-fibronectin complexes, which are abundant around tumors, and then release of manganese ions (Mn2+ ) to the metastasis in response to pathological parameters (mild acidity and elevated H2 O2 ). The localized release of Mn2+ and its interaction with proteins affects a marked amplification of T1 -weighted magnetic resonance (MR) signals. In vivo T1 -weighted MRI experiments reveal that UMFNP-CREKA can detect metastases at an unprecedented minimum detection limit of 0.39 mm, which has significantly extended the detection limit of previously reported MRI probe.
- Published
- 2019
48. Surface Functionalization of Polymeric Nanoparticles with Umbilical Cord-Derived Mesenchymal Stem Cell Membrane for Tumor-Targeted Therapy
- Author
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Wen Fei Dong, Lirong Zhang, Jing Zhao, Bin Wang, Xiao Zhao, Yinlong Zhang, Guangjun Nie, Mohammad Taleb, Na Yang, Yixin Huang, Yanping Ding, and Keman Cheng
- Subjects
0301 basic medicine ,Materials science ,Cell Survival ,Polymers ,Surface Properties ,Cell ,Antineoplastic Agents ,02 engineering and technology ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Drug Delivery Systems ,Drug Stability ,Biomimetic Materials ,medicine ,Human Umbilical Vein Endothelial Cells ,Animals ,Humans ,General Materials Science ,Cells, Cultured ,Mesenchymal stem cell ,Cell Membrane ,Mesenchymal Stem Cells ,021001 nanoscience & nanotechnology ,PLGA ,030104 developmental biology ,Membrane ,medicine.anatomical_structure ,Targeted drug delivery ,chemistry ,Drug delivery ,Biophysics ,Surface modification ,Nanoparticles ,Nanocarriers ,0210 nano-technology - Abstract
Multiple cell plasma membranes have been utilized for surface functionalization of synthetic nanomaterials and construction of biomimetic drug delivery systems for cancer treatment. The natural characters and facile isolation of original cells facilitate the biomedical applications of plasma membranes in functionalizing nanocarriers. Human umbilical cord-derived mesenchymal stem cells (MSCs) have been identified to show tropism toward malignant lesions and have great advantages in ease of acquisition, low immunogenicity, and high proliferative ability. Here, we developed a poly(lactic- co-glycolic acid) (PLGA) nanoparticle with a layer of plasma membrane from umbilical cord MSC coating on the surface for tumor-targeted delivery of chemotherapy. Functionalization of MSC plasma membrane significantly enhanced the cellular uptake efficiency of PLGA nanoparticles, the tumor cell killing efficacy of PLGA-encapsulated doxorubicin, and most importantly the tumor-targeting and accumulation of the nanoparticles. As a result, this MSC-mimicking nanoformulation led to remarkable tumor growth inhibition and induced obvious apoptosis within tumor lesions. This study for the first time demonstrated the great potential of umbilical cord MSC plasma membranes in functionalizing nanocarriers with inherent tumor-homing features and the high feasibility of such biomimetic nanoformulations in cancer therapy.
- Published
- 2018
49. Carboxylic Acid Fullerene (C60) Derivatives Attenuated Neuroinflammatory Responses by Modulating Mitochondrial Dynamics
- Author
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Yange Wang, Keman Cheng, Yuanqin Jiang, Peiyan Yang, Tong Zhou, Shefang Ye, and Mingliang Chen
- Subjects
chemistry.chemical_classification ,MAPK/ERK pathway ,Reactive oxygen species ,Nano Express ,Carboxylic acid ,Cell ,Mitochondria dynamics ,Mitochondrion ,Biology ,Condensed Matter Physics ,Bioinformatics ,Neuroprotection ,Cell biology ,Fission/fusion ,medicine.anatomical_structure ,Materials Science(all) ,chemistry ,Fullerene derivatives ,medicine ,General Materials Science ,Mitochondrial fission ,Microglia ,Protein kinase A - Abstract
Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60–COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell-based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60–COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (ΔΨm) were also significantly inhibited by C60–COOH. Moreover, we also found that C60–COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives.
- Published
- 2015
50. Targeted Co-delivery of the Iron Chelator Deferoxamine and a HIF1α Inhibitor Impairs Pancreatic Tumor Growth.
- Author
-
Jiayan Lang, Xiao Zhao, Xiuchao Wang, Ying Zhao, Yiye Li, Ruifang Zhao, Keman Cheng, Yao Li, Xuexiang Han, Xiaowei Zheng, Hao Qin, Geranpayehvaghei, Marzieh, Jian Shi, Anderson, Gregory J., Jihui Hao, He Ren, and Guangjun Nie
- Published
- 2019
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