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Article ; Online: Improving combination cancer immunotherapy by manipulating dual immunomodulatory signals with enzyme-triggered, cell-penetrating peptide-mediated biomodulators.

Pang, Guibin / Chen, Piao / Cao, Xuewei / Yu, Huan / Zhang, Leshuai W / Zhao, Jian / Wang, Fu-Jun

2024 Volume 12, Issue 3, Page(s) 776–789

Abstract: Immunosuppressive tumor microenvironments challenge the effectiveness of protein-based biopharmaceuticals in cancer immunotherapy. Reestablishing tumor cell immunogenicity by enhancing calreticulin (CRT) exposure is expected to improve tumor ... ...

Abstract	Immunosuppressive tumor microenvironments challenge the effectiveness of protein-based biopharmaceuticals in cancer immunotherapy. Reestablishing tumor cell immunogenicity by enhancing calreticulin (CRT) exposure is expected to improve tumor immunotherapy. Given that CRT translocation is inherently modulated by phosphorylated eIF2α, the selective inhibition of protein phosphatase 1 (PP1) emerges as an effective strategy to augment tumor immunogenicity. To harness the PP1-disrupting potential of GADD34-derived motifs and address their limited intracellular delivery, we integrated these sequences into an enzyme-triggered, cell-penetrating peptide-mediated chimeric protein scaffold. This design not only facilitates efficient cytoplasmic delivery of these immunostimulatory motifs to induce "eat-me" signaling, but also provides a versatile platform for combination immunotherapy. Fabrication of biomodulators with cytotoxic BLF1 provides additional "eat-me" signaling through phosphatidylserine exposure or that with an immunomodulatory designed ankyrin repeat protein disables "don't-find-me" signaling by antagonizing PD-L1. Notably, these bifunctional biomodulators exhibit remarkable ability to induce macrophage phagocytosis, dendritic cell maturation, and CD8
MeSH term(s)	Humans ; Cell-Penetrating Peptides ; Immunotherapy ; Antineoplastic Agents/pharmacology ; Neoplasms/pathology ; Immunologic Factors ; Tumor Microenvironment ; Cell Line, Tumor
Chemical Substances	Cell-Penetrating Peptides ; Antineoplastic Agents ; Immunologic Factors
Language	English
Publishing date	2024-01-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2693928-9
ISSN	2047-4849 ; 2047-4830
ISSN (online)	2047-4849
ISSN	2047-4830
DOI	10.1039/d3bm01605f
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Neutrophils-mediated bioinspired nanoagents for noninvasive monitoring of inflammatory recruitment dynamics and navigating phototherapy in rheumatoid arthritis.

Yu, Hongchang / Wu, Yanxian / Xu, Jingwei / Wang, Yangyun / Cheng, Xiaju / Zhang, Leshuai W / Qin, Jianzhong / Wang, Yong

Biomaterials advances

2024 Volume 158, Page(s) 213764

Abstract: Neutrophils play a crucial role in inflammatory immune responses, but their in vivo homing to inflammatory lesions remains unclear, hampering precise treatment options. In this study, we employed a biomineralization-inspired multimodal nanoagent to label ...

Abstract	Neutrophils play a crucial role in inflammatory immune responses, but their in vivo homing to inflammatory lesions remains unclear, hampering precise treatment options. In this study, we employed a biomineralization-inspired multimodal nanoagent to label neutrophils, enabling noninvasive monitoring of the dynamic process of inflammatory recruitment and guiding photothermal therapy in rheumatoid arthritis. Our nanoagents allowed visualization of neutrophil fate through magnetic resonance imaging, photoacoustic imaging, and fluorescence imaging in the first and second near-infrared windows. Histopathology and immunofluorescence analysis revealed pronounced inflammatory cell infiltration in rheumatoid arthritis compared to the normal limb. Furthermore, the recruitment quantity of neutrophils positively correlated with the inflammatory stage. Additionally, the inherent photothermal effect of the nanoagents efficiently ablated inflammatory cells during the optimal homing time and inflammatory phase. This neutrophil imaging-guided photothermal therapy precisely targeted inflammatory nuclei in rheumatoid arthritis and downregulated pro-inflammatory cytokines in serum. These results demonstrate that in vivo tracking of inflammatory immune response cells can significantly optimize the treatment of inflammatory diseases, including rheumatoid arthritis.
MeSH term(s)	Humans ; Neutrophils ; Phototherapy ; Photothermal Therapy ; Arthritis, Rheumatoid/therapy ; Biomineralization
Language	English
Publishing date	2024-01-11
Publishing country	Netherlands
Document type	Journal Article
ISSN	2772-9508
ISSN (online)	2772-9508
DOI	10.1016/j.bioadv.2024.213764
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Derivation of the toxicological threshold of silicon element in the extractables and leachables from the pharmaceutical packaging and process components.

Hao, Pengchao / Wang, Yingying / Sun, Xiongfei / Wang, Jinhui / Zhang, Leshuai W

Toxicology and industrial health

2022 Volume 38, Issue 12, Page(s) 819–834

Abstract: Silicon is one of the most monitored elements in extractables and leachables studies of pharmaceutical packaging systems and related components. There is a need to review and evaluate toxicological thresholds of silicon because of its direct contact with ...

Abstract	Silicon is one of the most monitored elements in extractables and leachables studies of pharmaceutical packaging systems and related components. There is a need to review and evaluate toxicological thresholds of silicon because of its direct contact with drug products (DP) especially a liquid form of DP with the widely used pharmaceutical packaging systems made of silicon materials like glass and silicone. It is required by regulatory authorities to test silicon content in DP; however, there are no official guidelines on the toxicology of silicon that are currently available, yet the knowledge of toxicological thresholds of silicon is critical to justify the analytical limit of quantification (LOQ). Therefore, we reviewed the toxicity of silicon to derive a toxicological threshold by literature review of toxicity studies of both inorganic and organic silicon compounds. Oral toxicity is low for inorganic silicon like silicon dioxide or organic silicon polymers such as silicone tube/silicone oil (polydimethylsiloxane, or namely, PDMS as the major ingredient). In comparison, inhalational toxicity of silicon dioxide leads to pulmonary silicosis or even lung cancer. When orally administered, the toxicity of silicon dioxide, glass, polymers, or PDMS oligomers varies depending on their morphology, molecular weight (MW), and degrees of polymerization. PDMS with high MW has minimal toxic symptoms with non-detectable degradation/elimination by both intraperitoneal and subcutaneous administration routes, while exposure to either PDMS or small molecule dimethyl silicone compounds by the intravenous administration route may lead to death. We here determined a general parenteral permitted daily exposure (PDE) of 93 μg/day for inorganic silicon element and 100 μg/day for organic silicon element by reviewing toxicological data of both forms of silicon. In conclusion, this work provides evidence for pharmaceutical companies and regulatory agencies on the PDEs of silicon elements in pharmaceutical packaging and process components through a variety of administration routes.
MeSH term(s)	Molecular Weight ; Polymers ; Silicon Dioxide ; Silicones/toxicity ; Drug Packaging
Chemical Substances	Polymers ; Silicon Dioxide (7631-86-9) ; Silicones
Language	English
Publishing date	2022-11-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	56831-4
ISSN	1477-0393 ; 0748-2337
ISSN (online)	1477-0393
ISSN	0748-2337
DOI	10.1177/07482337221123368
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Zs.A 2268: Show issues

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Article ; Online: Harnessing astaxanthin-loaded diselenium cross-linked apotransferrin nanoparticles for the treatment of secretory otitis media.

Yang, Siqi / Wu, Yanxian / Cheng, Xiaju / Zhang, Leshuai W / Yu, Yafeng / Wang, Yong / Wang, Yangyun

Journal of controlled release : official journal of the Controlled Release Society

2023 Volume 365, Page(s) 398–411

Abstract: Secretory otitis media (SOM) is a clinical condition characterized by the accumulation of fluids and oxidative stress in the middle ear, leading to hearing impairment and infection complications. One potential solution for mitigating oxidative stress ... ...

Abstract	Secretory otitis media (SOM) is a clinical condition characterized by the accumulation of fluids and oxidative stress in the middle ear, leading to hearing impairment and infection complications. One potential solution for mitigating oxidative stress associated with SOM is the use of antioxidants such as astaxanthin. However, its effectiveness is limited due to its poor bioavailability and rapid oxidation. Herein, we developed a novel diselenium-crosslinked apotransferrin enriched with astaxanthin (AST@dSe-AFT) nanoparticles to augment the transport of astaxanthin across biological membranes, resulting in increased bioavailability and reduced oxidative stress in SOM. Our research demonstrated that AST@dSe-AFT efficiently accumulated in the middle ear, allowing for controlled delivery of astaxanthin in response to reactive oxygen species and reducing oxidative stress. Additionally, AST@dSe-AFT stimulated macrophages to polarize towards M2 phenotype and neutrophils to polarize towards N2 phenotype, thereby facilitating an anti-inflammatory response and tissue restoration. Importantly, AST@dSe-AFT exhibited no toxicity or adverse effects, suggesting its potential for safety and future clinical translation. Our findings suggested that AST@dSe-AFT represents a promising approach for the treatment of secretory otitis media and other oxidative stress-related disorders.
MeSH term(s)	Humans ; Otitis Media with Effusion/drug therapy ; Antioxidants/therapeutic use ; Oxidative Stress ; Nanoparticles ; Apoproteins ; Transferrin ; Xanthophylls
Chemical Substances	apotransferrin ; astaxanthine (8XPW32PR7I) ; Antioxidants ; Apoproteins ; Transferrin ; Xanthophylls
Language	English
Publishing date	2023-11-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	632533-6
ISSN	1873-4995 ; 0168-3659
ISSN (online)	1873-4995
ISSN	0168-3659
DOI	10.1016/j.jconrel.2023.11.040
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Zs.A 2055: Show issues

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Article ; Online: Chemotherapy-Sensitized

Wang, Yangyun / Wu, Yanxian / Li, Liubing / Ma, Chunjie / Zhang, Shaodian / Lin, Subin / Zhang, Leshuai W / Wang, Yong / Gao, Mingyuan

ACS nano

2023 Volume 17, Issue 7, Page(s) 6247–6260

Abstract: How to effectively treat malignant osteosarcoma remains clinically challenging. Programmed delivery of chemotherapeutic agents and immunostimulants may offer a universal strategy for killing osteosarcoma cells while simultaneously ... ...

Abstract	How to effectively treat malignant osteosarcoma remains clinically challenging. Programmed delivery of chemotherapeutic agents and immunostimulants may offer a universal strategy for killing osteosarcoma cells while simultaneously eliciting
MeSH term(s)	Humans ; Calcium ; Organophosphonates/therapeutic use ; CD8-Positive T-Lymphocytes ; Osteosarcoma/drug therapy ; Bone Neoplasms/drug therapy ; Vaccination ; Cell Line, Tumor ; Doxorubicin/chemistry ; Tumor Microenvironment
Chemical Substances	Calcium (SY7Q814VUP) ; Organophosphonates ; Doxorubicin (80168379AG)
Language	English
Publishing date	2023-03-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.2c09685
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Radioresponsive Delivery of Toll-like Receptor 7/8 Agonist for Tumor Radioimmunotherapy Enabled by Core-Cross-Linked Diselenide Nanoparticles.

Wu, Yanxian / Qin, Jianzhong / Gu, Yuan / Zhao, Gang / Xu, Pei / Lin, Subin / Cheng, Xiaju / Zhang, Leshuai W / Wang, Yangyun / Wang, Yong

ACS nano

2024 Volume 18, Issue 4, Page(s) 2800–2814

Abstract: The development of a radioresponsive delivery platform has led to an innovative combination radioimmunotherapy strategy for treating tumors. However, controlling the release of immunomodulators by local ... ...

Abstract	The development of a radioresponsive delivery platform has led to an innovative combination radioimmunotherapy strategy for treating tumors. However, controlling the release of immunomodulators by local radiotherapy
MeSH term(s)	Humans ; Toll-Like Receptor 7/agonists ; Radioimmunotherapy ; Antineoplastic Agents ; Neoplasms/drug therapy ; Adjuvants, Immunologic ; Nanoparticles/chemistry
Chemical Substances	Toll-Like Receptor 7 ; Antineoplastic Agents ; Adjuvants, Immunologic
Language	English
Publishing date	2024-01-16
Publishing country	United States
Document type	Journal Article
ISSN	1936-086X
ISSN (online)	1936-086X
DOI	10.1021/acsnano.3c05882
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Toxicity assessment of six titanium dioxide nanoparticles in human epidermal keratinocytes.

Zhang, Leshuai W / Monteiro-Riviere, Nancy A

Cutaneous and ocular toxicology

2019 Volume 38, Issue 1, Page(s) 66–80

Abstract: Purpose: The aim of this study was to evaluate and compare the toxicity of six different types of titanium dioxide (TiO: Materials and methods: Six TiO: Results: TiO: Conclusions: Based on cell viability, only sample B was slightly cytotoxic to ...

Abstract	Purpose: The aim of this study was to evaluate and compare the toxicity of six different types of titanium dioxide (TiO Materials and methods: Six TiO Results: TiO Conclusions: Based on cell viability, only sample B was slightly cytotoxic to HEK and samples B and A* have the potential to cause inflammation indicated by an increase in IL-6.
MeSH term(s)	Cells, Cultured ; Cytokines/metabolism ; Humans ; Keratinocytes/drug effects ; Keratinocytes/metabolism ; Metal Nanoparticles/toxicity ; Titanium/toxicity
Chemical Substances	Cytokines ; titanium dioxide (15FIX9V2JP) ; Titanium (D1JT611TNE)
Language	English
Publishing date	2019-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	605635-0
ISSN	1556-9535 ; 1556-9527 ; 0731-3829
ISSN (online)	1556-9535
ISSN	1556-9527 ; 0731-3829
DOI	10.1080/15569527.2018.1527848
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Zs.A 1782: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Dose matters: Direct killing or immunoregulatory effects of natural polysaccharides in cancer treatment.

Pang, Guibin / Wang, Fujun / Zhang, Leshuai W

Carbohydrate polymers

2018 Volume 195, Page(s) 243–256

Abstract: Polysaccharides from natural resources possess anti-tumor activities for decades, but the efficacy of polysaccharides as the adjuvant drugs for cancer treatment at prescribed doses remains open for debate. In this review, molecular mechanisms involved in ...

Abstract	Polysaccharides from natural resources possess anti-tumor activities for decades, but the efficacy of polysaccharides as the adjuvant drugs for cancer treatment at prescribed doses remains open for debate. In this review, molecular mechanisms involved in direct killing effects of polysaccharides, including apoptosis, cell cycle arrest and mitochondria/DNA damage were described. However, the concentrations/doses used to reach the direct killing effects are too high to be applicable. Polysaccharides can also exert anti-tumor effects through immunoregulation at lower doses, and the effects of polysaccharides on natural killer cells, dendritic cells and other lymphocytes for tumor destruction, along with the receptor recognition and downstream signaling pathways, were delineated. Unfortunately, the prescribed doses of polysaccharides are too low to stimulate immunoresponse, resulting in the failure of some clinical trials. Therefore, understanding the sophisticated mechanisms of the immunoregulatory function of natural polysaccharides with refined doses for clinical use will help the standardization of traditional medicine.
MeSH term(s)	Animals ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Clinical Trials as Topic ; Dose-Response Relationship, Drug ; Humans ; Immunologic Factors/administration & dosage ; Immunologic Factors/pharmacology ; Immunologic Factors/therapeutic use ; Neoplasms/drug therapy ; Polysaccharides/administration & dosage ; Polysaccharides/pharmacology ; Polysaccharides/therapeutic use
Chemical Substances	Antineoplastic Agents ; Immunologic Factors ; Polysaccharides
Language	English
Publishing date	2018-04-30
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2018.04.100
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Dose matters: Direct killing or immunoregulatory effects of natural polysaccharides in cancer treatment

Pang, Guibin / Wang, Fujun / Zhang, Leshuai W

Carbohydrate polymers. 2018 Sept. 01, v. 195

2018

Abstract	Polysaccharides from natural resources possess anti-tumor activities for decades, but the efficacy of polysaccharides as the adjuvant drugs for cancer treatment at prescribed doses remains open for debate. In this review, molecular mechanisms involved in direct killing effects of polysaccharides, including apoptosis, cell cycle arrest and mitochondria/DNA damage were described. However, the concentrations/doses used to reach the direct killing effects are too high to be applicable. Polysaccharides can also exert anti-tumor effects through immunoregulation at lower doses, and the effects of polysaccharides on natural killer cells, dendritic cells and other lymphocytes for tumor destruction, along with the receptor recognition and downstream signaling pathways, were delineated. Unfortunately, the prescribed doses of polysaccharides are too low to stimulate immunoresponse, resulting in the failure of some clinical trials. Therefore, understanding the sophisticated mechanisms of the immunoregulatory function of natural polysaccharides with refined doses for clinical use will help the standardization of traditional medicine.
Keywords	DNA damage ; adjuvants ; antineoplastic activity ; apoptosis ; cell cycle checkpoints ; clinical trials ; dendritic cells ; drugs ; immunomodulation ; mitochondria ; natural killer cells ; natural resources ; neoplasms ; polysaccharides ; signal transduction ; traditional medicine
Language	English
Dates of publication	2018-0901
Size	p. 243-256.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1501516-6
ISSN	1879-1344 ; 0144-8617
ISSN (online)	1879-1344
ISSN	0144-8617
DOI	10.1016/j.carbpol.2018.04.100
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Gadolinium-Bisphosphonate Nanoparticle-Based Low-Dose Radioimmunotherapy for Osteosarcoma.

Zhang, Shaodian / Wu, Yanxian / Yu, Jiangkun / Ma, Chunjie / Wang, Yangyun / Wang, Yong / Li, Liubing / Zhang, Leshuai W

ACS biomaterials science & engineering

2022 Volume 8, Issue 12, Page(s) 5329–5337

Abstract: Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may ... ...

Abstract	Osteosarcoma is a malignant osteogenic tumor with a high metastatic rate commonly occurring in adolescents. Although radiotherapy is applied to treat unresectable osteosarcoma with radiation resistance, a high dose of radiotherapy is required, which may weaken the immune microenvironment. Therefore, there is an urgent need to develop novel agents to maximize the radiotherapeutic effects by eliciting immune activation effects. In this study, we synthesized therapeutic gadolinium-based metal-bisphosphonate nanoparticles (NPs) for osteosarcoma treatment that can be combined with radiotherapy. The gadolinium ion (Gd) was chelated with zoledronic acid (Zol), a commonly used drug to prevent/treat osteoporosis or bone metastases from advanced cancers, and stabilized by ovalbumin (OVA) to produce OVA-GdZol NPs. OVA-GdZol NPs were internalized into K7M2 osteosarcoma cells, showing a high sensitization effect under X-ray irradiation. Cell pretreatment of OVA-GdZol NPs significantly enhanced the radiation therapeutic effect in vitro by reducing the cell colonies and increased the signal of γH2AX-positive cells. More importantly, OVA-GdZol NPs promoted the maturation of bone marrow-derived dendritic cells (BMDCs) and M1 polarization of macrophages. The inhibitory effect on K7M2 osteosarcoma of OVA-GdZol NPs and X-ray radiation was evident, indicated by a significantly reduced tumor volume, high survival rate, and decreased lung metastasis. Meanwhile, both innate and adaptive immune systems were activated to exert a strong antitumor effect. The above results highly suggest that OVA-GdZol NPs serve as both radiosensitizers and immune adjuvants, suitable for the sequential combination of vaccination and radiotherapy.
Language	English
Publishing date	2022-11-16
Publishing country	United States
Document type	Journal Article
ISSN	2373-9878
ISSN (online)	2373-9878
DOI	10.1021/acsbiomaterials.2c00880
Database	MEDical Literature Analysis and Retrieval System OnLINE

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