scholarly journals Tumor-derived biomimetic nanozyme with immune evasion ability for synergistically enhanced low dose radiotherapy

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chunyu Huang ◽  
Zeming Liu ◽  
Mingzhu Chen ◽  
Liang Du ◽  
Chunping Liu ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Low Dose ◽  
Immune Escape ◽  
Redox Homeostasis ◽  
Low Dose Radiotherapy ◽  
Tumor Tissues ◽  
High Doses ◽  
Intracellular Hydrogen Peroxide

AbstractHigh doses of radiation can cause serious side effects and efficient radiosensitizers are urgently needed. To overcome this problem, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for enhanced low-dose radiotherapy (RT). CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH-OXD) and peroxidase (POD) activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2 Gy) can provide a substantial suppression of tumor proliferation. This is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes. Graphical Abstract

scholarly journals Tumor-Derived Biomimetic Nanozyme With Immune Evasion Ability For Synergistically Enhanced Low Dose Radiotherapy

2021 ◽  
Author(s):  
Chunyu Huang ◽  
Zeming Liu ◽  
Mingzhu Chen ◽  
Liang Du ◽  
Yongfa Zheng ◽  
...  
Keyword(s):  
High Performance ◽  
Low Dose ◽  
Immune Escape ◽  
Redox Homeostasis ◽  
Low Dose Radiotherapy ◽  
Tumor Tissues ◽  
High Doses ◽  
Intracellular Hydrogen Peroxide

Abstract High doses of radiation can cause serious side effects and drug resistance, high-performance radiosensitizers are urgently needed. To overcome this issue, we developed a biomimetic nanozyme system (CF) by coating pyrite (FeS2) into tumor-derived exosomes for use in combination with low-dose RT. CF system give FeS2 with immune escape and homologous targeting abilities. After administration, CF with both glutathione oxidase (GSH) and peroxidase activities can significantly lower the content of GSH in tumor tissues and catalyze intracellular hydrogen peroxide (H2O2) to produce a large amount of ·OH for intracellular redox homeostasis disruption and mitochondria destruction, thus reducing RT resistance. Experiments in vivo and in vitro showed that combining CF with RT (2Gy) can provide a substantial suppression of tumor proliferation. To summarize, this is the first attempt to use exosomes bionic FeS2 nanozyme for realizing low-dose RT, which broaden the prospects of nanozymes.

scholarly journals Platelet Membranes Coated Gold Nanocages for Tumor Targeted Drug Delivery and Amplificated Low-Dose Radiotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Mingzhu Chen ◽  
Ping Wang ◽  
Dazhen Jiang ◽  
Zhirong Bao ◽  
Hong Quan
Keyword(s):  
Side Effects ◽  
Tumor Cells ◽  
Low Dose ◽  
Immune Escape ◽  
Radiation Energy ◽  
Platelet Membranes ◽  
Low Dose Radiotherapy ◽  
Gold Nanocages

Continuous high doses of radiation can cause irreversible side effects and radiation resistance; thus, advanced radiosensitizers are urgently needed. To overcome this problem, we developed a nano platelet radiosensitization system (PCA) by coating the chemotherapeutic drug cisplatin (CDDP) loaded gold nanocages (AuNs) within the platelet membrane. The developed PCA system may enable AuNs to have immune escape and targeting capabilities. After administration, PCA will actively target tumor cells and avoid being cleared by the immune system. Subsequently, CDDP, which destroys tumor cell DNA, can not only kill tumor cells directly but also combine with AuNs, which deposit radiation energy into tumor tissues, reducing RT resistance. In vivo and in vitro studies revealed that the combination of PCA with RT (2Gy) efficiently inhibits tumor proliferation without causing side effects such as inflammation. To conclude, this is the first attempt to use platelet membranes to correctly transport AuNs while also accomplishing low-dose RT, which could help AuNs-based tumor RT become more effective.

scholarly journals Toll-Like Receptor Signaling in Airborne Burkholderia thailandensis Infection

2009 ◽  
Vol 77 (12) ◽  
pp. 5612-5622 ◽  
Author(s):  
T. Eoin West ◽  
Thomas R. Hawn ◽  
Shawn J. Skerrett
Keyword(s):  
Low Dose ◽  
Inflammatory Responses ◽  
High Dose ◽  
Tlr Signaling ◽  
Necrosis Factor Alpha ◽  
Airborne Infection ◽  
Essential Components ◽  
High Doses

ABSTRACT Melioidosis is a tropical disease endemic in southeast Asia and northern Australia caused by the gram-negative soil saprophyte Burkholderia pseudomallei. Although infection is often systemic, the lung is frequently involved. B. thailandensis is a closely related organism that at high doses causes lethal pneumonia in mice. We examined the role of Toll-like receptors (TLRs), essential components of innate immunity, in vitro and in vivo during murine B. thailandensis pneumonia. TLR2, TLR4, and TLR5 mediate NF-κB activation by B. thailandensis in transfected HEK293 or CHO cells. In macrophages, TLR4 and the adaptor molecule MyD88, but not TLR2 or TLR5, are required for tumor necrosis factor alpha production induced by B. thailandensis. In low-dose airborne infection, TLR4 is needed for early, but not late, bacterial containment, and MyD88 is essential for control of infection and host survival. TLR2 and TLR5 are not necessary to contain low-dose infection. In high-dose airborne infection, TLR2 deficiency confers a slight survival advantage. Lung and systemic inflammatory responses are induced by low-dose inhaled B. thailandensis independently of individual TLRs or MyD88. These findings suggest that redundancy in TLR signaling or other MyD88-dependent pathways may be important in pneumonic B. thailandensis infection but that MyD88-independent mechanisms of inflammation are also activated. TLR signaling in B. thailandensis infection is substantially comparable to signaling induced by virulent B. pseudomallei. These studies provide additional insights into the host-pathogen interaction in pneumonic Burkholderia infection.

scholarly journals Selective Expression of Variant Surface Antigens Enables Plasmodium falciparum to Evade Immune Clearance in vivo

2020 ◽  
Author(s):  
Marvin Chew ◽  
Weijian Ye ◽  
Radoslaw Igor Omelianczyk ◽  
Charisse Flerida Pasaje ◽  
Regina Hoo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Immune Evasion ◽  
Immune Escape ◽  
Killer Cell ◽  
Surface Antigens ◽  
Variant Surface Antigens ◽  
Immune Clearance ◽  
Macrophage Phagocytosis

AbstractPlasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA and the RIFIN PF3D7_1254800 provides the parasite with protection from macrophage phagocytosis and natural killer cell mediated killing. Taken together, these findings reveal new insights on the molecular and cellular mechanisms that coordinate the immune escape process the parasite utilizes in vivo. As immune evasion may be particularly important during the establishment of the blood stage infection when parasite numbers are still relatively small, identification of specific parasite variant surface antigens provides targets for developing more effective vaccines by targeting parasite immune evasion.

scholarly journals Injectable Hydrogel for Synergetic Low Dose Radiotherapy, Chemodynamic Therapy and Photothermal Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Mingzhu Chen ◽  
Ziqi Wang ◽  
Weilong Suo ◽  
Zhirong Bao ◽  
Hong Quan
Keyword(s):  
Photothermal Therapy ◽  
Low Dose ◽  
Tumor Therapy ◽  
Intratumoral Injection ◽  
Low Dose Radiation ◽  
Injectable Hydrogel ◽  
Low Dose Radiotherapy ◽  
Dose Radiation

Higher doses of radiotherapy (RT) are associated with resistance induction, therefore highly selective and controllable radiosensitizers are urgently needed. To address this issue, we developed a FeGA-based injectable hydrogel system (FH) that can be used in combination with low-dose radiation. Our FH can deliver FeGA directly to the tumor site via intratumoral injection, where it is a reservoir-based system to conserve FeGA. The photothermal properties of FeGA steadily dissolve FH under laser irradiation, and, simultaneously, FeGA reacts with a large amount of H2O2 in the cell to produce OH (Fenton reaction) which is highly toxic to mitochondria, rendering the cell inactive and reducing radiotherapy resistance. In vivo and in vitro studies suggest that combining the FH and NIR irradiation with RT (2Gy) can significantly reduce tumor proliferation without side effects such as inflammation. To conclude, this is the first study to achieve combined chemodynamic therapy (CDT) and photothermal therapy (PTT) in situ treatment, and the best therapeutic effect can be obtained with a low-dose radiation combination, thus expanding the prospects of FeGA-based tumor therapy.

scholarly journals Promotion of tumor progression induced by continuous low-dose administration of antineoplastic agent gemcitabine or gemcitabine combined with cisplatin

2021 ◽  
Author(s):  
Yanshen CHEN ◽  
Hua LIU ◽  
Qiaowei ZHENG ◽  
Houli LI ◽  
Huining YOU ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Tumor Cells ◽  
Antineoplastic Agents ◽  
Low Dose ◽  
Tumor Formation ◽  
Dose Administration ◽  
Tumor Tissues ◽  
Low Dose Chemotherapy

Abstract Background: There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated.Methods: Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues.Results: The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells. Conclusions: These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents.

Results of a phase II study to evaluate the biological effects of intratumoral (ITu) reolysin in combination with low dose radiotherapy (RT) in patients (Pts) with advanced cancers

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14514-e14514 ◽  
Author(s):  
M. Saunders ◽  
A. Anthoney ◽  
M. Coffey ◽  
K. Mettinger ◽  
B. Thompson ◽  
...  
Keyword(s):  
Low Dose ◽  
Biological Effects ◽  
Performance Status ◽  
Target Lesion ◽  
Open Label ◽  
Ecog Performance Status ◽  
Low Dose Radiotherapy ◽  
Secondary Endpoints

e14514 Background: Reolysin, a wild type reovirus serotype 3 Dearing strain, replicates preferentially in Ras-activated cancer cells. In vitro and in vivo data have shown that combining reolysin and radiation (RT) significantly increases RT-induced cytotoxicity. A completed phase I trial of ITu reolysin and RT demonstrated that the combination was well tolerated and resulted in local and systemic responses. Methods: This open-label, single-arm, multicenter Phase 2 study combined ITu reolysin with low-dose fractionated RT. 20 Gy was given in 5 consecutive daily 4 Gy fractions combined with 2 ITu injections of reolysin (1x1010 TCID50) on days 2 & 4. The primary endpoint was objective tumor response rate in treated lesions. Secondary endpoints were to evaluate: viral replication, immune response and safety. Pts with ECOG performance status ≤2, with refractory advanced or metastatic cancers were eligible. Results: 16 heavily pre-treated pts (9 male, median age 66 yrs, ECOG 0:4pts; 1:12pts) with advanced cancer: melanoma (5), colorectal (4), gastric (1), ovarian (1), pancreas (1), lung (1), cholangiocarcinoma (1), sinus (1), and thyroid (1) were enrolled since Dec 2006. Most pts had received prior chemotherapy (13 pts) or RT (5 pts). No related serious adverse effects were observed during the study. Toxicities related to treatment were Grade 1 or 2: chills, pyrexia, headache, lethargy, anorexia, vomiting, shivering, nausea, and mild injection site pain. Of 14 pts evaluable for response, 13 pts had stable disease or better in the treated target lesion. Of these, partial responses were observed in 4 pts (lung, melanoma x 2, gastric) and minor responses were observed in 2 pts (thyroid, ovarian). Antibody responses to reolysin were delayed compared to previous results with intravenous administration. Conclusions: The combination of ITu reolysin and low dose RT was well tolerated and resulted in marked responses or stabilization in the treated target lesions for most of the pts evaluated to date. Further study in the radical setting is warranted. [Table: see text]

scholarly journals Requirements for Identification of Low Dose and Non-Linear Mutagenic Responses to Ionising Radiation

Dose-Response ◽  
2007 ◽  
Vol 5 (4) ◽  
pp. dose-response.0 ◽  
Author(s):  
Pamela J. Sykes ◽  
Tanya K. Day
Keyword(s):  
Low Dose ◽  
Threshold Model ◽  
Dose Range ◽  
Cellular Transformation ◽  
Low Dose Radiation ◽  
Spontaneous Frequency ◽  
High Doses ◽  
Dose Radiation

Cancer results from multiple changes in gene expression that can occur both genetically and epigenetically. High doses of radiation can lead to mutations and cancer. At high doses the number of mutations caused by radiation is essentially linear with dose. Low dose radiation induced protective responses observed for cancer in vivo and cellular transformation in vitro would predict that hormetic responses would also be observed in mutation assays. Although there are a large number of different mutation assays available, very few are able to detect changes in mutation frequency in response to very low doses of DNA damaging agents. The easiest way to cope with this lack of data in the low dose range is to invoke a linear-no-threshold model for risk assessment. The reasons for the lack of data are discussed. In order to identify hormetic mutation responses, assays need to have a spontaneous frequency that is high enough to enable a reduction below spontaneous frequency to be detected in a feasible number of scored cells and also need to be able to identify both genetic and epigenetic changes. The pKZ1 chromosomal inversion assay fits the criteria for detecting hormetic responses to low dose radiation.

In Vivo Effect of Suloctidil as an Antiplatelet Agent

1979 ◽  
Vol 41 (03) ◽  
pp. 465-474 ◽  
Author(s):  
Marcia R Stelzer ◽  
Thomas S Burns ◽  
Robert N Saunders
Keyword(s):  
Ex Vivo ◽  
Antiplatelet Agent ◽  
Ratio Method ◽  
Platelet Aggregate ◽  
Permanent Effect ◽  
Platelet Aggregates ◽  
5 Ht Uptake ◽  
High Doses

SummaryThe relationship between the effects of suloctidil in vivo as an antiplatelet agent and in vitro as a modifier of platelet serotonin (5-HT) parameters was investigated. Suloctidil was found to be effective in reducing platelet aggregates formation in the retired breeder rat as determined using the platelet aggregate ratio method (PAR) with an ED50 of 16.1 mg/kg 24 hours post administration. In contrast to the hypothesis that 5-HT depletion is involved in the anti-aggregatory mechanism of suloctidil, no correlation was found between platelet 5- HT content and this antiplatelet activity. Reduction of platelet 5-HT content required multiple injections of high doses (100 mg/kg/day) of suloctidil. Suloctidil administration for 8 days at 100 mg/kg/day, which lowered platelet 5-HT content by 50%, resulted in no permanent effect on ex vivo platelet 5-HT uptake or thrombin-induced release, nor alteration in the plasma 5-HT level. However, these platelets exhibited a short-lived, significant increase in percent leakage of 5-HT after 30 minutes of incubation. Therefore, suloctidil treatment at high doses may with time result in platelet 5-HT depletion, however this effect is probably not related to the primary anti-aggregatory activity of the drug.

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