scholarly journals Development of A Decahedral Nanoenzyme Capable of Overcoming Hypoxia to Facilitate the Iodine-125 Radiosensitization of Esophageal Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Dechao Jiao ◽  
Kunpeng Wu ◽  
Kaihao Xu ◽  
Yiming Liu ◽  
Deyao Zhao ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Energy Deposition ◽  
Radiation Energy ◽  
Therapeutic Approaches ◽  
Internal Radiotherapy ◽  
Novel Approach ◽  
Tumor Tissues ◽  
Important Direction ◽  
Iodine 125

Radioisotopes have long been leveraged for internal radiotherapy-mediated cancer treatment. However, such therapeutic approaches are associated with serious side effects, and their efficacy is limited by intratumoral hypoxia. Herein, we prepared a folic acid-decorated palladium decahedral platform capable of enhancing the radiotherapeutic efficacy of iodine-125 (125I) seed treatment. This decahedral nanoenzyme was able to target tumor regions and catalyze the conversion of intracellular H2O2 to O2, thereby alleviating hypoxia within the tumor microenvironment. In addition, palladium was hypoxia can be alleviated, on the other hand, palladium was able to enhance the radiotherapeutic energy deposition within tumor tissues. The results of this analysis indicated that synthesized decahedral constructs can efficiently target and modify the hypoxic tumor microenvironment while simultaneously enhancing radiation energy deposition therein. Relative to palladium nanodots, the prolonged in vivo circulation of these decahedral constructs better enabled them to facilitate sustained radiosensitization. Overall, the results of this study highlight a novel approach to improving the therapeutic utility of 125I seed interstitial implantation, thus underscoring an important direction for future clinical research.

scholarly journals Tryptanthrin exerts anti-breast cancer effects both in vitro and in vivo through modulating the inflammatory tumor microenvironment

2021 ◽  
Vol 71 (2) ◽  
pp. 245-266
Author(s):  
Qingfang Zeng ◽  
Cairong Luo ◽  
Junlae Cho ◽  
Donna Lai ◽  
Xiangchun Shen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Colony Formation ◽  
Migration And Invasion ◽  
Mouse Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tumor Tissues ◽  
Mcf 7

AbstractTryptanthrin is an indole quinazoline alkaloid from the indigo-bearing plants, such as Isatis indigotica Fort. Typically, this natural compound shows a variety of pharmacological activities such as antitumor, antibacterial, anti-inflammatory and antioxidant effects. This study was conducted to assess the antitumor activity of tryptanthrin in breast cancer models both in vitro and in vivo, and to explore the important role of the inflammatory tumor microenvironment (TME) in the antitumor effects of tryptanthrin. Human breast adenocarcinoma MCF-7 cells were used to assess the antitumor effect of tryptanthrin in vitro. MTT assay and colony formation assay were carried out to monitor the antiproliferative effect of tryptanthrin (1.56~50.0 μmol L−1) on inhibiting the proliferation and colony formation of MCF-7 cells, respectively. The migration and invasion of MCF-7 cells were evaluated by wound healing assay and Transwell chamber assay, respectively. Moreover, the 4T1 murine breast cancer model was established to examine the pharmacological activity of tryptanthrin, and three groups with different doses of tryptanthrin (25, 50 and 100 mg kg−1) were set in study. Additionally, tumor volumes and organ coefficients were measured and calculated. After two weeks of tryptanthrin treatment, samples from serum, tumor tissue and different organs from tumor-bearing mice were collected, and the enzyme-linked immunosorbent assay (ELISA) was performed to assess the regulation of inflammatory molecules in mouse serum. Additionally, pathological examinations of tumor tissues and organs from mice were evaluated through hematoxylin and eosin (H&E) staining. The expression of inflammatory proteins in tumor tissues was measured by immunohistochemistry (IHC) and Western blotting. Tryptanthrin inhibited the proliferation, migration and invasion of MCF-7 cells, up-regulated the protein level of E-cadherin, and down-regulated those of MMP-2 and Snail, as suggested by the MCF-7 cell experiment. According to the results from in vivo experiment, tryptanthrin was effective in inhibiting tumor growth, and it showed favorable safety without inducing the fluctuations of body mass and organ coefficient (p > 0.05). In addition, tryptanthrin also suppressed the expression levels of NOS1, COX-2 and NF-κB in mouse tumor tissues, and regulated those of IL-2, IL-10 and TNF-α in the serum of tumor cells-transplanted mice. Tryptanthrin exerted its anti-breast cancer activities through modulating the inflammatory TME both in vitro and in vivo.

Tumor DDR1 deficiency reduces liver metastasis by colon carcinoma and impairs stromal reaction

2021 ◽  
Author(s):  
Irene Romayor ◽  
Joana Márquez ◽  
Aitor Benedicto ◽  
Alba Herrero ◽  
Beatriz Arteta ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Tumor Microenvironment ◽  
Tumor Development ◽  
Immunohistochemical Analysis ◽  
Tyrosine Kinase Receptor ◽  
Ecm Remodeling ◽  
Cell Functions ◽  
Tumor Tissues

Colorectal cancer (CRC) colonization of the liver and its further metastatic growth are the result of complex interaction between the tumor cell, the collagenous extracellular matrix (ECM) and the hepatic sinusoidal cells (SCs). Discoidin domain receptor 1 (DDR1) is a tyrosine kinase receptor activated by collagen and a bad prognosis factor in cancer. DDR1 signaling regulates key cell functions for tumor development, such as proliferation, migration, invasion and metalloproteinases (MMPs) secretion. However, the mechanisms underlying the implication of DDR1 in the conformation of the metastatic niche in the liver remain poorly known. In this study, we used an experimental model of liver metastasis from CRC to investigate the role of DDR1 in the context of the pro-metastatic crosstalk between tumor cells and the hepatic stroma. Bioinformatics and immunohistochemical analysis revealed that DDR1 was highly expressed in tumor tissues from patients with primary CRC and hepatic CRC metastasis. Besides, DDR1 overexpression was associated with poor outcome. In vitro, SCs-derived soluble factors promoted DDR1 phosphorylation and MMP2 production by CRC cells. In vivo, tumor DDR1 participated in hepatic ECM remodeling by modulating the expression of collagen and MMP2, and stimulated the recruitment of stromal cells into the tumor microenvironment. In addition, tumor DDR1 favored SCs ability to modify the ECM organization by controlling the expression of collagen and MMPs. Altogether, our results show that tumor DDR1 plays an important role in the desmoplastic response of hepatic tumor microenvironment during CRC invasion and growth.

scholarly journals Rapamycin Promotes ROS-Mediated Cell Death via Functional Inhibition of xCT Expression in Melanoma Under γ-Irradiation

2021 ◽  
Vol 11 ◽  
Author(s):  
Yunseo Woo ◽  
Hyo-Ji Lee ◽  
Jeongyeon Kim ◽  
Seung Goo Kang ◽  
Sungjin Moon ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Mtor Signaling ◽  
Γ Irradiation ◽  
Γ Radiation ◽  
Hypoxic Conditions ◽  
Tumor Tissues ◽  
Γ Rays

Although many cancer patients are administered radiotherapy for their treatment, the interaction between tumor cells and macrophages in the tumor microenvironment attenuates the curative effects of radiotherapy. The enhanced activation of mTOR signaling in the tumors promotes tumor radioresistance. In this study, the effects of rapamycin on the interaction between tumor cells and macrophages were investigated. Rapamycin and 3BDO were used to regulate the mTOR pathway. In vitro, tumor cells cocultured with macrophages in the presence of each drug under normoxic or hypoxic conditions were irradiated with γ–rays. In vivo, mice were irradiated with γ–radiation after injection with DMSO, rapamycin and 3BDO into tumoral regions. Rapamycin reduced the secretion of IL-4 in tumor cells as well as YM1 in macrophages. Mouse recombinant YM1 decreased the enhanced level of ROS and the colocalized proportion of both xCT and EEA1 in irradiated tumor cells. Human recombinant YKL39 also induced results similar to those of YM1. Moreover, the colocalized proportion of both xCT and LC3 in tumor tissues was elevated by the injection of rapamycin into tumoral regions. Overall, the suppression of mTOR signaling in the tumor microenvironment might be useful for the improvement of tumor radioresistance.

Nanomized tumor-microenvironment-active NIR fluorescent prodrug for ensuring synchronous occurrences of drug release and fluorescence tracing

2019 ◽  
Vol 7 (9) ◽  
pp. 1503-1509 ◽  
Author(s):  
Qiang Li ◽  
Jun Cao ◽  
Qi Wang ◽  
Jie Zhang ◽  
Shiqin Zhu ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Tumor Microenvironment ◽  
Drug Release ◽  
Real Time ◽  
Tumor Targeting ◽  
Activation Process ◽  
Novel Approach ◽  
Real Time Tracking ◽  
Targeting Ability

A nanomized NIR fluorescent prodrug was developed with improved bioavailability and tumor-targeting ability. Nanomized tumor-microenvironment-active NIR DCM-S-GEM/PEG prodrug provides a novel approach to realize long real-time tracking of drug delivery and activation process without systemic toxicity in vivo.

scholarly journals Nanoparticle-Mediated Lipid Metabolic Reprogramming of T Cells in Tumor Microenvironments for Immunometabolic Therapy

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Dongyoon Kim ◽  
Yina Wu ◽  
Qiaoyun Li ◽  
Yu-Kyoung Oh
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Tumor Microenvironment ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Metabolic Reprogramming ◽  
Killing Effect ◽  
Tumor Tissues

Highlights aCD3/F/AN, anti-CD3e f(ab′)2 fragment-modified and fenofibrate-encapsulated amphiphilic nanoparticle, reprogrammed mitochondrial lipid metabolism of T cells. aCD3/F/AN specifically activated T cells in glucose-deficient conditions mimicking tumor microenvironment, and exerted an effector killing effect against tumor cells. In vivo treatment with aCD3/F/AN increased T cell infiltration, cytokine production, and prevented tumor growth. Abstract We report the activation of anticancer effector functions of T cells through nanoparticle-induced lipid metabolic reprogramming. Fenofibrate was encapsulated in amphiphilic polygamma glutamic acid-based nanoparticles (F/ANs), and the surfaces of F/ANs were modified with an anti-CD3e f(ab′)2 fragment, yielding aCD3/F/ANs. An in vitro study reveals enhanced delivery of aCD3/F/ANs to T cells compared with plain F/ANs. aCD3/F/AN-treated T cells exhibited clear mitochondrial cristae, a higher membrane potential, and a greater mitochondrial oxygen consumption rate under glucose-deficient conditions compared with T cells treated with other nanoparticle preparations. Peroxisome proliferator-activated receptor-α and downstream fatty acid metabolism-related genes are expressed to a greater extent in aCD3/F/AN-treated T cells. Activation of fatty acid metabolism by aCD3/F/ANs supports the proliferation of T cells in a glucose-deficient environment mimicking the tumor microenvironment. Real-time video recordings show that aCD3/F/AN-treated T cells exerted an effector killing effect against B16F10 melanoma cells. In vivo administration of aCD3/F/ANs can increase infiltration of T cells into tumor tissues. The treatment of tumor-bearing mice with aCD3/F/ANs enhances production of various cytokines in tumor tissues and prevented tumor growth. Our findings suggest the potential of nanotechnology-enabled reprogramming of lipid metabolism in T cells as a new modality of immunometabolic therapy.

scholarly journals Design and Mechanism of Action of a New Prototype of Combi-Molecule “Programed” to Release Bioactive Species at a pH Range Akin to That of the Tumor Microenvironment

2021 ◽  
Vol 14 (2) ◽  
pp. 160
Author(s):  
Anne-Laure Larroque-Lombard ◽  
Etienne Chatelut ◽  
Jean-Pierre Delord ◽  
Diane-Charlotte Imbs ◽  
Philippe Rochaix ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Xenograft Model ◽  
Mek Inhibitor ◽  
Cytotoxic Agents ◽  
Growth Delay ◽  
Novel Approach ◽  
Mitogen Activated Protein ◽  
Ph Range

The clinical use of cytotoxic agents is plagued by systemic toxicity. We report a novel approach that seeks to design a “combi-molecule” to behave as an alkylating agent on its own and to undergo acid-catalyzed conversion to two bioactive species at a pH range akin to that of a tumor microenvironment: an AL530 prototype was synthesized and we studied its ability to release a chlorambucil analogue (CBL-A) plus a potent mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) inhibitor (PD98059) at different pHs in buffered solutions, plasma and tumors. Its potency was compared in vitro with CBL+PD98059 (SRB assay) and in vivo in a xenograft model. Its target modulation was studied by western blotting and immunohistochemistry. AL530 released PD98059+CBL-A at mild acidic pH and in vitro was fivefold more potent than CBL and three-to-fivefold more potent than CBL+PD98059. In vivo it released high levels of PD98059 in tumors with a tumor/plasma ratio of five. It induced γ-H2AX phosphorylation and blocked pErk1,2, indirectly indicating its ability to damage DNA and modulate MEK. It induced significant tumor delay and less toxicity at unachievable doses for CBL and CBL+PD98059. We demonstrated the feasibility of a pH-labile combi-molecule capable of delivering high MEK inhibitor concentration in tumors, damaging DNA therein, and inducing tumor growth delay.

Dosimetry and Radioenhancement Comparison of Gold Nanoparticles in Kilovoltage and Megavoltage Radiotherapy using MAGAT Polymer Gel Dosimeter

2019 ◽  
Vol 9 (2Apr) ◽  
Author(s):  
S Farahani ◽  
N Riyahi Alam ◽  
S Haghgoo ◽  
M Khoobi ◽  
Gh Geraily ◽  
...  
Keyword(s):  
Gold Nanoparticles ◽  
3D Visualization ◽  
Energy Levels ◽  
Polymer Gel ◽  
External Radiotherapy ◽  
Dose Enhancement ◽  
Internal Radiotherapy ◽  
Boost Radiotherapy

Background: Numerous unique characteristics of the nanosized gold, including high atomic number, low toxicity, and high biocompatibility make it one of the most appropriate nanostructures to boost radiotherapy efficacy. Many in-vivo and in-vitro investigations have indicated that gold nanoparticles (AuNPs) can significantly increase tumor injuries in low kilovoltage radiotherapy. While deep-lying tumors require much higher energy levels with greater penetration power, and investigations carried out in megavoltage energy range show contradictory results.Objective: In this study, we quantitatively assess and compare dose enhancement factors (DEFs) obtained through AuNPs under radiation of Cobalt-60 source (1.25MeV) versus Iridium-192 source (0.380 KeV) using MAGAT gel dosimeter.Material and Methods: MAGAT polymer gel in both pure and combined with 0.2 mM AuNPs was synthesized. In order to quantify the effect of energy on DEF, irradiation was carried out by Co-60 external radiotherapy and Ir-192 internal radiotherapy. Finally, readings of irradiated and non-irradiated gels were performed by MR imaging.Result: The radiation-induced R2 (1/T2) changes of the gel tubes doped with AuNPs compared to control samples, upon irradiation of beams released by Ir-192 source showed a significant dose enhancement (15.31% ±0.30) relative to the Co-60 external radiotherapy (5.85% ±0.14).Conclusion: This preliminary study suggests the feasibility of using AuNPs in radiation therapy (RT), especially in low-energy sources of brachytherapy. In addition, MAGAT polymer gel, as a powerful dosimeter, could be used for 3D visualization of radiation dose distribution of AuNPs in radiotherapy.

scholarly journals Marker for the pre-clinical development of bone substitute materials

2017 ◽  
Vol 3 (2) ◽  
pp. 711-715
Author(s):  
Michael de Wild ◽  
Simon Zimmermann ◽  
Marcel Obrecht ◽  
Michel Dard
Keyword(s):  
Bone Graft ◽  
Mechanical Stability ◽  
Clinical Performance ◽  
Ex Vivo ◽  
Region Of Interest ◽  
Defect Site ◽  
Novel Approach ◽  
Bone Substitute Materials ◽  
Clinical Experiments

AbstractThin mechanically stable Ti-cages have been developed for the in-vivo application as X-ray and histology markers for the optimized evaluation of pre-clinical performance of bone graft materials. A metallic frame defines the region of interest during histological investigations and supports the identification of the defect site. This standardization of the procedure enhances the quality of pre-clinical experiments. Different models of thin metallic frameworks were designed and produced out of titanium by additive manufacturing (Selective Laser Melting). The productibility, the mechanical stability, the handling and suitability of several frame geometries were tested during surgery in artificial and in ex-vivo bone before a series of cages was preclinically investigated in the female Göttingen minipigs model. With our novel approach, a flexible process was established that can be adapted to the requirements of any specific animal model and bone graft testing.

scholarly journals Oxidized Phospholipids in Tumor Microenvironment Stimulate Tumor Metastasis via Regulation of Autophagy

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 558
Author(s):  
Jin Kyung Seok ◽  
Eun-Hee Hong ◽  
Gabsik Yang ◽  
Hye Eun Lee ◽  
Sin-Eun Kim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Autophagic Flux ◽  
Oxidized Phospholipids ◽  
Mcf7 Cells ◽  
Mesenchymal Transition ◽  
Tumor Tissues

Oxidized phospholipids are well known to play physiological and pathological roles in regulating cellular homeostasis and disease progression. However, their role in cancer metastasis has not been entirely understood. In this study, effects of oxidized phosphatidylcholines such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC) on epithelial-mesenchymal transition (EMT) and autophagy were determined in cancer cells by immunoblotting and confocal analysis. Metastasis was analyzed by a scratch wound assay and a transwell migration/invasion assay. The concentrations of POVPC and 1-palmitoyl-2-glutaroyl-sn-glycero-phosphocholine (PGPC) in tumor tissues obtained from patients were measured by LC-MS/MS analysis. POVPC induced EMT, resulting in increase of migration and invasion of human hepatocellular carcinoma cells (HepG2) and human breast cancer cells (MCF7). POVPC induced autophagic flux through AMPK-mTOR pathway. Pharmacological inhibition or siRNA knockdown of autophagy decreased migration and invasion of POVPC-treated HepG2 and MCF7 cells. POVPC and PGPC levels were greatly increased at stage II of patient-derived intrahepatic cholangiocarcinoma tissues. PGPC levels were higher in malignant breast tumor tissues than in adjacent nontumor tissues. The results show that oxidized phosphatidylcholines increase metastatic potential of cancer cells by promoting EMT, mediated through autophagy. These suggest the positive regulatory role of oxidized phospholipids accumulated in tumor microenvironment in the regulation of tumorigenesis and metastasis.

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