Surface PEGylated Cancer Cell Membrane-Coated Nanoparticles for Codelivery of Curcumin and Doxorubicin for the Treatment of Multidrug Resistant Esophageal Carcinoma

ObjectiveThe emergence of multi-drug resistance (MDR) in esophageal carcinoma has severely affected the effect of chemotherapy and shortened the survival of patients. To this end, we intend to develop a biomimetic nano-targeting drug modified by cancer cell membrane, and investigate its therapeutic effect.MethodsThe degradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) co-loaded with doxorubicin (DOX) and curcumin (Cur) were prepared by solvent evaporation method. TE10 cell membrane and Distearoyl phosphatidylethanolamine-polyethylene glycol (DSPE-PEG) were then coated on the PLGA NPs by membrane extrusion to prepare the PEG-TE10@PLGA@DOX-Cur NPs (PMPNs). Size and zeta potential of the PMPNs were analyzed by lazer particle analyzer, and the morphology of PMPNs was observed by transmission electron microscope. The TE10 cell membrane protein on PMPNs was analyzed by gel electrophoresis. The DOX-resistant esophageal cancer cell model TE10/DOX was established through high-dose induction. The In vitro homologous targeting ability of PMPNs was evaluated by cell uptake assay, and the in vitro anti-tumor effect of PMPNs was assessed through CCK-8, clone formation and flow cytometry. A Balb/c mouse model of TE10/DOX xenograft was constructed to evaluate the anti-tumor effect in vivo and the bio-safety of PMPNs.ResultsThe prepared cell membrane coated PMPNs had a regular spherical structure with an average diameter of 177 nm. PMPNs could directly target TE10 and TE10/DOX cells or TE10/DOX xenografted tumor and effectively inhibit the growth of DOX-resistant esophageal carcinoma. Besides, the PMPNs was confirmed to have high biosafety.ConclusionIn this study, a targeted biomimetic nano-drug delivery system PMPNs was successfully prepared, which overcome the MDR of esophageal carcinoma by co-delivering DOX and sensitizer curcumin.

Download Full-text

Cancer Cell Membrane Decorated Silica Nanoparticle Loaded with miR495 and Doxorubicin to Overcome Drug Resistance for Effective Lung Cancer Therapy

Nanoscale Research Letters ◽

10.1186/s11671-019-3143-3 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 3

Author(s):

Jinyuan He ◽

Chulian Gong ◽

Jie Qin ◽

Mingan Li ◽

Shaohong Huang

Keyword(s):

Lung Cancer ◽

Cancer Therapy ◽

Cell Membrane ◽

Cancer Cells ◽

Cancer Cell ◽

Silica Nanoparticle ◽

Glycoprotein P ◽

Lung Cancer Therapy

Abstract Current cancer therapy usually succumbs to many extracellular and intracellular barriers, among which untargeted distribution and multidrug resistance (MDR) are two important difficulties responsible for poor outcome of many drug delivery systems (DDS). Here, in our study, the dilemma was addressed by developing a cancer cell membrane (CCM)-coated silica (SLI) nanoparticles to co-deliver miR495 with doxorubicin (DOX) for effective therapy of lung cancer (CCM/SLI/R-D). The homologous CCM from MDR lung cancer cells (A549/DOX) was supposed to increase the tumor-homing property of the DDS to bypass the extracellular barriers. Moreover, the MDR of cancer cells were conquered through downregulation of P-glycoprotein (P-gp) expression using miR495. It was proved that miR495 could significantly decrease the expression of P-gp which elevated intracellular drug accumulation in A549/DOX. The in vitro and in vivo results exhibited that CCM/SLI/R-D showed a greatly enhanced therapeutic effect on A549/DOX, which was superior than applying miR495 or DOX alone. The preferable effect of CCM/SLI/R-D on conquering the MDR in lung cancer provides a novel alternative for effective chemotherapy of MDR cancers.

Download Full-text

Hyperbaric Oxygen Enhanced Mitochondria-Targeted Chemotherapy in Bladder Cancer

10.21203/rs.3.rs-111008/v1 ◽

2020 ◽

Author(s):

Chongxing Shen ◽

Xiaofeng Yue ◽

Linyong Dai ◽

Jianwu Wang ◽

Jinjin Li ◽

...

Keyword(s):

Bladder Cancer ◽

Cancer Cells ◽

Cancer Cell ◽

Hyperbaric Oxygen ◽

Cell Uptake ◽

Bladder Cancer Cells ◽

First Time ◽

Mitochondria Targeting

Abstract Background: Bladder cancer has a high rate of recurrence and drug resistance due to a lack of effective therapies. IR-780 iodide, a near-infrared (NIR) mitochondria-targeting fluorescent agent, has been demonstrated to achieve higher selectivity than other drugs in different tumor types. In the study, we aimed to investigate the anti-tumor effect of IR-780 combined with hyperbaric oxygen (HBO) on bladder cancer.Methods: Using in vitro cell line data, in vivo model data and clinical data, we tested the ability of IR-780 to selectively accumulate in bladder cancer. We also evaluated the anti-tumor effect of IR-780 combined or not with HBO both in vitro and in vivo, and explored the potential mechanism of its anti-tumor effect. Results: We revealed for the first time that IR-780 selectively accumulated in bladder cancer (bladder cancer cells, xenografts and bladder cancer samples from patients) and could induce cancer cell apoptosis by targeting the mitochondrial complex I protein NDUFS1. Further study displayed that the combination with HBO could significantly enhance the antitumor effect of IR-780 in vitro by promoting cancer cell uptake and inducing excessive mitochondrial reactive oxygen species (ROS) production, while suppressing tumor growth and recurrence in animal models without causing apparent toxicity. Moreover, this combination antitumor strategy was also demonstrated in drug-resistant bladder cancer cells (T24/DDP) and xenografts. Conclusions: These data identify for the first time a combination of IR-780 and HBO (IR-780+HBO), which exhibits mitochondria-targeting and therapeutic capabilities, as a novel treatment paradigm for bladder cancer.

Download Full-text

A Predominant Oxidative Renal Metabolite of Empagliflozin in Male Mice Is Cytotoxic in Mouse Renal Tubular Cells but not Genotoxic

International Journal of Toxicology ◽

10.1177/1091581817735090 ◽

2017 ◽

Vol 36 (6) ◽

pp. 440-448 ◽

Cited By ~ 6

Author(s):

James D. Smith ◽

Zimei Huang ◽

Patricia A. Escobar ◽

Pamela Foppiano ◽

Hlaing Maw ◽

...

Keyword(s):

Male Mouse ◽

Cell Model ◽

Metabolic Stress ◽

Renal Tumors ◽

High Dose ◽

Renal Tubular Cells ◽

Primary Mouse ◽

Renal Tubular

In a previously reported CD-1 mouse 2-year carcinogenicity study with the sodium glucose cotransporter-2 inhibitor empagliflozin, an increased incidence of renal tubular adenomas and carcinomas was identified only in the male high-dose group. Follow-up investigative studies have shown that the renal tumors in male high-dose mice were preceded by a number of renal degenerative/regenerative findings. Prior cross-species in vitro metabolism studies using microsomes identified an oxidative metabolite (M466/2) predominantly formed in the male mouse kidney and which spontaneously degrades to a metabolite (M380/1) and reactive 4-OH crotonaldehyde (CTA). In order to further evaluate potential modes of action for empagliflozin-associated male mouse renal tumors, we report here a series of in vitro investigative toxicology studies conducted to evaluate the cytotoxic and genotoxic potential of empagliflozin and M466/2. To assess the cytotoxic potential of empagliflozin and M466/2, a primary mouse renal tubular epithelial (mRTE) cell model was used. In mRTE cells, M466/2-derived in vitro 4-OH CTA exposure was cytotoxic, while empagliflozin was not cytotoxic or mitogenic. Empagliflozin and M466/2 were not genotoxic, supporting an indirect mode of action for empagliflozin-associated male mouse renal tumorigenesis. In conclusion, these in vitro data show that M466/2-derived 4-OH CTA exposure is associated with cytotoxicity in renal tubule cells and may be involved in promoting compound-related in vivo renal metabolic stress and chronic low-level renal injury, in turn supporting a nongenotoxic mode of tumor pathogenesis specific to the male mouse.

Download Full-text

Cell membrane–camouflaged liposomes for tumor cell–selective glycans engineering and imaging in vivo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2022769118 ◽

2021 ◽

Vol 118 (30) ◽

pp. e2022769118

Author(s):

Zhengwei Liu ◽

Faming Wang ◽

Xinping Liu ◽

Yanjuan Sang ◽

Lu Zhang ◽

...

Keyword(s):

Cell Membrane ◽

Tumor Cell ◽

Cancer Cells ◽

Cancer Cell ◽

Dynamic Change ◽

Membrane Receptors ◽

Cancer Subtypes ◽

Corona Formation

The dynamic change of cell-surface glycans is involved in diverse biological and pathological events such as oncogenesis and metastasis. Despite tremendous efforts, it remains a great challenge to selectively distinguish and label glycans of different cancer cells or cancer subtypes. Inspired by biomimetic cell membrane–coating technology, herein, we construct pH-responsive azidosugar liposomes camouflaged with natural cancer-cell membrane for tumor cell–selective glycan engineering. With cancer cell–membrane camouflage, the biomimetic liposomes can prevent protein corona formation and evade phagocytosis of macrophages, facilitating metabolic glycans labeling in vivo. More importantly, due to multiple membrane receptors, the biomimetic liposomes have prominent cell selectivity to homotypic cancer cells, showing higher glycan-labeling efficacy than a single-ligand targeting strategy. Further in vitro and in vivo experiments indicate that cancer cell membrane–camouflaged azidosugar liposomes not only realize cell-selective glycan imaging of different cancer cells and triple-negative breast cancer subtypes but also do well in labeling metastatic tumors. Meanwhile, the strategy is also applicable to the use of tumor tissue–derived cell membranes, which shows the prospect for individual diagnosis and treatment. This work may pave a way for efficient cancer cell–selective engineering and visualization of glycans in vivo.

Download Full-text

Epoxyscillirosidine Induced Cytotoxicity and Ultrastructural Changes in a Rat Embryonic Cardiomyocyte (H9c2) Cell Line

Toxins ◽

10.3390/toxins11050284 ◽

2019 ◽

Vol 11 (5) ◽

pp. 284

Author(s):

Hamza Isa ◽

Gezina Ferreira ◽

Jan Crafford ◽

Christoffel Botha

Keyword(s):

Cell Membrane ◽

Cell Line ◽

Structural Changes ◽

Cell Model ◽

Cell Membrane Permeability ◽

Ultrastructural Changes ◽

H9c2 Cell ◽

High Dose ◽

H9c2 Cell Line

Moraea pallida Bak. (yellow tulp) poisoning is the most important cardiac glycoside-induced intoxication in ruminants in South Africa. The toxic principle, 1α, 2α-epoxyscillirosidine, is a bufadienolide. To replace the use of sentient animals in toxicity testing, the aim of this study was to evaluate the cytotoxic effects of epoxyscillirosidine on rat embryonic cardiomyocytes (H9c2 cell line). This in vitro cell model can then be used in future toxin neutralization or toxico-therapy studies. Cell viability, evaluated with the methyl blue thiazol tetrazolium (MTT) assay, indicated a hormetic dose/concentration response, characterized by a biphasic low dose stimulation and high dose inhibition. Increased cell membrane permeability and leakage, as expected with necrotic cells, were demonstrated with the lactate dehydrogenase (LDH) assay. The LC50 was 382.68, 132.28 and 289.23 μM for 24, 48, and 72 h respectively. Numerous cytoplasmic vacuoles, karyolysis and damage to the cell membrane, indicative of necrosis, were observed at higher doses. Ultra-structural changes suggested that the cause of H9c2 cell death, subsequent to epoxyscillirosidine exposure, is necrosis, which is consistent with myocardial necrosis observed at necropsy. Based on the toxicity observed, and supported by ultra-structural findings, the H9c2 cell line could be a suitable in vitro model to evaluate epoxyscillirosidine neutralization or other therapeutic interventions in the future.

Download Full-text

IN VITRO AND IN VIVO BIOCOMPATIBILITY STUDIES OF ZNO NANOPARTICLES

International Journal of Modern Physics B ◽

10.1142/s0217979209061275 ◽

2009 ◽

Vol 23 (06n07) ◽

pp. 1566-1571 ◽

Cited By ~ 21

Author(s):

YUFENG ZHENG ◽

RANZHONG LI ◽

YUEDAN WANG

Keyword(s):

Zno Nanoparticles ◽

Cell Model ◽

Apoptotic Cell ◽

L929 Cell ◽

High Dose ◽

Zno Nanoparticle ◽

Nanoparticle Suspension ◽

Liver And Kidney

The in vitro and in vivo biocompatibility of the ZnO nanoparticles were evaluated using cell model and animal model, by MTT assay, flow cell cytometry, pathological optical and electron microscopy examinations. Both the L929 cell and Hela cell proliferative activity were strongly inhibited by the presence of ZnO nanoparticles, no matter cultured with low dose and high dose suspension. AnnexinV-FITC/PI-FCM assay showed that the number of necrotic cell and apoptotic cell increased significantly. Feeding the ZnO nanoparticle suspension through digestive tract would lead to the damage to some primary organs (heart, lung, liver and kidney). Further investigation by TEM showed the expanded sarcoplasmic reticulum and organelle vacuolation features.

Download Full-text

Biomimetic Upconversion Nanoparticles and Gold Nanoparticles for Novel Simultaneous Dual-Modal Imaging-Guided Photothermal Therapy of Cancer

Cancers ◽

10.3390/cancers12113136 ◽

2020 ◽

Vol 12 (11) ◽

pp. 3136 ◽

Cited By ~ 1

Author(s):

Ruliang Wang ◽

Han Yang ◽

Rongxin Fu ◽

Ya Su ◽

Xue Lin ◽

...

Keyword(s):

Cell Membrane ◽

Cancer Cell ◽

Photothermal Therapy ◽

Tumor Targeting ◽

Imaging System ◽

Imaging Systems ◽

Coated Nanoparticles ◽

Cancer Theranostics

Multimodal imaging-guided near-infrared (NIR) photothermal therapy (PTT) is an interesting and promising cancer theranostic method. However, most of the multimodal imaging systems provide structural and functional information used for imaging guidance separately by directly combining independent imaging systems with different detectors, and many problems arise when trying to fuse different modal images that are serially taken by inviting extra markers or image fusion algorithms. Further, most imaging and therapeutic agents passively target tumors through the enhanced permeability and retention (EPR) effect, which leads to low utilization efficiency. To address these problems and systematically improve the performance of the imaging-guided PTT methodology, we report a novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as a platform for PTT-based cancer theranostics. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. In vitro and in vivo evaluation of macrophage escape and active homologous tumor targeting were performed. Cancer cell membrane-coated nanoparticles (CC-NPs) displayed excellent immune evasion ability, longer blood circulation time, and higher tumor targeting specificity compared to normal PEGylated nanoparticles, which led to highly specific upconversion luminescence (UCL) imaging and PTT-based anti-tumor efficacy. The anti-cancer efficacy of the dual-modal imaging-guided PTT was also evaluated both in vitro and in vivo. Dual-modal imaging yielded precise anatomical and functional information for the PTT process, and complete tumor ablation was achieved with CC-AuNPs. Our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics.

Download Full-text

MEST promotes lung cancer invasion and metastasis by interacting with VCP to activate NF-κB signaling

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02107-1 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Yang Wang ◽

Jing Zhang ◽

Yang-Jia Li ◽

Nan-Nan Yu ◽

Wan-Ting Liu ◽

...

Keyword(s):

Lung Cancer ◽

Signaling Pathway ◽

Cancer Cell ◽

Cancer Metastasis ◽

Cell Model ◽

Metastatic Cancer ◽

Lung Cancer Cell ◽

Invasion And Metastasis

Abstract Background Cell invasion is a hallmark of metastatic cancer, leading to unfavorable clinical outcomes. In this study, we established two highly invasive lung cancer cell models (A549-i8 and H1299-i8) and identified mesoderm-specific transcript (MEST) as a novel invasive regulator of lung cancer. We aim to characterize its biological function and clinical significance in lung cancer metastasis. Methods Transwell invasion assay was performed to establish high-invasive lung cancer cell model. Immunohistochemistry (IHC) was used to detect MEST expression in tumor tissues. Mass spectrometry and bioinformatic analyses were used to identify MEST-regulated proteins and binding partners. Co-immunoprecipitation assay was performed to detect the interaction of MEST and VCP. The biological functions of MEST were investigated in vitro and in vivo. Immunofluorescence staining was conducted to explore the colocalization of MEST and VCP. Results MEST overexpression promoted metastasis of lung cancer cells in vivo and in vitro by activating NF-κB signaling. MEST increased the interaction between VCP and IκBα, which accelerated IκBα degradation and NF-κB activation. Such acceleration was abrogated by VCP silencing, indicating that MEST is an upstream activator of the VCP/IκBα/NF-κB signaling pathway. Furthermore, high expressions of MEST and VCP were associated with poor survival of lung cancer patients. Conclusion Collectively, these results demonstrate that MEST plays an important role in driving invasion and metastasis of lung cancer by interacting with VCP to coordinate the IκBα/NF-κB pathway. Targeting the MEST/VCP/IκBα/NF-κB signaling pathway may be a promising strategy to treat lung cancer.

Download Full-text

Endogenous hydrogen sulfide sulfhydrates IKKβ at cysteine 179 to control pulmonary artery endothelial cell inflammation

Clinical Science ◽

10.1042/cs20190514 ◽

2019 ◽

Vol 133 (20) ◽

pp. 2045-2059 ◽

Cited By ~ 4

Author(s):

Da Zhang ◽

Xiuli Wang ◽

Siyao Chen ◽

Selena Chen ◽

Wen Yu ◽

...

Keyword(s):

Hydrogen Sulfide ◽

Endothelial Cell ◽

Pulmonary Artery ◽

Cell Model ◽

Site Directed Mutagenesis ◽

Critical Event ◽

Hypertensive Rats ◽

Pulmonary Artery Endothelial Cell

Abstract Background: Pulmonary artery endothelial cell (PAEC) inflammation is a critical event in the development of pulmonary arterial hypertension (PAH). However, the pathogenesis of PAEC inflammation remains unclear. Methods: Purified recombinant human inhibitor of κB kinase subunit β (IKKβ) protein, human PAECs and monocrotaline-induced pulmonary hypertensive rats were employed in the study. Site-directed mutagenesis, gene knockdown or overexpression were conducted to manipulate the expression or activity of a target protein. Results: We showed that hydrogen sulfide (H2S) inhibited IKKβ activation in the cell model of human PAEC inflammation induced by monocrotaline pyrrole-stimulation or knockdown of cystathionine γ-lyase (CSE), an H2S generating enzyme. Mechanistically, H2S was proved to inhibit IKKβ activity directly via sulfhydrating IKKβ at cysteinyl residue 179 (C179) in purified recombinant IKKβ protein in vitro, whereas thiol reductant dithiothreitol (DTT) reversed H2S-induced IKKβ inactivation. Furthermore, to demonstrate the significance of IKKβ sulfhydration by H2S in the development of PAEC inflammation, we mutated C179 to serine (C179S) in IKKβ. In purified IKKβ protein, C179S mutation of IKKβ abolished H2S-induced IKKβ sulfhydration and the subsequent IKKβ inactivation. In human PAECs, C179S mutation of IKKβ blocked H2S-inhibited IKKβ activation and PAEC inflammatory response. In pulmonary hypertensive rats, C179S mutation of IKKβ abolished the inhibitory effect of H2S on IKKβ activation and pulmonary vascular inflammation and remodeling. Conclusion: Collectively, our in vivo and in vitro findings demonstrated, for the first time, that endogenous H2S directly inactivated IKKβ via sulfhydrating IKKβ at Cys179 to inhibit nuclear factor-κB (NF-κB) pathway activation and thereby control PAEC inflammation in PAH.

Download Full-text