Engineering of Cascade-Responsive Nanoplatform to Inhibit Lactate Efflux for Enhanced Tumor Chemo-Immunotherapy

Li, Ké; Lin, Changjian; He, Ye; Lu, Lu; Xu, Kun; Tao, Bailong; Xia, Zengzilu; Zeng, Rui; Mao, Yulan; Luo, Zhong; Cai, Kaiyong

doi:10.1021/acsnano.0c07071

Cited by 102 publications

(98 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As such, high glycolytic (A) Inositol Phosphate Metabolism pathway (B) Tryptophan metabolism rates of cancer cells can lead to the increased generation of lactate and an accumulation of H+ ions, which ultimately induce an acidified tumor microenvironment [37]. The presence of MCT2 facilitates the relocation of lactic acid and enhances its utilization as an energy substrate, thereby reducing glycolysis and preventing pro-tumoral polarity changes in TAMs while preserving the innate immune cell function [5,[38][39][40]. Furthermore, MCT2 has been reported to be located in the mitochondria with a role for mitochondrial metabolism, and inhibition of MCT2 suppresses colorectal cancer progression via the induction of mitochondrial dysfunction [41].…”

Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporter-2 Expression Restricts Tumor Growth in a Murine Model of Lung Cancer: A Multi-Omic Analysis

Qiao

Raju

Shyu

et al. 2021

IJMS

View full text Add to dashboard Cite

Monocarboxylate transporter 2 (MCT2) is a major high-affinity pyruvate transporter encoded by the SLC16A7 gene, and is associated with glucose metabolism and cancer. Changes in the gut microbiota and host immune system are associated with many diseases, including cancer. Using conditionally expressed MCT2 in mice and the TC1 lung carcinoma model, we examined the effects of MCT2 on lung cancer tumor growth and local invasion, while also evaluating potential effects on fecal microbiome, plasma metabolome, and bulk RNA-sequencing of tumor macrophages. Conditional MCT2 mice were generated in our laboratory using MCT2loxP mouse intercrossed with mCre-Tg mouse to generate MCT2loxP/loxP; Cre+ mouse (MCT2 KO). Male MCT2 KO mice (8 weeks old) were treated with tamoxifen (0.18 mg/g BW) KO or vehicle (CO), and then injected with mouse lung carcinoma TC1 cells (10 × 105/mouse) in the left flank. Body weight, tumor size and weight, and local tumor invasion were assessed. Fecal DNA samples were extracted using PowerFecal kits and bacterial 16S rRNA amplicons were also performed. Fecal and plasma samples were used for GC−MS Polar, as well as non-targeted UHPLC-MS/MS, and tumor-associated macrophages (TAMs) were subjected to bulk RNAseq. Tamoxifen-treated MCT2 KO mice showed significantly higher tumor weight and size, as well as evidence of local invasion beyond the capsule compared with the controls. PCoA and hierarchical clustering analyses of the fecal and plasma metabolomics, as well as microbiota, revealed a distinct separation between the two groups. KO TAMs showed distinct metabolic pathways including the Acetyl-coA metabolic process, activation of immune response, b-cell activation and differentiation, cAMP-mediated signaling, glucose and glutamate processes, and T-cell differentiation and response to oxidative stress. Multi-Omic approaches reveal a substantial role for MCT2 in the host response to TC1 lung carcinoma that may involve alterations in the gut and systemic metabolome, along with TAM-related metabolic pathway. These findings provide initial opportunities for potential delineation of oncometabolic immunomodulatory therapeutic approaches.

show abstract

Section: Discussionmentioning

confidence: 99%

Monocarboxylate Transporter-2 Expression Restricts Tumor Growth in a Murine Model of Lung Cancer: A Multi-Omic Analysis

Qiao

Raju

Shyu

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Finally, lactate promotes the infiltrations of immunosuppressive cells, including M2 macrophages-like tumor-associated macrophages [ 63 ], N2 neutrophils-like tumor-associated neutrophils [ 125 ], bone marrow-derived myeloid suppressor cells (MDSCs) [ 126 ] and Tregs cells [ 127 ], which effectively inhibits the ant-tumor immune responses and promote immune escape. Therefore, reducing the accumulation and acidification of lactate in the TME is an important link to activate tumor immunity [ 128 ].…”

Section: Comprehensive Antitumor Therapeutic System Of “Metal-oxidase” System Combined With Other Therapiesmentioning

confidence: 99%

Fenton/Fenton-like metal-based nanomaterials combine with oxidase for synergistic tumor therapy

et al. 2021

View full text Add to dashboard Cite

Chemodynamic therapy (CDT) catalyzed by transition metal and starvation therapy catalyzed by intracellular metabolite oxidases are both classic tumor treatments based on nanocatalysts. CDT monotherapy has limitations including low catalytic efficiency of metal ions and insufficient endogenous hydrogen peroxide (H2O2). Also, single starvation therapy shows limited ability on resisting tumors. The “metal-oxidase” cascade catalytic system is to introduce intracellular metabolite oxidases into the metal-based nanoplatform, which perfectly solves the shortcomings of the above-mentioned monotherapiesIn this system, oxidases can not only consume tumor nutrients to produce a “starvation effect”, but also provide CDT with sufficient H2O2 and a suitable acidic environment, which further promote synergy between CDT and starvation therapy, leading to enhanced antitumor effects. More importantly, the “metal-oxidase” system can be combined with other antitumor therapies (such as photothermal therapy, hypoxia-activated drug therapy, chemotherapy, and immunotherapy) to maximize their antitumor effects. In addition, both metal-based nanoparticles and oxidases can activate tumor immunity through multiple pathways, so the combination of the “metal-oxidase” system with immunotherapy has a powerful synergistic effect. This article firstly introduced the metals which induce CDT and the oxidases which induce starvation therapy and then described the “metal-oxidase” cascade catalytic system in detail. Moreover, we highlight the application of the “metal-oxidase” system in combination with numerous antitumor therapies, especially in combination with immunotherapy, expecting to provide new ideas for tumor treatment.

show abstract

“…As is already well-known, the TME is characterized by high GSH with concentration 7-10 times higher than that of normal tissues. Therefore, GSH could act as an endogenous stimulus to trigger the release of NO [172,173]. Song et al previously synthesized a new type of NO donor, named a nitrate-functionalized D-α-tocopheryl polyethylene glycol succinate (TNO 3 ).…”

Section: Glutathione-triggered No Nanomedicinesmentioning

confidence: 99%

“…Tumor cells produce a large amount of lactic acid because of their rapid growth and enhanced glycolysis metabolism, leading to the weakly acidic TME (pH 6.5~6.8) [174,175]. Therefore, an increasingly number of studies have taken advantage of the acidic TME and designed different pH-responsive NO-releasing nanomedicines based on it in recent years [173,[176][177][178]. For example, Sung et al designed a pH-sensitive release nanosystem loaded with chemotherapeutic drugs and the NO donor diethylenetriamine diazeniumdiolate (DETA NONOate).…”

Section: Ph-triggered No Nanomedicinesmentioning

confidence: 99%

Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy

et al. 2021

View full text Add to dashboard Cite

Gas therapy has received widespread attention from the medical community as an emerging and promising therapeutic approach to cancer treatment. Among all gas molecules, nitric oxide (NO) was the first one to be applied in the biomedical field for its intriguing properties and unique anti-tumor mechanisms which have become a research hotspot in recent years. Despite the great progress of NO in cancer therapy, the non-specific distribution of NO in vivo and its side effects on normal tissue at high concentrations have impaired its clinical application. Therefore, it is important to develop facile NO-based nanomedicines to achieve the on-demand release of NO in tumor tissue while avoiding the leakage of NO in normal tissue, which could enhance therapeutic efficacy and reduce side effects at the same time. In recent years, numerous studies have reported the design and development of NO-based nanomedicines which were triggered by exogenous stimulus (light, ultrasound, X-ray) or tumor endogenous signals (glutathione, weak acid, glucose). In this review, we summarized the design principles and release behaviors of NO-based nanomedicines upon various stimuli and their applications in synergistic cancer therapy. We also discuss the anti-tumor mechanisms of NO-based nanomedicines in vivo for enhanced cancer therapy. Moreover, we discuss the existing challenges and further perspectives in this field in the aim of furthering its development.

show abstract

Engineering of Cascade-Responsive Nanoplatform to Inhibit Lactate Efflux for Enhanced Tumor Chemo-Immunotherapy

Cited by 102 publications

References 54 publications

Monocarboxylate Transporter-2 Expression Restricts Tumor Growth in a Murine Model of Lung Cancer: A Multi-Omic Analysis

Monocarboxylate Transporter-2 Expression Restricts Tumor Growth in a Murine Model of Lung Cancer: A Multi-Omic Analysis

Fenton/Fenton-like metal-based nanomaterials combine with oxidase for synergistic tumor therapy

Stimuli Responsive Nitric Oxide-Based Nanomedicine for Synergistic Therapy

Contact Info

Product

Resources

About