GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy

Liu, Xiaohan; Li, Yanhua; Wang, Kaiye; Chen, Yuanyuan; Shi, Mingwan; Zhang, Xia; Pan, Wei; Li, Na; Tang, Bo

doi:10.1021/acs.nanolett.1c03089

Cited by 101 publications

(76 citation statements)

References 41 publications

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“…On the other hand, as the end product of glycolysis, lactate also can be regarded as another indicator for verifying whether glycolysis inhibition. Specifically, the glycolysis inhibition is typically accompanied with the reduction in lactate 10 . The result in Figure 4 E demonstrated that as compared with the free drugs, the LND-Pep-cyclen was more effective in decreasing the intracellular lactate concentration, which was coincident with the result in Figure 4 C. It is well known that the first step in glycolysis is the glucose being catalyzed by HK to 6-phosphate glucose.…”

Section: Resultsmentioning

confidence: 99%

Mitochondrion-targeted supramolecular “nano-boat” simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy

Gao¹,

Wang²,

Guo³

et al. 2022

Theranostics

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Rationale: Tumor energy metabolism has been a well-appreciated target of cancer therapy; however, the metabolism change of cancer cells between oxidative phosphorylation and glycolysis poses a challenge to the above. In this study, we constructed an innovative mitochondrion-targeted supramolecular “nano-boat” based on peptide self-assembly for tumor combined chemo-radiotherapy by simultaneously inhibiting the dual energy metabolism. Methods: A lipophilic self-assembled peptide and a positively charged cyclen were integrated to fabricate a brand new mitochondrion-targeted nano-platform for the first time. The indices of mitochondrial dysfunction including mitochondrial membrane potential, apoptosis proteins expression and ultrastructure change were evaluated using a JC-1 probe, western blotting and biological transmission electron microscopy, respectively. Energy metabolism assays were conducted on a Seahorse XF24 system by detecting the oxygen consumption rate and the glycolytic proton efflux rate. The radio-sensitization effect was investigated by colony formation, the comet assay, and γ-H2AX staining. Results: The supramolecular “nano-boat” could selectively kill cancer cells by much higher enrichment and reactive oxygen species generation than those in normal cells. In the cancer cells treated with the supramolecular “nano-boat”, the dysfunctional morphological changes of the mitochondrial ultrastructure including swelling and pyknosis were evidently observed, and the endogenous mitochondrial apoptosis pathway was effectively triggered by abundant of cytochrome C leaking out. Concurrently, the dual metabolic pathways of glycolysis and oxidative phosphorylation were severely inhibited. More importantly, the supramolecular “nano-boat” displayed an excellent radio-sensitization effect with a sensitization enhancement ratio value as high as 2.58, and hence, in vivo efficiently combining radiotherapy yielded an enhanced chemo-radiotherapy effect. Conclusion: Our study demonstrated that the rationally designed peptide-based “nano-boat” could efficiently induce cancer cell apoptosis by the energy metabolism inhibition involving multiple pathways, which may provide the motivation for designing novel and universal mitochondria-targeted drug delivery systems for cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Mitochondrion-targeted supramolecular “nano-boat” simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy

Gao¹,

Wang²,

Guo³

et al. 2022

Theranostics

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“…As an effective inhibitor of glycolysis, Lonidamine (LND) is an effective inhibitor of hexokinase II (HK II), a rate-limiting enzyme for glycolysis pathways. A GSH-responsive nanodrug that is loaded with LND restrains the glycolysis of tumor cells and inhibits tumor growth (Liu et al, 2021). In a similar manner, a nanodrug consists of 1-(4-pyridyl)-3-(2-quinoline)-2-propyl-1-one (PFK15), which is a PFKFB3 inhibitor targeting glycolysis metabolism (Zhao et al, 2020a).…”

Section: Aerobic Glycolysis and Mitochondrial Aerobic Respirationmentioning

confidence: 99%

Nanomedicines Targeting Metabolism in the Tumor Microenvironment

Ren

Zheng²,

Gao³

et al. 2022

Front. Bioeng. Biotechnol.

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Cancer cells reprogram their metabolism to meet their growing demand for bioenergy and biosynthesis. The metabolic profile of cancer cells usually includes dysregulation of main nutritional metabolic pathways and the production of metabolites, which leads to a tumor microenvironment (TME) having the characteristics of acidity, hypoxic, and/or nutrient depletion. Therapies targeting metabolism have become an active and revolutionary research topic for anti-cancer drug development. The differential metabolic vulnerabilities between tumor cells and other cells within TME provide nanotechnology a therapeutic window of anti-cancer. In this review, we present the metabolic characteristics of intrinsic cancer cells and TME and summarize representative strategies of nanoparticles in metabolism-regulating anti-cancer therapy. Then, we put forward the challenges and opportunities of using nanoparticles in this emerging field.

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“…Several researchers have focused on developing functional carriers with reduction responsiveness based on two strategies: insertion of disulfide bonds in the polymer backbone or using reduction-sensitive cross-linking molecules ( Gulfam et al, 2017 ; Conte et al, 2018 ; Deng et al, 2018 ; Monteiro et al, 2020 ). Glutathione (GSH) levels inside and outside cancer cells are markedly different ( Lai et al, 2021 ; Liu et al, 2021 ). Nanocarriers with reducing properties can achieve drug release more accurately and rapidly.…”

Section: Non-specific Targeted Therapeutic Nanocarriers For Treatment Of Bladder Cancermentioning

confidence: 99%

Functional Nanomedicines for Targeted Therapy of Bladder Cancer

et al. 2021

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Bladder cancer is one of most common malignant urinary tract tumor types with high incidence worldwide. In general, transurethral resection of non-muscle-invasive bladder cancer followed by intravesical instillation of chemotherapy is the standard treatment approach to minimize recurrence and delay progression of bladder cancer. However, conventional intravesical chemotherapy lacks selectivity for tumor tissues and the concentration of drug is reduced with the excretion of urine, leading to frequent administration and heavy local irritation symptoms. While nanomedicines can overcome all the above shortcomings and adhere to the surface of bladder tumors for a long time, and continuously and efficiently release drugs to bladder cancers. The rapid advances in targeted therapy have led to significant improvements in drug efficacy and precision of targeted drug delivery to eradicate tumor cells, with reduced side-effects. This review summarizes the different available nano-systems of targeted drug delivery to bladder cancer tissues. The challenges and prospects of targeted therapy for bladder cancer are additionally discussed.

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GSH-Responsive Nanoprodrug to Inhibit Glycolysis and Alleviate Immunosuppression for Cancer Therapy

Cited by 101 publications

References 41 publications

Mitochondrion-targeted supramolecular “nano-boat” simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy

Mitochondrion-targeted supramolecular “nano-boat” simultaneously inhibiting dual energy metabolism for tumor selective and synergistic chemo-radiotherapy

Nanomedicines Targeting Metabolism in the Tumor Microenvironment

Functional Nanomedicines for Targeted Therapy of Bladder Cancer

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