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Nanomicelles for GLUT1-targeting hepatocellular carcinoma therapy based on NADPH depletion
Congyi Zhang1, Zehui Liu2, Feng Wang2
1Department of Hepatic Surgery, Second Affiliated Hospital of Harbin Medical University, Harbin, China.
Abstract:
Hepatocellular carcinoma (HCC) is a malignant tumor leading cancer-associated high mortality worldwide. Unfortunately, the most commonly used drug therapeutics not only lack of target ability and efficiency, but also exhibit severe systemic toxicity to normal tissues. Thus, effective and targeted nanodrug of HCC therapy is emerging as a more important issue. Here, we design and develop the novel nanomicelles, namely Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT). This micelle compound with high purity comprise two parts, which can self-assemble into nanoscale micelle. The outer shell is selected mannose as hydrophilic moiety, while the inner core is nitroimidazole as hydrophobic moiety. In the cell experiment, Man-NIT was more cellular uptake by HCCLM3 cells due to the mannose modification. Mannose as a kind of glucose transporter 1 (GLUT1) substrate, can specifically recognize and bind to over-expressed GLUT1 on carcinoma cytomembrane. The nitroimidazole moiety of Man-NIT was reduced by the over-expressed nitroreductase with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as the cofactor, resulting in transient deletion of NADPH and glutathione (GSH). The increase of reactive oxygen species (ROS) in HCCLM3 cells disturbed the balance of redox, and finally caused the death of tumor cells. Additional in vivo experiment was conducted using twenty-four male BALB/c nude mice to build the tumor model. The results showed that nanomicelles were accumulated in the liver of mice. The tumor size and pathological features were obviously improved after nanomicelles treatment. It indicates that namomicelles have a tumor inhibition effect, especially Man-NIT, which may be a potential nanodrug of chemotherapeutics for HCC therapy.
Insights
Novel nanomicelles, Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT), show promise for hepatocellular carcinoma (HCC) therapy by targeting cancer cells and reducing tumor growth. This targeted approach offers a potential alternative to conventional treatments.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Hepatocellular carcinoma (HCC) presents a significant global health challenge with high mortality rates.
- Current HCC treatments often lack specificity and cause severe systemic toxicity.
- Developing targeted nanodrugs is crucial for effective HCC therapy.
Purpose of the Study:
- To design and develop novel nanomicelles, Mannose-polyethylene glycol 600-Nitroimidazole (Man-NIT), for targeted HCC therapy.
- To investigate the cellular uptake, mechanism of action, and in vivo efficacy of Man-NIT in HCC models.
Main Methods:
- Self-assembly of Man-NIT nanomicelles with mannose (hydrophilic) and nitroimidazole (hydrophobic) components.
- In vitro studies using HCCLM3 cells to assess cellular uptake via glucose transporter 1 (GLUT1) and the mechanism of action involving nitroreductase, NADPH, GSH, and ROS.
- In vivo studies using a HCC tumor model in BALB/c nude mice to evaluate nanomicelle accumulation, tumor inhibition, and pathological improvements.
Main Results:
- Man-NIT demonstrated enhanced cellular uptake in HCCLM3 cells due to mannose binding to over-expressed GLUT1.
- The nitroimidazole core was reduced by nitroreductase, leading to NADPH and GSH depletion, increased reactive oxygen species (ROS), and subsequent tumor cell death.
- In vivo studies showed nanomicelle accumulation in the liver, significant tumor size reduction, and improved pathological features in treated mice.
Conclusions:
- Man-NIT nanomicelles exhibit targeted delivery and potent therapeutic effects against HCC.
- The mechanism involves specific cellular uptake and intracellular redox imbalance, leading to tumor cell death.
- Man-NIT represents a promising nanodrug candidate for effective and targeted hepatocellular carcinoma chemotherapy.
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