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Published on: January 24, 2025
Aminoglucose-functionalized, redox-responsive polymer nanomicelles for overcoming chemoresistance in lung cancer
Yi Zhou1, Huaying Wen1, Liang Gu1
1Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, Guangdong, China.
Background:
Chemotherapeutic drugs used for cancer therapy frequently encounter multiple-drug resistance (MDR). Nanoscale carriers that can target tumors to accumulate and release drugs intracellularly have the greatest potential for overcoming MDR. Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells was exploited to assemble aminoglucose (AG)-conjugated, redox-responsive nanomicelles from a single disulfide bond-bridged block polymer of polyethylene glycol and polylactic acid (AG-PEG-SS-PLA). However, whether this dual functional vector can overcome MDR in lung cancer is unknown.
Results:
In this experiment, AG-PEG-SS-PLA was synthetized successfully, and paclitaxel (PTX)-loaded AG-PEG-SS-PLA (AG-PEG-SS-PLA/PTX) nanomicelles exhibited excellent physical properties. These nanomicelles show enhanced tumor targeting as well as drug accumulation and retention in MDR cancer cells. Caveolin-dependent endocytosis is mainly responsible for nanomicelle internalization. After internalization, the disulfide bond of AG-PEG-SS-PLA is cleaved in the presence of high intracellular glutathione levels, causing the hydrophobic core to become a polar aqueous solution, which subsequently results in nanomicelle disassembly and the rapid release of encapsulated PTX. Reduced drug resistance was observed in cancer cells in vitro. The caspase-9 and caspase-3 cascade was activated by the AG-PEG-SS-PLA/PTX nanomicelles through upregulation of the pro-apoptotic proteins Bax and Bid and suppression of the anti-apoptotic protein Bcl-2, thereby increasing apoptosis. Furthermore, significantly enhanced tumor growth inhibition was observed in nude mice bearing A549/ADR xenograft tumors after the administration of AG-PEG-SS-PLA/PTX nanomicelles via tail injection.
Conclusions:
These promising results indicate that AG-PEG-SS-PLA/PTX nanomicelles could provide the foundation for a paradigm shift in MDR cancer therapy.
Insights
This study developed novel dual-functional nanomicelles (AG-PEG-SS-PLA/PTX) to overcome multidrug resistance (MDR) in lung cancer. The nanomicelles effectively target tumors, release drugs intracellularly, and inhibit cancer growth, offering a new therapeutic strategy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Multidrug resistance (MDR) is a major challenge in cancer chemotherapy.
- Nanoscale drug delivery systems offer potential for overcoming MDR by targeting tumors and enabling intracellular drug release.
- Glucose transporter-1 (GLUT-1) and glutathione (GSH) overexpression in cancer cells presents a therapeutic target.
Purpose of the Study:
- To investigate the efficacy of aminoglucose (AG)-conjugated, redox-responsive nanomicelles (AG-PEG-SS-PLA) loaded with paclitaxel (PTX) in overcoming MDR in lung cancer.
- To evaluate the tumor targeting, intracellular drug release, and anti-cancer effects of these novel nanomicelles.
Main Methods:
- Synthesis of AG-PEG-SS-PLA block polymer and formation of PTX-loaded nanomicelles (AG-PEG-SS-PLA/PTX).
- Evaluation of nanomicelle physical properties, tumor targeting, cellular uptake (caveolin-dependent endocytosis), and intracellular drug release triggered by glutathione (GSH).
- Assessment of in vitro drug resistance reduction, apoptosis induction (caspase-9, caspase-3, Bax, Bid, Bcl-2), and in vivo tumor growth inhibition in A549/ADR xenograft models.
Main Results:
- Successfully synthesized AG-PEG-SS-PLA/PTX nanomicelles with excellent physical properties.
- Demonstrated enhanced tumor targeting, accumulation, and retention in MDR cancer cells.
- Observed intracellular PTX release via disulfide bond cleavage in response to high GSH levels, leading to reduced drug resistance and apoptosis induction.
- Showed significantly enhanced tumor growth inhibition in vivo.
Conclusions:
- AG-PEG-SS-PLA/PTX nanomicelles show significant promise for overcoming MDR in lung cancer.
- This dual-functional nanocarrier system represents a potential paradigm shift in MDR cancer therapy.
