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Mechanistic Insights into Sphingomyelin Nanoemulsions as Drug Delivery Systems for Non-Small Cell Lung Cancer Therapy
Emma Ramos Docampo1,2,3,4, Jenifer García-Fernández1, Inés Mármol5
1Nano-Oncology and Translational Therapeutics Unit, Health Research Institute of Santiago de Compostela (IDIS), University Hospital of Santiago de Compostela (CHUS), SERGAS, 15706 Santiago de Compostela, Spain.
Abstract:
Sphingomyelin nanoemulsions (SNs) are promising drug delivery systems with potential for treating challenging tumors, including non-small cell lung cancer (NSCLC), which has a poor prognosis and a 5-year survival rate below 5%. Understanding the toxicity mechanisms and intracellular behavior of SNs is crucial for optimizing their therapeutic application. This study aims to investigate the interaction between SNs and A549 lung adenocarcinoma cells, focusing on their cytotoxic effects and mechanisms of cellular toxicity. SNs were synthesized and characterized for size, surface charge, and stability. A549 cells were treated with varying concentrations of SNs, and cellular uptake pathways were assessed using inhibitors of energy-dependent processes. Cytotoxicity was evaluated through an alamarBlue assay to determine the IC50 value after 24 h. Mechanisms of toxicity, including lysosomal and mitochondrial involvement, were examined using co-localization studies, mitochondrial membrane potential assays, and markers of apoptosis. SNs exhibited rapid cellular uptake via energy-dependent pathways. The IC50 concentration for A549 cells was 0.89 ± 0.15 mg/mL, suggesting favorable cytocompatibility compared to other nanocarriers. At IC50, SNs induced apoptosis characterized by lysosomal damage, mitochondrial membrane permeabilization, and the release of apoptotic factors. These effects disrupted autophagic flux and contributed to cell death, demonstrating potential for overcoming drug resistance. Resveratrol-loaded SNs showed enhanced cytotoxicity, supporting their application as targeted drug delivery vehicles. This study highlights the potential of SNs as efficient drug delivery systems for NSCLC therapy, offering insights into their cellular interactions and toxicity mechanisms. These findings pave the way for the rational design of SN-based therapeutic platforms for cancer and other mitochondria-related diseases.
Insights
Sphingomyelin nanoemulsions (SNs) effectively deliver drugs to lung cancer cells, inducing apoptosis via mitochondrial and lysosomal damage. These SNs show promise for targeted cancer therapy.
Area of Science:
- Nanomedicine
- Cancer Biology
- Cellular Toxicology
Background:
- Non-small cell lung cancer (NSCLC) has a poor prognosis, necessitating novel therapeutic strategies.
- Sphingomyelin nanoemulsions (SNs) are emerging as potential drug delivery systems for challenging tumors.
- Understanding SNs' cellular interactions and toxicity is key for optimizing cancer treatment.
Purpose of the Study:
- To investigate the interaction of SNs with A549 lung adenocarcinoma cells.
- To elucidate the cytotoxic effects and mechanisms of SNs in NSCLC cells.
- To assess SNs' potential as a drug delivery platform for NSCLC therapy.
Main Methods:
- SNs synthesized and characterized for physicochemical properties.
- A549 cells treated with SNs; cellular uptake pathways analyzed using energy-dependent process inhibitors.
- Cytotoxicity evaluated via alamarBlue assay (IC50 determination); apoptosis, lysosomal, and mitochondrial functions assessed.
Main Results:
- SNs demonstrated rapid, energy-dependent cellular uptake into A549 cells.
- The IC50 of SNs against A549 cells was 0.89 ± 0.15 mg/mL, indicating good cytocompatibility.
- SNs induced apoptosis through lysosomal damage, mitochondrial membrane permeabilization, and disrupted autophagic flux.
Conclusions:
- SNs exhibit favorable cytocompatibility and induce apoptosis in NSCLC cells via mitochondrial and lysosomal pathways.
- SNs disrupt autophagic flux, suggesting potential for overcoming drug resistance in NSCLC.
- SNs represent a promising platform for targeted drug delivery in NSCLC and other diseases involving mitochondrial dysfunction.
