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Enhanced Subcellular Trafficking of Resveratrol Using Mitochondriotropic Liposomes in Cancer Cells
1College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University, Incheon 21936, Korea.
Abstract:
Mitochondria are membrane-enclosed organelles present in most eukaryotic cells, described as "power houses of the cell". The mitochondria can be a target for inducing cancer cell death and for developing strategies to bypass multi drug resistance (MDR) mechanisms. 4-Carboxybutyl triphenylphosphonium bromide-polyethylene glycol-distearoylphosphatidylethanolamine (TPP-DSPE-PEG) and dequalinium-polyethylene glycol-distearoylphosphatidylethanolamine (DQA-DSPE-PEG) were synthesized as mitochondriotropic molecules. Mitochondria-targeting liposomes carrying resveratrol were constructed by modifying the liposome's surface with TPP-PEG or DQA-PEG, resulting in TLS (Res) and DLS (Res), respectively, with the aim to obtain longer blood circulation and enhanced permeability and retention (EPR). Both TLS (Res) and DLS (Res) showed dimensions of approximately 120 nm and a slightly positive zeta potential. The enhanced cellular uptake and selective accumulation of TLS (Res) and DLS (Res) into the mitochondria were demonstrated by behavioral observation of rhodamine-labeled TLS or DLS, using confocal microscopy, and by resveratrol quantification in the intracellular organelle, using LC-MS/MS. Furthermore, TLS (Res) and DLS (Res) induced cytotoxicity of cancer cells by generating reactive oxygen species (ROS) and by dissipating the mitochondrial membrane potential. Our results demonstrated that TLS (Res) and DLS (Res) could provide a potential strategy to treat cancers by mitochondrial targeting delivery of therapeutics and stimulation of the mitochondrial signaling pathway.
Insights
Novel mitochondria-targeting liposomes loaded with resveratrol demonstrate enhanced cancer cell death. These liposomes, TLS (Res) and DLS (Res), selectively accumulate in mitochondria, generating reactive oxygen species and disrupting membrane potential for effective cancer therapy.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Biology
Background:
- Mitochondria are crucial organelles and a key target for cancer therapy.
- Mitochondria-targeting strategies can overcome multi-drug resistance (MDR) in cancer cells.
- Resveratrol exhibits anti-cancer properties but requires effective delivery.
Purpose of the Study:
- To synthesize mitochondriotropic liposomes for targeted delivery of resveratrol.
- To evaluate the efficacy of these liposomes in inducing cancer cell death via mitochondrial pathways.
- To assess the potential of these liposomes in overcoming MDR mechanisms.
Main Methods:
- Synthesis of TPP-DSPE-PEG and DQA-DSPE-PEG for mitochondriotropic liposomes.
- Construction of resveratrol-loaded liposomes (TLS (Res) and DLS (Res)) with enhanced permeability and retention (EPR).
- Confocal microscopy and LC-MS/MS to confirm cellular uptake and mitochondrial accumulation.
Main Results:
- TLS (Res) and DLS (Res) liposomes exhibited ~120 nm size and positive zeta potential.
- Demonstrated enhanced cellular uptake and selective mitochondrial accumulation of resveratrol.
- Induced cancer cell cytotoxicity by generating reactive oxygen species (ROS) and dissipating mitochondrial membrane potential.
Conclusions:
- Mitochondria-targeting liposomes (TLS (Res) and DLS (Res)) are effective for delivering resveratrol.
- These liposomes offer a promising strategy for cancer treatment through mitochondrial targeting.
- The approach stimulates mitochondrial signaling pathways for therapeutic benefit.
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