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Mitochondria-Targeted Lipid Nanoparticles Loaded with Rotenone as a New Approach for the Treatment of Oncological
Leysan Vasileva1, Gulnara Gaynanova1, Darya Kuznetsova1
1Arbuzov Institute of Organic and Physical Chemistry, FRC Kazan Scientific Center, Russian Academy of Sciences, 8 Arbuzov Str., Kazan 420088, Russia.
Abstract:
This research is based on the concept that mitochondria are a promising target for anticancer therapy, including thatassociated with the use of oxidative phosphorylation blockers (mitochondrial poisons). Liposomes based on L-α-phosphatidylcholine (PC) and cholesterol (Chol) modified with cationic surfactants with triphenylphosphonium (TPPB-n, where n = 10, 12, 14, and 16) and imidazolium (IA-n(OH), where n = 10, 12, 14, and 16) head groups were obtained. The physicochemical characteristics of liposomes at different surfactant/lipid molar ratios were determined by dynamic/electrophoretic light scattering, transmission electron microscopy, and spectrophotometry. The hydrodynamic diameter of all the systems was within 120 nm with a polydispersity index of no more than 0.24 even after 2 months of storage. It was shown that cationization of liposomes leads to an increase in the internalization of nanocontainers in pancreatic carcinoma (PANC-1) and duodenal adenocarcinoma (HuTu 80) cells compared with unmodified liposomes. Also, using confocal microscopy, it was shown that liposomes modified with TPPB-14 and IA-14(OH) statistically better colocalize with the mitochondria of tumor cells compared with unmodified ones. At the next stage, the mitochondrial poison rotenone (ROT) was loaded into cationic liposomes. It was shown that the optimal loading concentration of ROT is 0.1 mg/mL. The Korsmeyer-Peppas and Higuchi kinetic models were used to describe the release mechanism of ROT from liposomes in vitro. A significant reduction in the IC50 value for the modified liposomes compared with free ROT was shown and, importantly, a higher degree of selectivity for the HuTu 80 cell line compared with the normal cells (SI value is 307 and 113 for PC/Chol/TPPB-14/ROT and PC/Chol/IA-14(OH)/ROT, respectively) occurred. It was shown that the treatment of HuTu 80 cells with ROT-loaded cationic liposomal formulations leads to a dose-dependent decrease in the mitochondrial membrane potential.
Insights
Cationic liposomes loaded with rotenone show enhanced cancer cell uptake and mitochondrial targeting. These novel drug delivery systems demonstrate improved selectivity and efficacy against tumor cells, offering a promising anticancer therapy.
Area of Science:
- Nanotechnology in Medicine
- Mitochondrial-Targeted Cancer Therapy
- Drug Delivery Systems
Background:
- Mitochondria are a key target for anticancer therapies, particularly using oxidative phosphorylation blockers.
- Liposomes are versatile nanocarriers for drug delivery, but enhancing their tumor cell interaction is crucial.
- Cationic modifications can improve liposome cellular uptake and organelle targeting.
Purpose of the Study:
- To develop and characterize cationic liposomes modified with triphenylphosphonium and imidazolium surfactants.
- To evaluate the enhanced internalization and mitochondrial colocalization of these liposomes in cancer cells.
- To assess the efficacy and selectivity of rotenone-loaded cationic liposomes as an anticancer strategy.
Main Methods:
- Synthesis and physicochemical characterization of liposomes using dynamic/electrophoretic light scattering, TEM, and spectrophotometry.
- Assessment of cellular internalization and mitochondrial colocalization via confocal microscopy in PANC-1 and HuTu 80 cells.
- In vitro drug release studies using Korsmeyer-Peppas and Higuchi models, and cytotoxicity assays (IC50) against cancer and normal cells.
Main Results:
- Cationized liposomes (≤120 nm, PDI ≤0.24) showed increased internalization in pancreatic and duodenal cancer cells.
- Liposomes modified with TPPB-14 and IA-14(OH) demonstrated superior colocalization with tumor cell mitochondria.
- Rotenone-loaded cationic liposomes exhibited reduced IC50 values and high selectivity (SI > 100) for HuTu 80 cells over normal cells.
Conclusions:
- Cationic liposomes effectively enhance the delivery of mitochondrial poisons to cancer cells.
- Modified liposomes show improved targeting to mitochondria and increased anticancer efficacy with greater selectivity.
- These findings support the potential of rotenone-loaded cationic liposomes for targeted cancer therapy.
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