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Mitochondria-Targeted Lipid Nanoparticles Loaded with Rotenone as a New Approach for the Treatment of Oncological Diseases

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.

 

Comments:

This research is fascinating! It delves into modifying liposomes to target mitochondria for anticancer therapy. Let's break down some key points:

1. **Liposome Modification**: The study modified liposomes using cationic surfactants with specific head groups (TPPB-n and IA-n(OH)) in combination with L-α-phosphatidylcholine (PC) and cholesterol (Chol).

2. **Characteristics of Modified Liposomes**: Physicochemical characteristics like size, polydispersity, and stability were analyzed. The liposomes maintained a small size (around 120 nm) with low polydispersity even after extended storage.

3. **Cellular Uptake**: The modified liposomes showed enhanced internalization into pancreatic carcinoma (PANC-1) and duodenal adenocarcinoma (HuTu 80) cells compared to unmodified ones.

4. **Mitochondrial Targeting**: Confocal microscopy revealed that specific modified liposomes better colocalized with the mitochondria of tumor cells compared to unmodified ones, specifically TPPB-14 and IA-14(OH).

5. **Loading with Mitochondrial Poison**: Rotenone (ROT), a mitochondrial poison, was effectively loaded into these modified liposomes at an optimal concentration of 0.1 mg/mL.

6. **Release Kinetics**: The release mechanism of ROT from these liposomes was studied using Korsmeyer-Peppas and Higuchi kinetic models.

7. **Anticancer Efficacy**: The modified liposomes loaded with ROT exhibited a significant reduction in IC50 values compared to free ROT. Additionally, they demonstrated higher selectivity for the HuTu 80 cell line over normal cells (as indicated by the selectivity index, SI).

8. **Impact on Mitochondrial Function**: Treatment with ROT-loaded cationic liposomes led to a dose-dependent decrease in the mitochondrial membrane potential of HuTu 80 cells.

This research holds promise for targeted anticancer therapy by effectively delivering a mitochondrial poison to specific cancer cells, potentially enhancing therapeutic outcomes while minimizing adverse effects on normal cells. The selectivity and efficacy demonstrated in this study are particularly encouraging.