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Published on: November 18, 2019
ROS-Responsive N-Alkylaminoferrocenes for Cancer-Cell-Specific Targeting of Mitochondria
Viktor Reshetnikov1, Steffen Daum1, Christina Janko2
1Friedrich-Alexander-University of Erlangen-Nürnberg, Department of Chemistry and Pharmacy, Organic Chemistry Chair II, Nikolaus-Fiebiger-Str. 10, 91058, Erlangen, Germany.
Abstract:
Mitochondrial membrane potential is more negative in cancer cells than in normal cells, allowing cancer targeting by delocalized lipophilic cations (DLCs). However, as the difference is rather small, these drugs affect also normal cells. Now a concept of pro-DLCs is proposed based on an N-alkylaminoferrocene structure. These prodrugs are activated by the reaction with reactive oxygen species (ROS) forming ferrocenium-based DLCs. Since ROS are overproduced in cancer, the high-efficiency cancer-cell-specific targeting of mitochondria could be achieved as demonstrated by fluorescence microscopy in combination with two fluorogenic pro-DLCs in vitro and in vivo. We prepared a conjugate of another pro-DLC with a clinically approved drug carboplatin and confirmed that its accumulation in mitochondria was higher than that of the free drug. This was reflected in the substantially higher anticancer effect of the conjugate.
Insights
New pro-drug strategies enhance cancer cell targeting. These novel compounds, activated by reactive oxygen species (ROS), specifically accumulate in cancer cell mitochondria, improving drug efficacy and reducing side effects.
Area of Science:
- Biochemistry
- Pharmacology
- Oncology
Background:
- Mitochondrial membrane potential differs between cancer and normal cells, enabling targeting by delocalized lipophilic cations (DLCs).
- Current DLCs exhibit limited cancer specificity due to small potential differences, affecting normal cells.
- Reactive oxygen species (ROS) are overproduced in cancer cells.
Purpose of the Study:
- To introduce a novel concept of pro-drugs (pro-DLCs) for enhanced cancer-specific mitochondrial targeting.
- To investigate the activation mechanism of pro-DLCs by ROS.
- To evaluate the anticancer efficacy of pro-DLCs and their conjugates.
Main Methods:
- Synthesis of N-alkylaminoferrocene-based pro-DLCs.
- In vitro and in vivo studies using fluorogenic pro-DLCs and fluorescence microscopy.
- Preparation and evaluation of a pro-DLC-carboplatin conjugate.
Main Results:
- Pro-DLCs are activated by ROS to form ferrocenium-based DLCs.
- Demonstrated high-efficiency, cancer-cell-specific mitochondrial targeting in vitro and in vivo.
- The pro-DLC-carboplatin conjugate showed enhanced mitochondrial accumulation and superior anticancer effect compared to free carboplatin.
Conclusions:
- Pro-DLCs offer a promising strategy for ROS-activated, cancer-specific mitochondrial targeting.
- This approach enhances drug accumulation in cancer mitochondria, leading to improved therapeutic outcomes.
- Pro-DLC conjugates represent a potential advancement in cancer therapy.
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