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Novel Efficient Cell-Penetrating, Peptide-Mediated Strategy for Enhancing Telomerase Inhibitor Oligonucleotides
Andrés Muñoz-Alarcón1, Jonas Eriksson1, Ülo Langel1,2
11 Department of Neurochemistry, Stockholm University , Stockholm, Sweden .
Abstract:
At present, there are several therapeutic approaches for targeting telomerase in tumors. One in particular, currently undergoing clinical trials, is based on synthetic lipid-modified oligonucleotide antagonists aimed at inhibiting the ribonucleoprotein subunit of human telomerase. However, while enabling efficient uptake, the lipid modifications reduce the potency of the therapeutic oligonucleotides compared to nonmodified oligonucleotides. Moreover, lipid modification may increase oligonucleotide accumulation in the liver causing undesirable hepatotoxicity. Noncovalent complexation strategies for cell-penetrating peptide (CPP)-mediated delivery present an option to circumvent the need for potency-reducing modifications, while allowing for a highly efficient uptake, and could significantly improve the efficiency of telomerase-targeting cancer therapeutics. Delivery of a nonlipidated locked nucleic acid/2'-O-methyl mixmer significantly inhibits the telomerase activity in treated HeLa cells. The inhibitory effect was further improved through addition of a CPP. Furthermore, calculated IC50-values for the oligonucleotide delivered by CPPs into HeLa cells are more than 20 times lower than telomerase inhibitor Imetelstat, currently undergoing clinical trials. These results emphasize the potential of CPP-mediated delivery of future pharmaceuticals and provide means by which to enhance an already promising therapeutic strategy for cancer treatment.
Insights
Cell-penetrating peptides (CPPs) enhance cancer drug delivery by improving uptake and potency of telomerase inhibitors. This strategy offers a promising alternative to lipid modifications, reducing potential toxicity and improving therapeutic efficiency.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Telomerase is a key target for cancer therapeutics.
- Current lipid-modified oligonucleotide antagonists face challenges with reduced potency and potential hepatotoxicity.
- Cell-penetrating peptide (CPP)-mediated delivery offers a noncovalent complexation strategy to improve oligonucleotide delivery.
Purpose of the Study:
- To evaluate the efficacy of CPP-mediated delivery of nonlipidated oligonucleotides as a cancer therapeutic strategy.
- To compare the potency of CPP-delivered oligonucleotides with existing telomerase inhibitors.
Main Methods:
- Delivery of nonlipidated locked nucleic acid/2'-O-methyl mixmer oligonucleotides into HeLa cells.
- Complexation of oligonucleotides with cell-penetrating peptides (CPPs) for enhanced delivery.
- Assessment of telomerase inhibition and calculation of IC50 values.
Main Results:
- Nonlipidated oligonucleotides significantly inhibited telomerase activity in HeLa cells.
- CPP-mediated delivery further enhanced the inhibitory effect.
- Oligonucleotides delivered by CPPs demonstrated over 20-fold lower IC50 values compared to the clinical-stage drug Imetelstat.
Conclusions:
- CPP-mediated delivery is a viable strategy to enhance the efficiency and reduce the toxicity of oligonucleotide-based cancer therapeutics.
- This approach significantly improves upon existing telomerase-targeting strategies, offering a more potent and potentially safer therapeutic option.
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