Sequence-specific DNA strand cleavage by 111In-labeled peptide nucleic acids

Area of Science:

• Biochemistry
• Molecular Biology
• Radiochemistry

Background:

• Peptide nucleic acids (PNAs) exhibit high affinity and sequence specificity for nucleic acids.
• PNAs are being explored for gene-targeted radiotherapeutics to deliver localized radiodamage.
• Developing methods to incorporate radionuclides into PNAs is crucial for their therapeutic potential.

Purpose of the Study:

• To develop a method for incorporating the Auger electron-emitting radionuclide indium-111 into PNA oligomers.
• To evaluate the efficiency of PNA-directed cleavage of single-stranded DNA targets.
• To compare the DNA damaging efficacy of (111)In-labeled PNAs with (111)In-labeled DNA oligomers.

Main Methods:

• Conjugation of diethylene triamine penta-acetic acid (DTPA) to PNA and DNA oligomers.
• Chelation of DTPA-conjugated PNA and DNA with (111)In(3+) to create radiolabeled probes.
• In vitro assessment of PNA-directed DNA strand cleavage by (111)In decay.

Main Results:

• (111)In-labeled PNA-DTPA conjugates induced highly localized DNA strand cleavage in single-stranded DNA targets.
• The yield of DNA strand breaks generated by (111)In decay was 5-7% for PNA-DTPA compared to ≤2% for DNA-DTPA.
• The yield of DNA strand breaks per nuclear decay was approximately 0.1 for PNA-directed delivery, three times higher than for DNA-directed delivery.

Conclusions:

• (111)In-labeled PNAs are significantly more effective than radiolabeled DNA oligonucleotides for site-specific DNA damage.
• PNA oligomers demonstrate potential as efficient radionuclide delivery vehicles for antisense/antigene radiotherapy.
• This study supports the advancement of PNA-based radiotherapeutics for clinical trials.