In Vitro Evaluation of No-Carrier-Added Radiolabeled Cisplatin ([^{189, 191}Pt]cisplatin) Emitting Auger Electrons

• Main Authors: Honoka Obata, Atsushi B. Tsuji, Hitomi Sudo, Aya Sugyo, Katsuyuki Minegishi, Kotaro Nagatsu, Mikako Ogawa, Ming-Rong Zhang
• Format: Article
• Language: English
• Published: MDPI AG 2021-04-01
• Series: International Journal of Molecular Sciences
• Subjects: Auger electron; cisplatin; ¹⁹¹Pt; ¹⁸⁹Pt; radio-drug; DNA double-strand break
• Online Access: https://www.mdpi.com/1422-0067/22/9/4622

Due to their short-range (2–500 nm), Auger electrons (Auger <i>e⁻</i>) have the potential to induce nano-scale physiochemical damage to biomolecules. Although DNA is the primary target of Auger <i>e</i>⁻, it remains challenging to maximize the interaction between Auger <i>e</i>⁻ and DNA. To assess the DNA-damaging effect of Auger <i>e</i>⁻ released as close as possible to DNA without chemical damage, we radio-synthesized no-carrier-added (n.c.a.) [^{189, 191}Pt]cisplatin and evaluated both its in vitro properties and DNA-damaging effect. Cellular uptake, intracellular distribution, and DNA binding were investigated, and DNA double-strand breaks (DSBs) were evaluated by immunofluorescence staining of γH2AX and gel electrophoresis of plasmid DNA. Approximately 20% of intracellular radio-Pt was in a nucleus, and about 2% of intra-nucleus radio-Pt bound to DNA, although uptake of n.c.a. radio-cisplatin was low (0.6% incubated dose after 25-h incubation), resulting in the frequency of cells with γH2AX foci was low (1%). Nevertheless, some cells treated with radio-cisplatin had γH2AX aggregates unlike non-radioactive cisplatin. These findings suggest n.c.a. radio-cisplatin binding to DNA causes severe DSBs by the release of Auger <i>e</i>⁻ very close to DNA without chemical damage by carriers. Efficient radio-drug delivery to DNA is necessary for successful clinical application of Auger <i>e</i>⁻.