Targeted Tumor Therapy with Radiolabeled DNA Intercalator: A Possibility? Preclinical Investigations with Lu-Acridine.

Objective: A DNA intercalating agent reversibly stacks between the adjacent base pairs of DNA and thus is expected to exhibit preferential localization in the tumorous lesions as tumors are associated with enhanced DNA replication. Therefore, radiolabeled DNA intercalators are supposed to have potential to be used in targeted tumor therapy. Working in this direction, an attempt was made to radiolabel 9-aminoacridine, a DNA intercalator, with Lu, one of the most useful therapeutic radionuclides, and study the potential of Lu-acridine in targeted tumor therapy. . 9-Aminoacridine was coupled with -NCS-benzyl-DOTA to facilitate radiolabeling, and the conjugate was radiolabeled with Lu. Different reaction parameters were optimized in order to obtain Lu-acridine complex with maximum radiochemical purity. stability of the radiolabeled complex was studied in normal saline and human blood serum. Biological behavior of the radiolabeled agent was studied both and using the Raji cell line and fibrosarcoma tumor-bearing Swiss mice, respectively.

Results: Lu-acridine complex was obtained with ~100% radiochemical purity under the optimized reaction conditions involving incubation of 1.5 mg/mL of ligand with Lu (1 mCi, 37 MBq) at 100°C at pH ~5 for 45 minutes. The complex maintained a radiochemical purity of >85% in saline at 6 d and >70% in human serum at 2 d postpreparation. cellular study showed uptake of the radiotracer (5.3 ± 0.13%) in the Raji cells along with significant cytotoxicity (78.06 ± 2.31% after 6 d). Biodistribution study revealed considerable accumulation of the radiotracer in tumor 9.98 ± 0.13 %ID/g within 1 h postadministration and retention therein till 6 d postadministration 4.00 ± 0.16 %ID/g with encouraging tumor to nontarget organ uptake ratios.

Conclusions: The present study, although preliminary, indicates the potential of Lu-acridine and thus radiolabeled DNA intercalators in targeted tumor therapy. However, further detailed evaluation is required to explore the actual potential of such agents in targeted tumor therapy.