Targeted tumor therapy with radiolabeled DNA intercalator: an attempt to prepare and evaluate the potential of ¹⁷⁷Lu-acridine

Acridine is a well-known DNA intercalator and thereby gets easily incorporated into DNA. Uncontrolled and rapid cell division being one of the primary characteristics of the tumor cells, it is expected that acridine or its suitable derivatives will have preferential accumulation in the tumorous lesions. Therefore, acridine derivatives labeled with suitable therapeutic radionuclide may have potential as agents for targeted tumor therapy. Working in this direction, an attempt was made to radiolabel 9-aminoacridine with ¹⁷⁷Lu and study the potential of ¹⁷⁷Lu-acridine complex as an agent for targeted tumor therapy. 9-aminoacridine was coupled with p-NCS-benzyl-DOTA in aqueous alkaline medium at room temperature and the conjugate was purified by repeated solvent extraction using chloroform and water. The acridine-DOTA conjugate was characterized by standard spectroscopic techniques, such as, FT-IR, 1H-NMR and mass spectrometry. Radiolabeling of the conjugate was carried out by incubating the conjugate (10 mg, 13.40 µM) with ¹⁷⁷Lu (1 mCi, 37 MBq) in ammonium acetate buffer (pH 5, 1 M) at 100 °C for a period of 45 min. The radiolabeled conjugate was characterized by HPLC using water and acetonitrile mixed with 0.1% trifluoro acetic acid as the mobile phase employing gradient elution technique. Various radiolabeling parameters were optimized to maximize the radiolabeling yield of ¹⁷⁷Lu-acridine complex. The stability of the radiolabeled preparation was studied by incubating the preparation in normal saline as well as in human blood serum. Biological behavior of the ¹⁷⁷Lu-acridine complex was studied both in-vitro and in-vivo using Raji cell line and fibrosarcoma tumor bearing Swiss mice, respectively. ¹⁷⁷Lu-acridine complex was obtained with ~100% radiochemical purity under the optimized reaction conditions involving incubation of 1.5 mg/mL of the conjugate with ¹⁷⁷Lu at 100 °C for 45 minutes. The complex maintained a radiochemical purity of >85% in normal saline till 6 d post-preparation and >70% in human blood serum till 2 d after preparation. In-vitro cellular study showed appreciable uptake of the radiotracer in the Raji cells. Biodistribution study revealed significant tumor accumulation ( (9.98±0.13)% IA in per gram of tumor) of the radiotracer within 1 h post-administration along with distribution of the activity in other non-target organs such as, blood, liver, GIT, kidneys etc. The non-accumulated activity showed gradual clearance through renal route. The present study indicates the potential of ¹⁷⁷Lu-acridine as an agent for targeted tumor therapy. However, further detailed evaluation of the agent is warranted to explore its actual potential. (author)