Abstract
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 177Lu, one of the most useful therapeutic radionuclides, and study the potential of 177Lu-acridine in targeted tumor therapy. Experiments. 9-Aminoacridine was coupled with p-NCS-benzyl-DOTA to facilitate radiolabeling, and the conjugate was radiolabeled with 177Lu. Different reaction parameters were optimized in order to obtain 177Lu-acridine complex with maximum radiochemical purity. In vitro stability of the radiolabeled complex was studied in normal saline and human blood serum. Biological behavior of the radiolabeled agent was studied both in vitro and in vivo using the Raji cell line and fibrosarcoma tumor-bearing Swiss mice, respectively. Results 177Lu-acridine complex was obtained with ~100% radiochemical purity under the optimized reaction conditions involving incubation of 1.5 mg/mL of ligand with 177Lu (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. In vitro 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 177Lu-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.
Highlights
Cancer is a generic term for a large group of diseases which is characterized by the rapid and abnormal growth of cells beyond their usual boundaries and can subsequently invade the adjoining parts of the body thereby spreading to other organs/tissues [1]
We report the synthesis of acridine-bifunctional chelating agent (BFCA) conjugate, its radiolabeling with 177Lu and preliminary in vitro and in vivo biological evaluation of 177Lu-acridine complex in order to comprehend the possibility of using radiolabeled DNA intercalators for targeted tumor therapy
1 h 1 d 6 d possibly be circumvented if the DNA intercalators are coupled with suitable therapeutic radionuclides, where the DNA intercalators play the role of targeting vector and therapeutic efficacy is imparted by the suitable particulates/radiations emanating from the attached radionuclide
Summary
Cancer is a generic term for a large group of diseases which is characterized by the rapid and abnormal growth of cells beyond their usual boundaries and can subsequently invade the adjoining parts of the body thereby spreading to other organs/tissues [1]. In the recent time, cancer has emerged as the second leading cause of death and accounts almost 1 in 6 deaths worldwide [3]. Early diagnosis and subsequent therapeutic intervention are essential in order to fight against cancer. Radiopharmaceuticals play an important role in combating various types of cancers, in the advanced stage of the disease, when the role of more conventional surgery and chemotherapy becomes limited. Developing newer molecular vectors and radiolabeled agents with improved characteristics is important to more effectively combat this disease
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