Lu-177-doxycycline as potential radiopharmaceutical: electrochemical characterization, radiolabeling, and biodistribution in tumor-bearing mice

Purpose Recent studies with doxycycline as adjuvant therapy to conventional chemotherapy have shown promising results in cancer therapy. The current study aimed to examine the capability of Lu-177-labeled tetracycline ligand, doxycycline hyclate, to use as an anticancer agent. Materials and methods Doxycycline was radiolabeled with beta-emitting radioisotope Lu-177. Complex formation and its interaction with DNA were investigated electrochemically. Binding of Lu-177-doxycycline to CT 26 cell line was done. Biodistribution of Lu-177-doxycycline was examined in healthy Wistar rats and CT26 colon carcinoma tumor-bearing mice by i.v. and i.p. administration, respectively. Results Doxycycline hyclate was successfully radiolabeled with Lu-177 in high radiolabeling yield (>99%). The radiolabeled complex was stable in vitro in saline and human serum over 72 h. Non-radioactive Lu-doxycycline complex formation was demonstrated electrochemically as well. Intercalative interactions of the doxycycline and Lu-doxycycline with DNA were proved using simultaneously spectrophotometric and electrochemical methods. The binding of the radiolabeled complex with plasma proteins was 4.0 +/- 0.4%. The partition coefficient showed the lipophilic nature of the complex similar to the free ligand. The binding curve demonstrates binding from 0.1 nM concentrations of Lu-177-doxycycline, with half-binding estimated similar to 100 nM. Biodistribution studies of Lu-177-doxycycline in CT26 colon tumor-bearing mice showed a satisfactory accumulation rate in the tumor (2.88 +/- 0.85% ID/g) 3 h after intraperitoneal injection. Both the hepatobiliary system and the urinary system were prominent as excretory routes of the radiolabeled complex. Conclusion Considering obtained results, Lu-177-doxycycline complex, due to its excellent electrochemical and biological characteristics, with emphasis on the binding ability to DNA via intercalative interaction as well as significant accumulation in the tumor, is suitable for further in vivo studies to investigate its potential use in cancer treatment.

Automated summary

Recent studies have shown promising results in cancer therapy with doxycycline as adjuvant therapy to conventional chemotherapy. The Lu-177-labeled tetracycline ligand, doxycycline hyclate, demonstrated high radiolabeling yield and stability in vitro. Biodistribution studies in CT26 colon tumor-bearing mice showed satisfactory accumulation in the tumor, suggesting potential for further in vivo studies for cancer treatment.