Influence of tumour size on targeted alpha therapy with 213Bi-[DOTA,Tyr3]octreotate (DOTA-TATE) in a small cell lung carcinoma (SCLC) mouse model.

Aim: Due to the short path length of alpha particles; around 80 µm for 213Bi, the therapeutic effects of targeted alpha therapy may differ in tumors of different size. In this study we investigated the therapeutic efficacy of 213Bi-DOTA-TATE in mice bearing H69 tumors of 2 different sizes: 50mm3 (small) and 200mm3 (large). In additional animals we estimated the absorbed radiation dose of 213Bi-DOTA-TATE in different tissues using biodistribution studies, focusing on tumor and kidneys. Experimental design: Labeling of 213Bi-DOTA-TATE was performed with an 225Ac/213Bi generator (222MBq), the specific activity of 213Bi-DOTA-TATE was ~30MBq/nmol. Male 6-8 weeks old BALB/c (nu/nu) nude mice were subcutaneously injected in the flank with human H69 SCLC cells. Animals with small (n=10) or large tumors (n=7) were treated once a day with 213Bi-DOTA-TATE (2-4 MBq/0.3 nmol) and control animals with small (n=10) or large tumors (n=10) received DOTA-TATE (0.3 nmol), all animals were treated for three consecutive days. Tumor size was monitored for 90 days. The absorbed radiation dose in the tumor was estimated by biodistribution studies at 10, 30, 60 and 120 min post injection (n=7 per time point). Results: Tumor volume decreased in all mice after 213Bi-DOTA-TATE treatment, the group with large tumors reduced to a median size of 10% (range 2-38%). Re-growth of tumors was observed at 20  2 days after treatment in the large tumor group with a tumor doubling time comparable to the initial growth and that of the control group: 15  7 days. More than 50% inhibition of tumor size in the group with small tumors and 100% in the group with large tumors were found compared to the control groups. The absorbed radiation dose was 0.9-1.8 Gy in the tumor and 4-8 Gy in the kidney in animals per treatment cycle with 2-4 MBq 213Bi-DOTA-TATE. The kidney uptake at p.i. 10 min was 44±9% IA/g with a clearance half-life of 8 min. At p.i. 120 min still 25±3% IA/g remained in the kidney. Maximum tumor uptake is at p.i. 30 min: 10±2% IA/g with a clearance half-life of 2.32 hrs. Conclusion: Therapy efficacy was not significantly different in smaller or larger tumors, and finally re-growth of tumor was found in all 213Bi-DOTA-TATE-treated animals. The cumulative absorbed dose in the kidney was 4 times higher than that in the tumor. 213Bi-DOTA-TATE has proven to have significant therapeutic efficacy for large and small tumor in the H69 tumor-bearing mice model, however reduction of uptake in kidneys using positively charged amino acids will be essential to avoid renal toxicity. Microdosimetric models may provide insight on both the dose to the nephron and it constituents and the RBE-weighted dose to the tumor.

CHAN Ho-Sze;  KONIJNENBERG M.W.;  DE BLOIS Erik;  KOELEWIJN S.J.;  MORGENSTERN Alfred;  BRUCHERTSEIFER Frank;  BREEMAN Wouter;  DE JONG Marion; 

2014-12-12

SPRINGER

JRC90200

1619-7070,   

https://publications.jrc.ec.europa.eu/repository/handle/JRC90200,   

10.1007/s00259-014-2901-9,