Non-covalent AFP-complexes attract a great interest due to their targeting ability to selectively induce apoptosis in the tumor cells using AFP-receptor mediated mechanism of endocytosis. An anticancer “magic bullet” should have both efficacy and specificity parts. We have used an effective apoptosis inducer to trigger the apoptosis. Alpha-fetoprotein was used to deliver apoptosis inducers specifically to cancer cells. The drug delivery system based on native AFP, which as shown, can bring agent inside the tumor cell via receptor-mediated endocytosis.
We evaluated in vivo the efficacy and the pharmacokinetic of the new oral atractyloside porcine AFP complex - AIMPILA.
The efficacy was studied using oral daily doses 0,1–0,4 mg/kg for 5-10 days on s.c. human tumor xenografts featuring different expression of AR: SW620/AR+, HepG2/AR++ and T47D/AR+++. Also, we studied AMP’s efficacy using corresponding doses in rabbit (VX2, AR+) tumors in
acid resistant capsules & the murine(P388) tumor (oral or intravenius).
Biodistribution of radioactive iodine labeled Aimpila and AFP in the tumor, stomach and blood compared to normal mammary gland was studied using a direct radiometry within 24 h following oral drug administration. The radioactivity was measured using gamma counter.
We founded that AMP caused a significant tumor growth inhibition in vivo depending of AFP expression in the tumors studied: T47D (Тreated/Сontrol = 22%) > HepG2 (Т/С = 51%) > SW620 (T/C = 70%) (model criterion T/C should be lower than 42%). The effect of Aimpila for non-human tumor models didn’t match the criterion.
Studing the biodistribution and pharmacokinetiс the tumor accumulation showed peak time of llabeled Aimpila was 6 times longer than AFP (3 versus 0.5 hours). The maximum concentration of iodine labeled Aimpla in the tumor was accumulated faster than in the mammary gland of the Balb/c nude+ mice with a peak time of 3h for T47D versus 6 hors for the control mammary gland. Maximum tumor/blood ratio was at 1 h for Iodine labeled Aimpila versus 6 hours for iodine AFP (0.86 and 0.83, respectively). After 6 hours both showed similar level of accumulation and the elimination rate in the tumor. The retention period was longer for the tumor as well (MRT = 12.3 h vs 9.5 h). By 24 h time period the radioactivity amount Aimpila in the tumor was 5 times higher than in the mammary gland (ID/g = 0.87±0.08% versus ID/g = 0.18±0.09%, respectively with p = 0.002).
We can state thet high efficacy of low doses orally administrated AMP was achieved due to the AR targeting, receptor-mediated binding resulting in long retention of AMP in T47D. Oral administration of AMP showed intestinal absorption and sufficient bioavailability.
The OncoShuttle™ technology was developed by Constab Pharmaceutical Inc., Toronto. Fast-Diag uses the technology and trademark according local license.
- BINDING CHARACTERIZATION OF THE TARGETING DRUG AIMPILA TO AFP RECEPTORS IN HUMAN TUMOR XENOGRAFTS / Tcherkassova J., Tsurkan S., Smirnova G., Borisova J., Treshalina H., Moro R. // Tumor Biology. 2017. V. 39. № 10. P. 1-11.
- Biodistribution of Alpha-Fetoprotein-Containing Noncovalent Complex Aimpila with Antitumor Activity / E. Yu. Grigor’eva, E. M. Treshchalina, A. A. Lipengolts, A. V. Smirnova, G. B. Smirnova, Yu. A. Borisova, and M. S. Kalishyan // Bulletin of Experimental Biology and Medicine, Vol. 164, No. 2, December, 2017 ONCOLOGY
-New drug AIMPILA targeted to AFP receptor: Oral anticancer therapy and biodistribution in vivo./ Sergei Tsurkan, Janneta Tcherkassova, Vera Gorbunova, Helen Treshalina, Elena Yu. Grigorieva // J Clin Oncol 36, 2018 (suppl; abstr e24232)
- New non-covalent complex with atractyloside supported Oncoshuttle technology using AFP as carrier. Aimpila preclinical development results S. Tsurkan, J. Tcherkassova, H. Treshalina, E.Y. Grigor'eva, I. Treshchalin, E. Pereverzeva, European Cancer Organisation 30th EORTC-NCI-AACR SYMPOSIUM