Developing radio-assisted chemotherapy

Objectives: Cisplatin is one of the most potent chemotherapeutics used in the treatment of solid tumors. However, patients treated with cisplatin suffer from severe side effects, and run the risk of developing therapy-resistant tumors. Preliminary studies [1-3] have indicated that incorporation of radioactive platinum isotopes in the cisplatin compound has the potential for synergistic effects that may overcome these issues. Several radioactive platinum isotopes are known to have a high multiplicity of Auger electrons per decay, as well as, gamma emissions useful for diagnostic SPECT imaging of the cisplatin distribution. Since DNA is the primary target of cisplatin, the Auger-emitting radio-platinum will also be positioned ideally to cause DNA double-strand breaks resulting in cell death. However, the small-scale initial studies used activation methods that were not viable for eventual translation to yields suitable for clinical application. Our goal is to develop improved production pathways to enable large-scale, cost-effective radio-assisted chemotherapy and to test the material in-vitro and in-vivo to quantify the synergistic effects.

Methods: We are pursuing two alternate methods for the large-scale production of activated cisplatin, photonuclear production via (y,n) reactions on the stable isotopes of platinum and transfer reactions initiated by beams such as alpha or lithium ions on targets of osmium or rhenium isotopes. The former is possible at the Argonne 20-kW electron linac (LEAF) and the later would be possible with an upgraded version of the Argonne superconducting ion linac (ATLAS). Proof-of-principle measurements to demonstrate the yields and specific activities possible using these two methods are in progress. The ion-induced reactions at ATLAS can be used to make no-carrier-added ¹⁹¹Pt (t_1/2 = 2.8 d) and ^193mPt (t_1/2 = 4.3d) Auger-electron emitters in quantities sufficient for DNA double-strand break quantification and in-vitro and in-vivo evaluation studies, as well as for eventual therapy [1,4].

Results: Cross sections of the (y,n) reactions on the stable isotopes of Pt have been measured using quasi-monochromatic gamma-ray beams at the TUNL HIγS facility and measurements of yields of light ion transfer reactions are in progress at ATLAS. The cross section measured at HIγS for ¹⁹¹Pt indicates that integral yields of this theranostic isotope at the Argonne electron linac will be large enough to enable clinical application of radio-assisted chemotherapy. Furthermore, the yields of both carrier-free ¹⁹¹Pt and ^193mPt, produced using the light ion transfer reactions ¹⁹⁰Os(⁴He,3n)¹⁹¹Pt and ¹⁹²Os(⁴He,3n)^193mPt reactions with > 1 barn cross sections [4], are high enough to support R&D and pre-clinical trials with existing alpha beam intensities, and there is a path to higher yields for cost-effective implementation of this technique with an upgraded ion linac.

Conclusions: Both the existing electron linac and an upgraded version of the superconducting ion linac at Argonne can produce clinically relevant activities of radio-platinum isotopes. Using these new activation pathways, radio-assisted chemotherapy using theranostic isotopes can be realized on a clinical scale, enabling enhanced cisplatin diagnostics and therapeutic efficacy. [asterisk]Funded by the U.S. D.O.E. and the Office of Nuclear Physics under Contract and Grant Nos. DE-AC02-06CH11357 & ST5001030 (ANL), DE-FG02-97ER41033 & DE-SC0018112 (Duke), DE-FG02-97ER41041 (UNC), and DE-SC0018325 (NCCU). References 1. Areberg, J., Studies of radioactive cisplatin (¹⁹¹Pt), Ph.D. Dissertation, Lund University, Malmö, Sweden, 2000. 2. Azure, M. T.; Sastry, K. S. R.; Archer, R. D.; Howell, R. W.; Rao, D. V., Biophys. Asp. Auger Process. 1992, 8 336-351. 3. Howell, R. W.; Kassis, A. I.; Adelstein, S. J.; Rao, D. V.; Wright, H. A.; Hamm, R. N.; Turner, J. E.; Sastry, K. S. R., Radiat. Res. 1994, 140, 55-62. 4. Uddin, M.S.; Scholten, B.; Hermanne, A.; Suda, S.; Coenen, H.H.; Qaim, S.M., Appl. Radiation and Isotopes 68 (2010) 2001-2006.