Separation of nuclear isomers for cancer therapeutic radionuclides based on nuclear decay after-effects

177Lu has sprung as a promising radionuclide for targeted therapy. The low soft tissue penetration of its β− emission results in very efficient energy deposition in small-size tumours. Because of this, 177Lu is used in the treatment of neuroendocrine tumours and is also clinically approved for prostate cancer therapy. In this work, we report a separation method that achieves the challenging separation of the physically and chemically identical nuclear isomers, 177mLu and 177Lu. The separation method combines the nuclear after-effects of the nuclear decay, the use of a very stable chemical complex and a chromatographic separation. Based on this separation concept, a new type of radionuclide generator has been devised, in which the parent and the daughter radionuclides are the same elements. The 177mLu/177Lu radionuclide generator provides a new production route for the therapeutic radionuclide 177Lu and can bring significant growth in the research and development of 177Lu based pharmaceuticals.


S1: Efficiency of the 177m Lu/ 177 Lu generator
The efficiency of 177m Lu/ 177 Lu generator is defined as the ratio of the collected 177 Lu activity divided by the theoretically produced 177  where α is known as the internal conversion coefficient, and is defined as; . = /01 2 − 3 4 1 ℎ 2 34 6 24 2 4 /01 2 − 3 4 6 3 73003 23 0 44 Hence, we define the probability of the decay following the internal conversion path as, P.I.C = + ,-+ . The 116KeV transition involved in the decay of 177m Lu to 177 Lu has a theoretical internal conversion coefficient value, α th = 30.7 [2,3]. Thus the P.I.C value is calculated to be 96.8%.

S2: Efficiency plots, while having a continuous flow of mobile phase:
As mentioned before, for each flow rate and temperature six to ten measurements were done and their average along with the standard deviation are plotted in figure S2.1

S4: Optimisation of elution flux and elution times for accumulation experiments
To optimize the elution flow rate and elution times, we did different accumulations and then different flow rates are used to elute the accumulated activity. The results obtained are summarized below: Further, to minimize the volume of eluted activity and to keep the dilution of eluted activity as low as possible. We studied elution profile of Lu-177 after accumulation for an hour while taking the fractions every 5 mins. The result are shown in the plot Figure S4.2. As seen from the plot, a trailing behaviour in the elution of Lu-177 is observed. After elution for about 60 minutes, 60% of the accumulated activity could be removed. Therefore we decided to do the elution of accumulated activity at 0.1 mL/min for 60 minutes.

S5. Detailed results from accumulation experiments.
For accumulation experiments, we were mainly interested in knowing if the separation of the isomers is possible for different accumulation periods. As shown in the Figure 4 of main text, the activity ratios and efficiencies follow almost a constant behaviour, with no substantial change at a particular temp. There was no big deviation from separation, and even under no mobile phase flow for time period upto 5 days the system was capable to separate the two isomers.

S6. Summary of the continuous and accumualtion experiments;
For a better understanding of the data presented in Figure 3 and Figure 4, the results are summarized in table 2 and 3 below:

S7. Determination of void volume of the column and linear velocities
After filling the column with stationary phase, tC-18 silica, we determined the void volume of the column in order to have an idea about the linear velocities of the mobile phase through the column. The experiment set up involved for determining the void volume of the column is shown in Figure 3. A peek column with dimensions diameter 3 mm and length 47 mm is filled with tC-18 silica. The column is connected with an injector, UV cell and a fraction collector using tubings of known volume (a,b,c).  The observed void volume is about 50% of the column volume. Using 0.175 mL as the void volume the linear velocities through the column can be calculated as; For 0.1 mL/min -26 mm/min, for 0.05 mL/min -13.42 mm/min, for 0.012 mL/min -3.22 mm/min.