Preclinical Investigation of ²¹²Pb-DOTAMTATE for Peptide Receptor Radionuclide Therapy in a Neuroendocrine Tumor...

Somatostatin analogues have been examined as a treatment for somatostatin receptor overexpressing tumors for years; specifically, octreotate (TATE) and octreotide (TOC). Several versions of these analogues coupled to beta or gamma nuclides are currently used as imaging agents, as treatments with peptide receptor radionuclide therapy (PRRT) for patients with neuroendocrine tumors or are being explored in preclinical and clinical settings. Our study describes the use of ²¹²Pb-DOTAMTATE, the octreotate analogue, in combination with ²¹²Pb, the parent of an alpha emitter. Preclinical studies demonstrated tumor targeting of ²¹²Pb-DOTAMTATE of >20% ID/g up to 24 hours post drug injection. The addition of kidney protection agents, including l-lysine and l-arginine decreases drug accumulation in the kidneys and the addition of ascorbic acid to the chelation mixture reduces oxidation of the drug product. ²¹²Pb-DOTAMTATE displays a favorable toxicity profile with single-dose injections of 20 microCi showing 100% survival and with nontoxic cumulative doses up to 45 microCi, when fractionated into three smaller doses of 15 microCi. In an initial efficacy study, a single 10 microCi injection of ²¹²Pb-DOTAMTATE extended the mean survival 2.4-fold. Efficacy was enhanced by giving three treatment cycles of ²¹²Pb-DOTAMTATE and reducing the time between injections to two weeks. Efficacy was optimized further by the addition of a chemo-sensitizing agent, 5-fluorouracil, given in combination with three cycles of 10 microCi ²¹²Pb-DOTAMTATE. These conditions led to 79% of the animals being tumor free at the end of the 31-week study suggesting that ²¹²Pb-DOTAMTATE alone or in combination with a chemotherapeutic may have positive clinical implications.