Comparative biodistributions and dosimetry of [¹⁷⁷Lu]DOTA-anti-bcl-2-PNA-Tyr³-octreotate and [¹⁷⁷Lu]DOTA-Tyr³-octreotate in a mouse model of B-cell lymphoma/leukemia.

INTRODUCTION:The B-cell lymphoma/leukemia-2 (bcl-2) proto-oncogene in non-Hodgkin's lymphoma (NHL) is a dominant inhibitor of apoptosis. We developed a (177)Lu-labeled bcl-2 antisense peptide nucleic acid (PNA)-peptide conjugate designed for dual modality NHL therapy, consisting of a radiopharmaceutical capable of simultaneously down-regulating apoptotic resistance and delivering cytotoxic internally emitted radiation. METHODS:DOTA-anti-bcl-2-Tyr(3)-octreotate was synthesized, labeled with (177)Lu, and purified using RP-HPLC. The PNA-peptide conjugate was evaluated in Mec-1 NHL-bearing mice and compared to [(177)Lu]DOTA-Tyr(3)-octreotate in biodistribution and excretion studies. These data were then used to generate in vivo dosimetry models. RESULTS:The PNA-peptide conjugate was readily prepared and radiolabeled in high yield and radiochemical purity. An in vivo blocking study determined that administration of 50 μg of non-radioactive PNA-peptide was the optimal mass for maximum delivery to the tumor. Based on that result, a dosing regimen of (177)Lu-PNA-peptide, for radiologic effect, followed by the optimal mass of non-radioactive compound, for antisense effect, was designed. Using that dosing regimen, biodistribution of the PNA-peptide showed uptake in the tumor with minimal washout over a 4-day period. Uptakes in receptor-positive normal organs were low and displayed nearly complete washout by 24h. Dosimetry models showed that the tumor absorbed dose of the PNA-peptide conjugate was approximately twice that of the peptide-only conjugate. CONCLUSIONS:Biodistribution data showed specific tumor targeting of the (177)Lu-labeled PNA-peptide compound with minimal receptor-positive normal tissue uptake when compared to [(177)Lu]DOTA-Tyr(3)-octreotate. In vivo dosimetry models predicted a more favorable tumor absorbed dose from [(177)Lu]DOTA-anti-bcl-2-Tyr(3)-octreotate.