title: 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.
abstract: BACKGROUND
  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.
authors.affiliation: Area of Pathobiology, University of Missouri, Columbia, MO; Research Service, Harry S. Truman Memorial Veterans' Hospital, Columbia, MO; Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO.
authors.forename: Ethan R
authors.initials: ER
authors.lastname: Balkin
authors.forename: Dijie
authors.initials: D
authors.lastname: Liu
authors.forename: Fang
authors.initials: F
authors.lastname: Jia
authors.forename: Varyanna C
authors.initials: VC
authors.lastname: Ruthengael
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Shaffer
authors.forename: William H
authors.initials: WH
authors.lastname: Miller
authors.forename: Michael R
authors.initials: MR
authors.lastname: Lewis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D019254:Genes, bcl-2 / Q000235:genetics*; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology / Q000532:radiotherapy*; D008187:Lutetium / Q000627:therapeutic use; D016393:Lymphoma, B-Cell / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D020320:Oligoribonucleotides, Antisense / Q000235:genetics*; D020135:Peptide Nucleic Acids / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000090063:Proto-Oncogene Mas; D011868:Radioisotopes / Q000627:therapeutic use; D011874:Radiometry; D014018:Tissue Distribution
chemical_list: D006573:Heterocyclic Compounds, 1-Ring; C000715470:MAS1 protein, human; D020320:Oligoribonucleotides, Antisense; D020135:Peptide Nucleic Acids; D010456:Peptides, Cyclic; D000090063:Proto-Oncogene Mas; D011868:Radioisotopes; C470036:octreotate, Tyr(3)-; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; D008187:Lutetium
keywords: (177)Lu; Peptide nucleic acid; Somatostatin receptor; Targeted antisense radiotherapy; bcl-2; non-Hodgkin’s Lymphoma