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 |
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| Affiliation: | 1. Area of Pathobiology, University of Missouri, Columbia, MO;2. Research Service, Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO;3. Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, MO;4. Nuclear Science and Engineering Institute, University of Missouri, Columbia, MO;5. University of Missouri Research Reactor Center, Columbia, MO;1. Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA 30329;2. Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322;1. Department of Nuclear Medicine, University of Amsterdam, Academic Medical Center, Amsterdam, The Netherlands;2. Graduate School of Neurosciences, Amsterdam, The Netherlands;3. Department of Nuclear Medicine, Medical Center Alkmaar, Alkmaar, The Netherlands;4. Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands;5. Department of Anatomy and Neurosciences, VU Medical Center, Amsterdam, The Netherlands;1. From the Division of Surgical Oncology, Baylor Scott & White Health, Texas A&M Health Science Center;2. Department of Surgery, UT Southwestern Medical Center;3. Endocrine Surgery, John Wayne Cancer Institute at Providence St. John''s Health Center;4. Department of Surgery, Oregon Health and Sciences University;5. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center;6. Department of General and Endocrine Surgery, Emory University School of Medicine;7. Department of Endocrine, Moffitt Cancer Center;8. Department of Surgery, Memorial Sloan-Kettering Cancer Center;9. Thyroid & Parathyroid Surgical Divisions, General Otolaryngology, Harvard Medical School. |
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| Abstract: | IntroductionThe B-cell lymphoma/leukemia-2 (bcl-2) proto-oncogene in non-Hodgkin’s lymphoma (NHL) is a dominant inhibitor of apoptosis. We developed a 177Lu-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.MethodsDOTA-anti-bcl-2-Tyr3-octreotate was synthesized, labeled with 177Lu, and purified using RP-HPLC. The PNA–peptide conjugate was evaluated in Mec-1 NHL-bearing mice and compared to [177Lu]DOTA-Tyr3-octreotate in biodistribution and excretion studies. These data were then used to generate in vivo dosimetry models.ResultsThe 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 177Lu-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 24 h. Dosimetry models showed that the tumor absorbed dose of the PNA–peptide conjugate was approximately twice that of the peptide-only conjugate.ConclusionsBiodistribution data showed specific tumor targeting of the 177Lu-labeled PNA–peptide compound with minimal receptor-positive normal tissue uptake when compared to [177Lu]DOTA-Tyr3-octreotate. In vivo dosimetry models predicted a more favorable tumor absorbed dose from [177Lu]DOTA-anti-bcl-2-Tyr3-octreotate. |
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