Enhancing Treatment Efficacy of 177 Lu-PSMA-617 with the Conjugation of an Albumin-Binding Motif: Preclinical Dosimetry and Endoradiotherapy Studies

Mol Pharm. 2018 Nov 5;15(11):5183-5191. doi: 10.1021/acs.molpharmaceut.8b00720. Epub 2018 Oct 5.

Abstract

We designed and evaluated a novel albumin-binder-conjugated 177Lu-PSMA-617 derivative, 177Lu-HTK01169, with an extended blood retention time to maximize the radiation dose delivered to prostate tumors expressing prostate-specific membrane antigen (PSMA). PSMA-617 and HTK01169 that contained N-[4-( p-iodophenyl)butanoyl]-Glu as an albumin-binding motif were synthesized using the solid-phase approach. Binding affinity to PSMA was determined by in vitro competition-binding assay. 177Lu labeling was performed in acetate buffer (pH 4.5) at 90 °C for 15 min. SPECT/CT imaging, biodistribution, and endoradiotherapy studies were conducted in mice bearing PSMA-expressing LNCaP tumor xenografts. Radiation dosimetry was calculated using OLINDA software. Lu-PSMA-617 and Lu-HTK01169-bound PSMA with high affinity ( Ki values = 0.24 and 0.04 nM, respectively). SPECT imaging and biodistribution studies showed that 177Lu-PSMA-617 and 177Lu-HTK01169 were excreted mainly via the renal pathway. With fast blood clearance (0.68%ID/g at 1 h postinjection), the tumor uptake of 177Lu-PSMA-617 peaked at 1 h postinjection (15.1%ID/g) and gradually decreased to 7.91%ID/g at 120 h postinjection. With extended blood retention (16.6 and 2.10%ID/g at 1 and 24 h, respectively), the tumor uptake of 177Lu-HTK01169 peaked at 24 h postinjection (55.9%ID/g) and remained at the same level by the end of the study (120 h). Based on dosimetry calculations, 177Lu-HTK01169 delivered an 8.3-fold higher radiation dose than 177Lu-PSMA-617 to LNCaP tumor xenografts. For the endoradiotherapy study, the mice treated with 177Lu-PSMA-617 (18.5 MBq) all reached humane end point (tumor volume >1000 mm3) by Day 73 with a median survival of 58 days. Mice treated with 18.5, 9.3, 4.6, or 2.3 MBq of 177Lu-HTK01169 had a median survival of >120, 103, 61, and 28 days, respectively. With greatly enhanced tumor uptake and treatment efficacy compared to 177Lu-PSMA-617 in preclinical studies, 177Lu-HTK01169 warrants further investigation for endoradiotherapy of prostate cancer.

Keywords: PSMA-617; albumin binder; endoradiotherapy; lutetium-177; prostate-specific membrane antigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albumins / metabolism
  • Animals
  • Antigens, Surface / metabolism*
  • Cell Line, Tumor
  • Dipeptides / administration & dosage*
  • Dipeptides / chemistry
  • Dipeptides / pharmacokinetics
  • Glutamate Carboxypeptidase II / antagonists & inhibitors
  • Glutamate Carboxypeptidase II / metabolism*
  • Heterocyclic Compounds, 1-Ring / administration & dosage*
  • Heterocyclic Compounds, 1-Ring / chemistry
  • Heterocyclic Compounds, 1-Ring / pharmacokinetics
  • Humans
  • Lutetium / administration & dosage*
  • Lutetium / chemistry
  • Lutetium / pharmacokinetics
  • Male
  • Mice
  • Prostatic Neoplasms / diagnostic imaging
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / radiotherapy*
  • Protein Interaction Domains and Motifs
  • Radioisotopes / administration & dosage*
  • Radioisotopes / chemistry
  • Radioisotopes / pharmacokinetics
  • Radiopharmaceuticals / administration & dosage*
  • Radiopharmaceuticals / chemistry
  • Radiopharmaceuticals / pharmacokinetics
  • Single Photon Emission Computed Tomography Computed Tomography / methods
  • Tissue Distribution
  • Xenograft Model Antitumor Assays

Substances

  • Albumins
  • Antigens, Surface
  • Dipeptides
  • Heterocyclic Compounds, 1-Ring
  • PSMA-617
  • Radioisotopes
  • Radiopharmaceuticals
  • Lutetium
  • Lutetium-177
  • FOLH1 protein, human
  • Glutamate Carboxypeptidase II