A Comparison of Evans Blue and 4-(p-Iodophenyl)butyryl Albumin Binding Moieties on an Integrin αv β6 Binding Peptide

Ryan A. Davis, Sven H. Hausner, Rebecca Harris, Julie L. Sutcliffe

Research output: Contribution to journalArticlepeer-review

Abstract

Serum albumin binding moieties (ABMs) such as the Evans blue (EB) dye fragment and the 4-(p-iodophenyl)butyryl (IP) have been used to improve the pharmacokinetic profile of many radiopharmaceuticals. The goal of this work was to directly compare these two ABMs when conjugated to an integrin αv β6 binding peptide (αv β6-BP); a peptide that is currently being used for positron emission tomography (PET) imaging in patients with metastatic cancer. The ABM-modified αv β6-BP peptides were synthesized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetracetic acid (DOTA) chelator for radiolabeling with copper-64 to yield [64 Cu]Cu DOTA-EB-αv β6-BP ([64 Cu]1) and [64 Cu]Cu DOTA-IP-αv β6-BP ([64 Cu]2). Both peptides were evaluated in vitro for serum albumin binding, serum stability, and cell binding and internalization in the paired engineered melanoma cells DX3puroβ6 (αv β6 +) and DX3puro (αv β6 −), and pancreatic BxPC-3 (αv β6 +) cells and in vivo in a BxPC-3 xenograft mouse model. Serum albumin binding for [64 Cu]1 and [64 Cu]2 was 53–63% and 42–44%, respectively, with good human serum stability (24 h: [64 Cu]1 76%, [64 Cu]2 90%). Selective αv β6 cell binding was observed for both [64 Cu]1 and [64 Cu]2 (αv β6 (+) cells: 30.3–55.8% and 48.5–60.2%, respectively, vs. αv β6 (−) cells <3.1% for both). In vivo BxPC-3 tumor uptake for both peptides at 4 h was 5.29 ± 0.59 and 7.60 ± 0.43% ID/g ([64 Cu]1 and [64 Cu]2, respectively), and remained at 3.32 ± 0.46 and 4.91 ± 1.19% ID/g, respectively, at 72 h, representing a >3-fold improve-ment over the non-ABM parent peptide and thereby providing improved PET images. Comparing [64 Cu]1 and [64 Cu]2, the IP-ABM-αv β6-BP [64 Cu]2 displayed higher serum stability, higher tumor accumulation, and lower kidney and liver accumulation, resulting in better tumor-to-organ ratios for high contrast visualization of the αv β6 (+) tumor by PET imaging.

Original languageEnglish (US)
Article number745
JournalPharmaceutics
Volume14
Issue number4
DOIs
StatePublished - Apr 2022

Keywords

  • 4-(p-iodophenyl)butyric acid
  • albumin binding moieties
  • Evans blue
  • improved pharmacokinetics
  • integrin α β
  • integrin α β binding peptide
  • peptides
  • PET imaging

ASJC Scopus subject areas

  • Pharmaceutical Science

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