The effect of bi-terminal PEGylation of an integrin  α_vβ₆-targeted ¹⁸F peptide on pharmacokinetics and tumor uptake

Journal Article · Thu Mar 26 00:00:00 EDT 2015 · Journal of Nuclear Medicine

DOI:https://doi.org/10.2967/jnumed.114.150680· OSTI ID:1345593

Hausner, Sven H. ^[1]; Bauer, Nadine ^[2]; Hu, Lina Y. ^[2]; Knight, Leah M. ^[3]; Sutcliffe, Julie L. ^[1]

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1. Univ. of California Davis, Sacramento, CA (United States); Univ. of California, Davis, CA (United States)
2. Univ. of California, Davis, CA (United States)
3. Univ. of California Davis, Sacramento, CA (United States)

Radiotracers based on the peptide A20FMDV2 selectively target the cell surface receptor integrin α_vβ₆. This integrin has been identified as a prognostic indicator correlating with the severity of disease for several challenging malignancies. In previous studies of A20FMDV2 peptides labeled with 4-¹⁸F-fluorobenzoic acid (¹⁸F-FBA), we have shown that the introduction of poly(ethylene glycol) (PEG) improves pharmacokinetics, including increased uptake in α_vβ₆-expressing tumors. The present study evaluated the effect of site-specific C-terminal or dual (N- and C-terminal) PEGylation, yielding ¹⁸F-FBA-A20FMDV2-PEG₂₈ (4) and ¹⁸F-FBA-PEG₂₈-A20FMDV2-PEG₂₈ (5), on α_vβ₆-targeted tumor uptake and pharmacokinetics. The results are compared with ¹⁸F-FBA–labeled A20FMDV2 radiotracers (1–3) bearing either no PEG or different PEG units at the N terminus. The radiotracers were prepared and radiolabeled on solid phase. Using 3 cell lines, DX3puroβ6 (α_vβ₆+), DX3puro (α_vβ₆–), and BxPC-3 (α_vβ₆+), we evaluated the radiotracers in vitro (serum stability; cell binding and internalization) and in vivo in mouse models bearing paired DX3puroβ6–DX3puro and, for 5, BxPC-3 xenografts. Here, the size and location of the PEG units significantly affected α_vβ₆ targeting and pharmacokinetics. Although the C-terminally PEGylated 4 showed some improvements over the un-PEGylated ¹⁸F-FBA-A20FMDV2 (1), it was the bi-terminally PEGylated 5 that displayed the more favorable combination of high α_vβ₆ affinity, selectivity, and pharmacokinetic profile. In vitro, 5 bound to α_vβ₆-expressing DX3puroβ6 and BxPC-3 cells with 60.5% ± 3.3% and 48.8% ± 8.3%, respectively, with a significant fraction of internalization (37.2% ± 4.0% and 37.6% ± 4.1% of total radioactivity, respectively). By comparison, in the DX3puro control 5 showed only 3.0% ± 0.5% binding and 0.9% ± 0.2% internalization. In vivo, 5 maintained high, α_vβ₆-directed binding in the paired DX3puroβ6–DX3puro model (1 h: DX3puroβ6, 2.3 ± 0.2 percentage injected dose per gram [%ID/g]; DX3puroβ6/DX3puro ratio, 6.5:1; 4 h: 10.7:1). In the pancreatic BxPC-3 model, uptake was 4.7 ± 0.9 %ID/g (1 h) despite small tumor sizes (20–80 mg). In conclusion, the bi-PEGylated radiotracer 5 showed a greatly improved pharmacokinetic profile, beyond what was predicted from individual N- or C-terminal PEGylation. It appears that the 2 PEG units acted synergistically to result in an improved metabolic profile including high α_vβ₆+ tumor uptake and retention.

• Research Organization: Univ. of California, Davis, CA (United States)
• Sponsoring Organization: USDOE Office of Science (SC)
• Grant/Contract Number: SC0002061
• OSTI ID: 1345593
• Journal Information: Journal of Nuclear Medicine, Vol. 56, Issue 5; ISSN 0161-5505
• Publisher: Society of Nuclear Medicine and Molecular Imaging
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES
integrin αvβ6
positron emission tomography
peptide
PEGylation
metabolism