Abstract 4205: Targeting a variety of cancers with NOTA-derivatized pH (low) insertion peptide (pHLIP) complexes with ⁶⁴Cu and ¹⁸F: What cancers are targetable

Abstract

Introduction: Although heterogeneous, the extracellular tumor environment is generally marked by decreased pH relative to nontumor tissues due to cancer cell metabolism. Using a pH-sensitive peptide to deliver diagnostic PET isotopes can provide clinicians with improved diagnostic tools for cancer-specific imaging and an alternative to receptor-based cancer targeting. pH (low) Insertion Peptides (pHLIPs) have previously been shown to target cancerous tissues and are able to deliver PET metals to the cancer site utilizing a NOTA-based chelator.

Methods: The thiol-containing cysteine moiety on the pHLIP peptide sequence was conjugated to the NOTA chelator. The NOTA-derivatized peptides were labeled with ⁶⁴CuCl₂ in 100 mM NH₄OAc (pH 5) solution; the [¹⁸F]-fluoride was reacted with AlCl₃ before forming the [¹⁸F]-AlF-NOTA-pHLIP complexes in NH₄OAc buffered reaction mixtures (pH ∼ 4.1). After purification and formulation, the radiolabeled peptides were injected intravenously into 4T1 breast, PC-3 prostate, LNCaP prostate, or B16-F10 melanoma tumor-bearing mice.

Results: The 4T1 tumor-bearing mice showed significant uptake > 10%ID/g by 4 h p.i. and continued to show increased uptake of the ⁶⁴Cu-NOTA-cysVar3 over 20 h. Tumors were visible in the 4T1 tumor-bearing mice as early as 2 h, but had the greatest tumor-to-background ratios at 24 h. Initial studies with B16-F10 tumor-bearing mice showed > 9%ID/g uptake in the tumor by 4 h p.i. with slight increase of ⁶⁴Cu-NOTA-cysVar3 uptake over 24 h. Due to the placement of the melanoma tumors away from internal organs, tumors were visible by 1 h p.i. Additionally, the size of the melanoma tumors did not affect the%ID/g of radiotracer uptake.

Conclusions: Our studies indicate that the NOTA-cys(pHLIP), specifically NOTA-cysVar3, radiolabeled with ⁶⁴Cu or ¹⁸F is a viable imaging tool for detecting highly metabolic tumors in preclinical mouse models.

Funding: NIH F32 CA186721 (D.W.D.), NIH R01 CA138468 (J.S.L.), NIH MSKCC Center Grant (P30-CA08748).

Citation Format: Dustin W. Demoin, Kimberly J. Edwards, Linden C. Wyatt, Mirkka Sarparanta, Jacob Pourat, Oleg A. Andreev, Yana K. Reshetnyak, Nerissa Viola-Villegas, Jason S. Lewis. Targeting a variety of cancers with NOTA-derivatized pH (low) insertion peptide (pHLIP) complexes with ⁶⁴Cu and ¹⁸F: What cancers are targetable. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4205.