Development of Novel Peptide-Based ⁶⁸Ga-Labeled Radiotracers for Detecting ROR1 Expression in Tumors

The study aimed to develop a series of 68Ga-labeled receptor tyrosine kinase orphan receptor 1 (ROR1)-targeted peptides and demonstrate the ability to evaluate the ROR1 expression of tumors. Three ROR1-targeted peptides (PR3, PR7, and 1036) were modified for connecting to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and then labeled with 68Ga. The radiolabeling yields of 68Ga-labeled ROR1-targeted peptides were assessed by high-performance liquid chromatography, and their stabilities were evaluated by thin-layer chromatography. In vitro, the specificity of 68Ga-labeled ROR1-targeted peptides was demonstrated in NCI-H1975 and HepG2 cells. In vivo, NCI-H1975 and HepG2 tumor-bearing mice were established for micro-PET/CT imaging. All 68Ga-labeled ROR1-targeted peptides had high radiolabeled yields and in vitro stability. The uptakes of 68Ga-DOTA-PEG4-PR3 and 68Ga-DOTA-PEG4-PR7 in NCI-H1975 tumor were significantly higher than those in HepG2 tumor at 15 and 30 min postinjection (all P < 0.05). After blocking with precursor, the NCI-H1975 tumor uptakes at 30 min of 68Ga-DOTA-PEG4-PR3 and 68Ga-DOTA-PEG4-PR7 at 30 min declined from 1.87 ± 0.32%ID/g to 1.02 ± 0.22%ID/g (P = 0.02) and from 1.53 ± 0.15%ID/g to 0.87 ± 0.24%ID/g (P = 0.011), respectively. However, there were no differences in the NCI-H1975 and HepG2 tumor uptakes of 68Ga-DOTA-KGGG-1036, and it cannot be blocked by DOTA-KGGG-1036. Overall, 68Ga-DOTA-PEG4-PR3 and 68Ga-DOTA-PEG4-PR7 have the potential to noninvasively evaluate the expression of ROR1 and are expected to guide the therapy targeting ROR1.

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