Abstract
Simple SummaryCationic amphiphilic peptides (CAPs), such as SVS-1, exhibit preferential cytotoxicity towards cancer cells. SVS-1 can also be used as a diagnostic tool for the detection of cancer. Here, we report the development of three 67Ga-labeled SVS-1 derivatives as potential cancer diagnostic agents. All of these radiotracers showed high accumulation in cancerous KB cells. Notably, the uptake of 67Ga-NOTA-KV6 and 67Ga-NOTA-HV6 into 3T3-L1 fibroblasts was significantly lower than in KB cells. In vivo biodistribution studies showed that 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6 exhibit high tumor accumulation, tumor/blood ratios (3.8–8.0), and tumor/muscle ratios (3.3–5.0) 120 min after administration. These radiolabeled SVS-1 analogues target the surface membranes of cancer cells, and are prospective scaffolds for in vivo imaging agents.SVS-1 is a cationic amphiphilic peptide (CAP) that exhibits a preferential cytotoxicity towards cancer cells over normal cells. In this study, we developed radiogallium-labeled SVS-1 (67Ga-NOTA-KV6), as well as two SVS-1 derivatives, with the repeating KV residues replaced by RV or HV (67Ga-NOTA-RV6 and 67Ga-NOTA-HV6). All three peptides showed high accumulation in epidermoid carcinoma KB cells (53–143% uptake/mg protein). Though 67Ga-NOTA-RV6 showed the highest uptake among the three CAPs, its uptake in 3T3-L1 fibroblasts was just as high, indicating a low selectivity. In contrast, the uptake of 67Ga-NOTA-KV6 and 67Ga-NOTA-HV6 into 3T3-L1 cells was significantly lower than that in KB cells. An endocytosis inhibition study suggested that the three 67Ga-NOTA-CAPs follow distinct pathways for internalization. In the biodistribution study, the tumor uptakes were found to be 4.46%, 4.76%, and 3.18% injected dose/g of tissue (% ID/g) for 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6, respectively, 30 min after administration. Though the radioactivity of these peptides in tumor tissue decreased gradually, 67Ga-NOTA-KV6, 67Ga-NOTA-RV6, and 67Ga-NOTA-HV6 reached high tumor/blood ratios (7.7, 8.0, and 3.8, respectively) and tumor/muscle ratios (5.0, 3.3, and 4.0, respectively) 120 min after administration. 67Ga-NOTA-HV6 showed a lower tumor uptake than the two other tracers, but it exhibited very low levels of uptake into peripheral organs. Overall, the replacement of lysine in SVS-1 with other basic amino acids significantly influenced its binding and internalization into cancer cells, as well as its in vivo pharmacokinetic profile. The high accessibility of these peptides to tumors and their ability to target the surface membranes of cancer cells make radiolabeled CAPs excellent candidates for use in tumor theranostics.
Highlights
Contrary to healthy cells, the surface membrane of cancer cells tends to be negatively charged due to the exposure of phosphatidylserine (PS) on the outer surface of the lipid bilayer [1,2,3], the changes in the composition of glycoprotein sugar chains [4,5], and the increase in sialic acid content [6,7]
Several hydrophobic cationic amphiphilic peptides (CAPs) have been reported to exhibit antitumor activity [8]. Their anticancer effects are thought to be driven by electrostatic interactions between the CAPs and the negatively charged surface membranes of cancer cells
Evaluation of the Internalization Pathway of CAPs Each cell line grown in a 12-well plate was incubated with 1.0 kBq of 67Ga-CAPs
Summary
The surface membrane of cancer cells tends to be negatively charged due to the exposure of phosphatidylserine (PS) on the outer surface of the lipid bilayer [1,2,3], the changes in the composition of glycoprotein sugar chains [4,5], and the increase in sialic acid content [6,7]. Several hydrophobic cationic amphiphilic peptides (CAPs) have been reported to exhibit antitumor activity [8] Their anticancer effects are thought to be driven by electrostatic interactions between the CAPs and the negatively charged surface membranes of cancer cells. The selective anticancer and membrane-interactive properties of SVS-1 make it a good lead peptide for the development of nuclear medicine imaging probes for cancer. Like KV6, CLIP6 exhibits high membrane permeability and selective toxicity towards cancer cells [18,19] This suggests that replacing the lysine residues in KV6 with other amino acids may lead to the development of highly selective derivatives with diverse physiological properties.
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