Abstract
Simple SummaryIn fluorescence imaging employing a targeting strategy, fluorescent dyes conjugated with ligands may alter the pharmacokinetics of the conjugates. The aim of this study was to investigate whether in vitro and in vivo cell uptake are affected when fluorescent dyes with different chemical properties are conjugated with a ligand. The results show that attention should be paid to the chemical properties of fluorescent dyes in designing fluorescent imaging agents.In molecular imaging, a targeting strategy with ligands is widely used because specificity can be significantly improved. In fluorescence imaging based on a targeting strategy, the fluorescent dyes conjugated with ligands may affect the targeting efficiency depending on the chemical properties. Herein, we used a cell-penetrating peptide (CPP) as a ligand with a variety of fluorescent cyanine dye. We investigated in vitro and in vivo cell uptake of the dye-CPP conjugates when cyanine dyes with differing charge and hydrophilicity/lipophilicity were used. The results showed that the conjugates with positively charged and lipophilic cyanine dyes accumulated in cancer cells in vitro, but there was almost no accumulation in tumors in vivo. On the other hand, the conjugates with negatively charged and hydrophilic cyanine dyes did not accumulate in cancer cells in vitro, but fluorescence was observed in tumors in vivo. These results show that there are some cases in which the cell uptake of the dye-peptide conjugates may differ significantly between in vitro and in vivo experiments due to the chemical properties of the fluorescent dyes. This suggests that attention should be paid to the chemical properties of fluorescent dyes in fluorescence imaging based on a targeting strategy.
Highlights
A targeting strategy with compounds that bind to specific biomolecules, so-called ligands, is widely used for molecular imaging and drug delivery
Dye-succinimidyl ester (SE) and dye-PCPP11 were analyzed by high-performance liquid chromatography (HPLC) under the same conditions; the retention times are shown in Table 1 because they are indicators of hydrophilicity/lipophilicity
A quantitative analysis of flow cytometry (FCM) showed that the accumulation of Cy3/Cy5-PCPP11 conjugates in BxPC3 cells at 24 h was significantly higher than that in BxPC3 cells at 3 h and that in NHDF cells at 24 h. These results indicated that the dye-PCPP11 accumulated of 14 in BxPC3 cells over time and the accumulation was influenced by the chemical 6properties of the fluorescent dyes, such as charge and hydrophilicity/lipophilicity
Summary
A targeting strategy with compounds that bind to specific biomolecules, so-called ligands, is widely used for molecular imaging and drug delivery. Due to ligands selectively binding to target cells, specificity can be significantly improved compared with a passive accumulation strategy [1,2]. Among various ligands, including antibodies, macromolecules, and small molecules, peptides are useful due to their tunable targeting properties (i.e., multi-valent peptides) and facile synthesis at a relatively low cost [3,4,5]. Among peptides suitable for a targeting strategy, cell-penetrating peptides (CPPs) are attractive candidates since they can be used as carriers for molecular imaging and as drug delivery vehicles for therapeutic compounds that do not cross the cellular membrane [6,7,8]. Peptides are becoming increasingly used as targeting molecules
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