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. 2020 Jun 11;25(11):2712.
doi: 10.3390/molecules25112712.

Pharmacokinetic Properties of 68Ga-labelled Folic Acid Conjugates: Improvement Using HEHE Tag

Anton Larenkov  1   2 , Marat Rakhimov  1 , Kristina Lunyova  1 , Olga Klementyeva  1 , Alesya Maruk  1 , Aleksei Machulkin  2   3
Affiliations

Pharmacokinetic Properties of 68Ga-labelled Folic Acid Conjugates: Improvement Using HEHE Tag

Anton Larenkov et al. Molecules. .

Abstract

The folate receptor (FR) is a promising cell membrane-associated target for molecular imaging and radionuclide therapy of cancer (FR-α) and potentially also inflammatory diseases (FR-β) through use of folic acid-based radioconjugate. FR is often overexpressed by cells of epithelial tumors, including tumors of ovary, cervix, endometrium, lungs, kidneys, etc. In healthy tissues, FR can be found in small numbers by the epithelial cells, mainly in the kidneys. Extremely high undesired accumulation of the folate radioconjugates in the renal tissue is a main drawback of FR-targeting concept. In the course of this work, we aimed to reduce the undesirable accumulation of folate radioconjugates in the kidneys by introducing a histidine/glutamic acid tag into their structure. Two folic acid based compounds were synthesized: NODAGA-1,4-butanediamine-folic acid (FA-I, as control) and NODAGA-[Lys-(HE)2]-folic acid (FA-II) which contains a (His-Glu)2 fragment. In vitro studies with FR (+) cells (KB and others) showed that both compounds have specificity for FR. Introduction of (HE)2-tag does not affect FR binding ability of the conjugates. In vivo biodistribution studies with normal laboratory animals, as well as with KB tumor bearing animals, were carried out. The results showed that introduction of the (HE)2 tag into the structure of folate radioconjugates can significantly reduce the accumulation of these compounds in non-target tissues and important organs (the accumulation in the kidneys is reduced 2-4 times), leaving the accumulation in tumor at least at the same level, and even increasing it.

Keywords: HEHE; KB cells; NODAGA-folate conjugate; PET imaging; folate receptor; folic acid; gallium-68; histidine-glutamic acid tag; kidney accumulation; pharmacokinetics; radiopharmaceuticals.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structure of FA-I and FA-II with marked moieties: red-folic acid vector moiety; black–NODAGA chelator for 68Ga coordination; green–linkers; blue–(HE)2-tag for pharmacokinetic properties optimization.
Scheme 1
Scheme 1
Synthesis NODAGA-1,4-buthanediamine--folic acid (FA-I).
Scheme 2
Scheme 2
Synthesis NODAGA-[Lys-(HE)2]--folic acid (FA-II).
Figure 2
Figure 2
In vitro accumulation of [68Ga]Ga-FA-I and [68Ga]Ga-FA-II in KB cell culture (mean ± SD, n = 3).
Figure 3
Figure 3
In vitro accumulation of [68Ga]Ga-FA-I and [68Ga]Ga-FA-II in HeLa, A549 and HCT-116 cell cultures (mean ± SD, n = 3).
Figure 4
Figure 4
Accumulation of [68Ga]Ga-FA-I and [68Ga]Ga-FA-II in kidneys (mean ± SD, n = 5).
Figure 5
Figure 5
Biodistribution of [68Ga]Ga-FA-I and [68Ga]Ga-FA-II in KB-tumor bearing BALB/c nude mice 30 and 60 min after i.v. injection (selected organs/tissues from Table 3).
Figure 6
Figure 6
Accumulation of [68Ga]Ga-FA-I and [68Ga]Ga-FA-II in kidneys and KB-tumor xenografts.
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References

    1. Kim E.E., Yang D.J. Targeted Molecular Imaging in Oncology. Springer; New York, NY, USA: 2001. pp. 62–111.
    1. Richter M., Zhang H. Receptor-targeted cancer therapy. DNA Cell Biol. 2005;24:271–282. doi: 10.1089/dna.2005.24.271. - DOI - PubMed
    1. Chen C., Ke J., Edward Zhou X., Yi W., Brunzelle J.S., Li J., Yong E.L., Xu H.E., Melcher K. Structural basis for molecular recognition of folic acid by folate receptors. Nature. 2013;500:486–489. doi: 10.1038/nature12327. - DOI - PMC - PubMed
    1. Muller C. Folate Based Radiopharmaceuticals for imaging and therapy of cancer and inflammation. Curr. Pharm. Des. 2012;18:1058–1083. doi: 10.2174/138161212799315777. - DOI - PubMed
    1. Müller C. Folate-based radiotracers for PET imaging-update and perspectives. Molecules. 2013;18:5005–5031. doi: 10.3390/molecules18055005. - DOI - PMC - PubMed

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