DOTA-dPEG® Bifunctional Chelators
A poster of the material in this PepTalk, in PDF format, is available here.
Targeted radiopharmaceuticals derived from DOTA conjugated to a biologic use bifunctional chelators (BFCs) consisting of a multidentate macrocycle for chelation of the radionuclide and a reactive functionality for covalent attachment to the targeting vector. A linker incorporated between the chelator and the biologic can influence the pharmacokinetics (PK) and biodistribution (BD) of the conjugate by altering physicochemical properties, including charge and hydrophilicity. Linkers based on the dPEG® backbone have been shown to have a profound effect on both ADCs and radioconjugates by influencing solubility, aggregation, PK, and BD due to the charge, hydrophilicity, and hydrodynamic volume imparted by the linker.
- Significant improvement of tumor/kidney ratios for diabodies1
- Optimal biodistribution of RGD peptide conjugates2
- Reduced off-target accumulation of bombesin-based conjugates 3,4
- Improved cell internalization and serum stability of neurotensin conjugates5
- Dramatic reduction in kidney uptake of minigastrin-based conjugates6
The ability to optimize the hydrophilic linker component in radioconjugates has been hindered by the unavailability of DOTA-based BFCs with hydrophilic dPEG® linkers of defined lengths and relevant functional groups for conjugation to the most important residues on the biologic component. This has resulted in the use of complicated multistep protocols like that shown in the figure where 1) the linker () is conjugated to the biologic, 2) the linker is deprotected or activated (), and 3) DOTA () is conjugated to the linker. In some cases subsequent deprotection of DOTA is also needed. This subjects the critical biologic to multiple steps that reduce yields and increase costs. In support of the rational design of both radiopeptides and radioimmunoconjugates, Quanta BioDesign has designed and synthesized DOTA-based bifunctional chelators with hydrophilic dPEG® linkers of defined lengths (dPEG® 4, 12, and 24) and critical reactive functionalities (active esters, maleimides and a-bromo acetamides, aminoxys, and DBCO), thus allowing single-step conjugation protocols and rapid optimization of linker properties and conjugation chemistries. Additional dPEG® lengths, architectures, and chemistries may be available on a custom basis.
1. L. Li, et al., Bioconjugate Chemistry, 22(4), 709 (2011). DOI: 10.1021/bc100464e
2. I. Dijkgraaf, et al., Nuclear Medicine and Biology, 34, 29 (2007).
3. I.E. Valverde, et al., Journal of Medicinal Chemistry, 59(8), 3867 (2016). DOI: 10.1021/acs.jmedchem.6b00025
4. R. Mansi, et al., Nuclear Medicine and Biology, 41, 464 (2014). DOI: 10.1016/j.nucmedbio.2014.03.014
5. A. Mascarin, et al., ChemMedChem, 11, 102 (2016). DOI: 10.1002/cmdc.201500468
6. P. Kolenc-Peitl, et al., Journal of Medicinal Chemistry, 54, 2602 (2011). DOI: 10.1002/cmdc.201500468
DOTA dPEG® Bifunctional Chelators are made in the USA, and exclusively invented, developed, and manufactured by Quanta BioDesign. All items available from Peptides International, including custom peptide synthesis, utilizing dPEG® products.