Tetrazine- and trans -cyclooctene-functionalised polypept(o)ides for fast bioorthogonal tetrazine ligation

The inverse electron demand Diels–Alder (IEDDA) reaction-initiated ligation between 1,2,4,5-tetrazines (Tz) and trans -cyclooctenes (TCO) is one of the fastest bioorthogonal reactions known today and is therefore increasingly used for in vivo click chemistry. Described herein is the synthesis of Tz-...

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Bibliographic Details
Published in:Polymer chemistry 2020-07, Vol.11 (27), p.4396-4407
Main Authors: Johann, Kerstin, Svatunek, Dennis, Seidl, Christine, Rizzelli, Silvia, Bauer, Tobias A., Braun, Lydia, Koynov, Kaloian, Mikula, Hannes, Barz, Matthias
Format: Article
Language:English
Subjects:
Chemical synthesis
Fluorescence
Ions
Liquid chromatography
Mass spectrometry
Micelles
Nanoparticles
NMR
Nuclear magnetic resonance
Polymer chemistry
Polymers
Polypeptides
Rate constants
Reaction kinetics
Ring opening polymerization
Spectrophotometry
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Summary:The inverse electron demand Diels–Alder (IEDDA) reaction-initiated ligation between 1,2,4,5-tetrazines (Tz) and trans -cyclooctenes (TCO) is one of the fastest bioorthogonal reactions known today and is therefore increasingly used for in vivo click chemistry. Described herein is the synthesis of Tz- and TCO-functionalised polypeptides, polypeptoids and polypeptide- block -polypeptoids (polypept(o)ides) by ring-opening polymerisation of the corresponding N -carboxyanhydrides using Tz- or TCO-functional amine initiators. Despite the reactivity of tetrazines, polymers with low dispersity and high end group integrity can be obtained as observed by gel permeation chromatography (GPC), nuclear magnetic resonance (NMR) spectroscopy and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. Amphiphilic Tz-functionalised block copolypept(o)ides were used to prepare polymeric micelles and organic colloids by miniemulsion techniques, which may find an application as clearing agents in pretargeted nuclear imaging and therapy using efficient in vivo click chemistry. The reaction kinetics of the tetrazine ligation using the synthesised polymers and the accessibility of the Tz groups on the polymeric nanoparticles were evaluated using UV–Vis and fluorescence correlation spectroscopy (FCS), and second-order rate constants were determined by stopped-flow spectrophotometry ensuring quantitative conversions in seconds at sub-millimolar concentrations (10–30 s).
ISSN:1759-9954
1759-9962
DOI:10.1039/D0PY00375A