Enzyme-Mediated In Situ Self-Assembly Promotes In Vivo Bioorthogonal Reaction for Pretargeted Multimodality Imaging

Angew Chem Int Ed Engl. 2021 Aug 9;60(33):18082-18093. doi: 10.1002/anie.202103307. Epub 2021 Jul 2.

Abstract

Pretargeted imaging has emerged as a promising approach to advance nuclear imaging of malignant tumors. Herein, we combine the enzyme-mediated fluorogenic reaction and in situ self-assembly with the inverse electron demand Diels-Alder (IEDDA) reaction to develop an activatable pretargeted strategy for multimodality imaging. The trans-cyclooctene (TCO) bearing small-molecule probe, P-FFGd-TCO, can be activated by alkaline phosphatase and in situ self-assembles into nanoaggregates (FMNPs-TCO) retained on the membranes, permitting to (1) amplify near-infrared (NIR) fluorescence (FL) and magnetic resonance imaging (MRI) signals, and (2) enrich TCOs to promote IEDDA ligation. The Gallium-68 (68 Ga) labeled tetrazine can readily conjugate the tumor-retained FMNPs-TCO to enhance radioactivity uptake in tumors. Strong NIR FL, MRI, and positron emission tomography (PET) signals are concomitantly achieved, allowing for pretargeted multimodality imaging of ALP activity in HeLa tumor-bearing mice.

Keywords: bioorthogonal reactions; in vivo imaging; mulitmodality; pretargeting; self-assembly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaline Phosphatase / chemistry
  • Alkaline Phosphatase / metabolism*
  • Animals
  • Cyclooctanes / chemistry
  • Cyclooctanes / metabolism*
  • Gallium Radioisotopes / chemistry
  • Gallium Radioisotopes / metabolism*
  • HeLa Cells
  • Humans
  • Mice
  • Molecular Structure
  • Multimodal Imaging*
  • Nanoparticles / chemistry
  • Neoplasms, Experimental / diagnostic imaging
  • Particle Size
  • Positron-Emission Tomography
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / metabolism*

Substances

  • Cyclooctanes
  • Gallium Radioisotopes
  • Small Molecule Libraries
  • Gallium-68
  • Alkaline Phosphatase