One-step flow synthesis and [Ga]Ga radiolabelling of metal phenolic network nanoparticles forPET tracking

Abstract

Metal-phenolic network (MPN) nanoparticles are growing in popularity as drug delivery vehicles due to their versatile binding interactions, with increased attention to their applications for positron emission tomography (PET) due to their inherent ability to coordinate radiometals. Whilst the ability to do this has only been shown with long-lived radionuclides such asZr andCu, the use of short-lived radionuclides remain unexplored due to the lengthy syntheses required. Fast incorporation of a radionuclide into a flow synthesis could alleviate this hurdle, producing a one-step, facile synthesis for PET imaging of these nanomaterials. Here we report the synthesis of MPN-based nanoparticles (67 ± 1 nm) using a flow mixing apparatus called a multi-inlet vortex mixer (MIVM). The particle structure consists of a [Ga]Ga-doped Fe()–tannic acid (TA) metal–phenolic network (MPN) core encapsulating the drug molecule rapamycin, with a polymer shell consisting of hyaluronic acid which has been modified with dopamine (HAd) (FRITH-MPNPs). A post-synthesis radiolabelling approach was implemented using [Ga]Gawith a high radiochemical yield (>68%), purity (>96%) and human serum stability (>97%), proving the ability to use these systems as PET imaging agents. To incorporate the radiolabel more stably within the core, a novel method is presented, directly incorporating the radiometal into the flow synthesis, creating a PET imaging guided drug delivery agent in a one-step process. [Ga]Ga-FRITH-MPNPs radiolabelledflow have an increased radiochemical yield (84%) compared with [Ga]Ga-FRITH-MPNPs radiolabelledthe post-synthesis radiolabelling approach (68%), as this provides access to binding sites in the core of the particle as well as decorating the surface. Furthermore, [Ga]Ga-FRITH-MPNPs radiolabelledflow maintain high radiochemical purity (97%) and serum stability (97%). These radiolabelled particles were characterised and compared to non-labelled FRITH-MPNPs using DLS, TEM, encapsulation efficiencyHPLC, ICP-MS, PXRD and zeta potential, which all show that radiolabelling does not significantly impact the structure.cytotoxicity of [Ga]Ga-FRITH-MPNPs on J774a.1 macrophages was negligible. PET imaging in a healthy mice showed high stability. Overall, this work shows that MPN-based nanoparticles called [Ga]Ga-FRITH-MPNPs can be effectively synthesised and simultaneously radiolabelled using a flow method, and imaged using PET/CT for future applications in immune system targeting. Metal-phenolic network nanoparticles are growing in popularity as drug delivery vehicles. One-step flow synthesis facilitates the incorporation of short-lived radionuclides, for PET imaging of these nanomaterials. toc