Host-guest chemistry pretargeted positron emission tomography
Jallinoja, Vilma
0000-0001-5857-6684
:
2022-10-19
Abstract
In the past two decades, monoclonal antibodies have established their role as effective therapeutic agents for several disease types. This has amplified the interest of using them as diagnostic and therapeutic tools in nuclear medicine by forming directly radiolabeled analogues of them. Unfortunately, these agents have had limited success in human use. Due to the long biological half-life of antibodies, they are radiolabeled with radionuclides possessing long physical half-lives. The inherent slow target accumulation and off-target excretion of these agents often results in dose limiting toxicities in human use.
Pretargeting is an alternative approach for utilizing antibodies in nuclear medicine with the aim of decreasing the radiation dose to the healthy tissue. In pretargeting, a pre-administered antibody is radiolabeled with a small molecule (radioligand) in vivo via highly specific interaction. Excitingly, the earlier reported pretargeting platforms have demonstrated to result in reduced whole-body radiation doses compared to the conventional antibody nuclear medicine technique. However, these approaches rely on pretargeting agents with compromised in vivo stability or modularity which could hinder the clinical approval or use of these strategies.
The presented work investigates the use of high affinity host-guest complexation as the basis for the specific pretargeting interaction between the antibody and the radioligand. The methodology was studied with a cucurbit[7]uril host modified carcinoembryonic antigen targeting antibody and a series of 68Ga/64Cu-labeled ferrocene or adamantane guest radioligands. The pretargeting performance of the agents was examined in vivo with biodistribution and positron emission tomography studies in human pancreatic cancer mouse models. We hypothesized that due to the high in vivo stability, biocompatibility and modularity of the host-guest molecule pair, the proposed methodology provides an ideal strategy for performing pretargeted nuclear medicine.
The synthesis of the pretargeting agents was successful and in the in vivo experiments with the lead pretargeting host-guest pair candidates demonstrated that the pretargeting approach resulted in specific and high tumor target uptake. The presented work secures great potential for the platform and allow further investigation of the methodology for pretargeted radioimmunotherapy studies.