Furin-Guided Intracellular ⁶⁸Ga Nanoparticle Formation Enhancing Tumor MicroPET Imaging

Abstract

Positron-emission tomography (PET) is routinely used in the clinic for tumor imaging with ultrahigh sensitivity, but tumor-targeted PET imaging probes are quite few. In this work, we rationally designed a furin-responsive radiotracer Acetyl-Arg-Val-Arg-Arg-Cys­(StBu)-Lys­(DOTA-68Ga)-CBT (CBT- 68 Ga) and demonstrated that coinjection of the radiotracer with its cold analogue CBT-Ga instructed the formation of 68Ga nanoparticles in furin-overexpressing MDA-MB-468 cancer cells, which significantly enhanced microPET imaging of the tumor in vivo. In vitro results showed that CBT-Ga subjected to furin-initiated CBT-Cys condensation reaction and self-assembly to form the nanoparticles CBT-Ga-NPs with an average diameter of 258.3 nm. In vivo microPET imaging results indicate that the mice coinjected with CBT- 68 Ga and CBT-Ga, which warrants 68Ga nanoparticle formation in their MDA-MB-468 tumors, had a tumor/liver ratio 9.1-fold of that of the mice only injected with CBT- 68 Ga. We envisioned that, by replacing the RVRR substrate of CBT- 68 Ga with other enzyme-specific ones and using the strategy of intracellular nanoparticle formation, a series of radioactive probes could be developed for more sensitive and precise tumor microPET imaging in the near future.

Nanoparticle‐Based Activatable Probes for Bioimaging

“…[75] In one study, furin cleavage of a precursor peptide induces self-assembly to form intracellular NPs to enhance tumor microPET imaging, achieving a tumor/liver ratio of 9.1-fold compared with the control. [42] In another study, furinmediated self-assembled NPs not only have a 6.5-fold olsalazine CEST signal but also increase the antitumor therapeutic effect by 5.2-fold compared to olsalazine without furin responsiveness, which showed an excellent "theranostic correlation" (R 2 = 0.97) between the imaging signal and therapeutic response (normalized tumor size). [43]…”

Engineering Intelligent Nanosystems for Enhanced Medical Imaging

“…Furthermore, furinmediated self-assembly has been reported for other modalities as well. [72,73] Size increase in response to caspase may serve to monitor levels of apoptosis in tumor tissue. [66,74] An et al designed a fluorescent peptide probe that self-assembles into fibrous superstructures (5.8 AE 0.6 nm in diameter) upon enzymatic cleavage by active caspase-3/7, leading to an enhanced accumulation in tumor regions ( Figure 2B).…”

Biomaterials based on noncovalent interactions of small molecules

“…1) ). This efficient and biocompatible condensation has received extensively exploration in the field of molecular imaging (Wang et al, 2019[ 78 ]) and cancer therapy (Yuan et al, 2015[ 109 ]).…”

“…The tunability and biocompatibility of EISA allow aberrant levels of enzymes to catalyze the accumulation of imaging agents in situ to obtain accurate and precise imaging. Pioneered by Liang et al (2010[ 58 ]), furin-guided CBT condensation initiates self-assembly process to form nanoparticles with dense imaging agents, facilitating MicroPET imaging (Wang et al, 2019[ 78 ]; Liu et al, 2015[ 62 ]), fluorescence (Li et al, 2019[ 55 ]), and phosphorescence imaging (Li et al, 2018[ 51 ]) in different cases. As reported by Liang et al, ALP-instructed self-assembly generates nanofibers for enhanced CT (Zheng et al, 2016[ 119 ]) and MRI (Dong et al, 2017[ 14 ]).…”