Nuclear molecular imaging with nanoparticles: radiochemistry, applications and translation

Abstract

Molecular imaging provides considerable insight into biological processes for greater understanding of health and disease. Numerous advances in medical physics, chemistry and biology have driven the growth of this field in the past two decades. With exquisite sensitivity, depth of detection and potential for theranostics, radioactive imaging approaches have played a major role in the emergence of molecular imaging. At the same time, developments in materials science, characterization and synthesis have led to explosive progress in the nanoparticle (NP) sciences. NPs are generally defined as particles with a diameter in the nanometre size range. Unique physical, chemical and biological properties arise at this scale, stimulating interest for applications as diverse as energy production and storage, chemical catalysis and electronics. In biomedicine, NPs have generated perhaps the greatest attention. These materials directly interface with life at the subcellular scale of nucleic acids, membranes and proteins. In this review, we will detail the advances made in combining radioactive imaging and NPs. First, we provide an overview of the NP platforms and their properties. This is followed by a look at methods for radiolabelling NPs with gamma-emitting radionuclides for use in single photon emission CT and planar scintigraphy. Next, utilization of positron-emitting radionuclides for positron emission tomography is considered. Finally, recent advances for multimodal nuclear imaging with NPs and efforts for clinical translation and ongoing trials are discussed.

Figure 1.

Nanoparticle (NP) radiolabelling strategies: a variety of NP labelling approaches have been applied for imaging applications, as demonstrated using the lipid bilayer of liposomal NPs and quantum dot. (a) Radiometal chelation to the particle surface, using pre-formed particles. (b) Direct association of the radioisotope with the NPs surface (inset shows phosphate heads of surrounding lipids associating with a zirconium ion). (c) Entrapment of radioisotope or radiotracers within the core of a NPs. (d) Radioisotope may also be directly incorporated into particles during its formulation, such as ¹⁰⁹Cd into a CdSe/ZnSe QD. DPPC, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine.

Figure 2.

Radiometal complexes for single photon emission CT and positron emission tomography imaging of nanoparticles (NPs). Chemical structures of ligands used for radiolabelling using metal isotopes. These ligands have been used to chelate radioisotopes to be covalently conjugated to the NP surface, or to encapsulate activity within particles. BAT, 6-[p-(bromoacetamido)benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid; CHX-DTPA, N-(2-amino-3-(4-isothiocyanatophenyl)propyl)cyclohexane-1,2-diamine-N,N′,N′,N″,N″-pentaacetic acid; DCPA, dipicolylamine alendronate; DFO, desferrioxamine; DO₃A, 1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane; DOTA, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; DTCBP₂, pentasodium mono(3-hydroxy-3,3-diphosphonato-propyl(methyl)dithiocarbamate; HMPAO, hexamethylpropyleneamine oxime; HYNIC, 6-hydrozinonicotinamide; NOTA, 1,4,7-triazacyclononane-N,N′,N″-triacetic acid; TETA, 1,4,8,11-tetraazacyclotetradecane-1,4,8, 11-tetraacetic acid.

Figure 3.

Fluorine-18 (¹⁸F) and halogenation prosthetic groups: (a) ¹⁸F is the most widely utilized positron emission tomography radioisotope and has been applied to several nanoparticle (NP) formulations. Si-FASH, 4-(di-tert-butyl[¹⁸F]fluorosilyl)benzenethiol. (b) Radioiodination and bromination can be readily accomplished for gamma emitting (¹²³I, ¹²⁵I) and positron emitting (¹²⁴I, ⁷⁶Br) radiosotopes.

Figure 4.

Whole-body positron emission tomography (PET)-CT imaging of ¹²⁴I-cRGDY–polyethylene glycol–Cornell dots. Intravenous injection of ¹²⁴I-cRGDY-PET-C-dots followed by repeat imaging in a Phase I safety and feasibility study (ClinicalTrials.gov identifier NCT01266096). Representative whole-body image of (a) CT, (b) PET at 4 h and (c) PET/CT at 4 h and (d) at 24 h. (e) Corresponding fluorine-18 fludeoxyglucose PET/CT image of hepatic metastasis in (a); (arrow). Colour and grey scales reflect PET standardized uptake value. Reproduced from Phillips et al with permission from American Association for the Advancement of Science.