Radiolabeled inorganic nanoparticles for positron emission tomography imaging of cancer: an overview

Abstract

Over the last few years, a plethora of radiolabeled inorganic nanoparticles have been developed and evaluated for their potential use as probes in positron emission tomography (PET) imaging of a wide variety of cancers. Inorganic nanoparticles represent an emerging paradigm in molecular imaging probe design, allowing the incorporation of various imaging modalities, targeting ligands, and therapeutic payloads into a single vector. A major challenge in this endeavor is to develop disease-specific nanoparticles with facile and robust radiolabeling strategies. Also, the radiolabeled nanoparticles should demonstrate adequate in vitro and in vivo stability, enhanced sensitivity for detection of disease at an early stage, optimized in vivo pharmacokinetics for reduced non-specific organ uptake, and improved targeting for achieving high efficacy. Owing to these challenges and other technological and regulatory issues, only a single radiolabeled nanoparticle formulation, namely "C-dots" (Cornell dots), has found its way into clinical trials thus far. This review describes the available options for radiolabeling of nanoparticles and summarizes the recent developments in PET imaging of cancer in preclinical and clinical settings using radiolabeled nanoparticles as probes. The key considerations toward clinical translation of these novel PET imaging probes are discussed, which will be beneficial for advancement of the field.

Figure 1

Schematic representation of the production and nuclear decay of the radioisotopes commonly used for radiolabeling inorganic nanoparticles for PET imaging.

Figure 2

Schematic representation of the methods for radiolabeling inorganic nanoparticles by (A) coordination of radiometal ions with chelators, (B) direct bombardment of nanoparticles with hadronic projectiles, (C) direct synthesis of nanoparticles using radioactive and non-radioactive precursors, and (D) post-synthesis radiolabeling without using chelator.

Figure 3

Schematic representation of EPR mediated passive targeting and active targeting using radiolabeled inorganic nanoparticles. Nanoparticles can passively target tumors through preferential passage through larger interendothelial junctions compared to those of healthy tissues. Nanoparticles can also be conjugated with suitable targeting agents, such as antibodies which are specific to proteins (receptors) more highly expressed in tumors than healthy tissue, to actively target tumors. Adapted from Kunjachan et al.

Figure 4

Molecular imaging using radiolabeled quantum dots. A) Representative whole-body coronal PET images of U87MG tumor-bearing mice at 1, 17, and 24 h p.i. of ⁶⁴Cu-labeled quantum dots. White arrow indicates tumor area; black arrow indicates liver area. B) Representative whole-body luminescence images of U87MG tumor-bearing mice at 1, 17, and 24 h p.i. of ⁶⁴Cu-labeled quantum dots. White arrow indicates tumor area; black arrow indicates liver area. Adapted from Sun et al.

Figure 5

Molecular imaging using radiolabeled gold nanoclusters. A) Representative PET images of U87MG tumor-bearing mice at 1, 3, and 8 h p.i. of ⁶⁴Cu-doped gold nanoclusters. Tumor is indicated by white circle; B) representative self-illuminating near infrared images of U87MG tumor-bearing mice at 1, 3, and 8 h p.i. of ⁶⁴Cu-doped gold nanoclusters. Tumor is indicated by black circle. Adapted from Gao et al.

Figure 6

Molecular imaging using radiolabeled silica nanoparticle. Representative PET images of 4T1 tumor-bearing mice at 0.5, 2, 5, 16 h p.i. of (i) ⁶⁴Cu-labeled mesoporous silica nanoparticles conjugated with TRC105 (targeted), (ii) ⁶⁴Cu-labeled mesoporous silica nanoparticles (non-targeted), or (c) ⁶⁴Cu-labeled mesoporous silica nanoparticles conjugated with TRC105 with a blocking dose of TRC105 (blocking). Tumors were indicated by yellow arrowheads. Adapted from Chen et al.

Figure 7

Molecular imaging using radiolabeled iron oxide nanoparticles. A) Representative in vivo near infrared images of U87MG tumor-bearing mice at 1 h, 4 h and 18 h p.i. of ⁶⁴Cu-labeled iron oxide nanoparticles; B) representative in vivo PET images results of U87MG tumor-bearing mice at 1 h, 4 h and 18 h p.i. of ⁶⁴Cu-labeled iron oxide nanoparticles; C) representative MRI images of U87MG tumor-bearing mice acquired before and 18 h p.i. Adapted from Xie et al.

Figure 8

Molecular imaging using radiolabeled upconversion nanoparticles. The radiolabeled upconversion nanoparticles were injected in the rear left footpad and imaged in six different modalities at 1 h p.i. Accumulation of the nanoparticles in the first draining lymph node is indicated with yellow arrows. A) Traditional fluorescence; B) upconversion image; C) PET image; D) merged PET/CT image; E) chemiluminescence image; F) photoacoustic images before and after injection show endogenous photoacoustic blood signal compared to the contrast enhancement that allowed visualization of the previously undetected lymph node. Adapted from Rieffej et al.

Figure 9

Molecular imaging and photothermal ablation therapy using intrinsically radiolabeled ⁶⁴CuS nanoparticles. A) Representative 3D photoacoustic images of U87MG tumor pre- and post-injection of CuS nanoparticles; B) representative in vivo PET images results of U87MG tumor-bearing mice at 2, 4, 8, 20, and 24 h p.i. of ⁶⁴CuS nanoparticles; C) representative photos of U87MG tumor-bearing mice at different days after treatment. Adapted from Wang et al.

Figure 10

Molecular imaging using radiolabeled reduced graphene oxide nanosheets anchored with iron oxide nanoparticles. A) Representative in vivo PET images results of 4T1 tumor-bearing mice at 0.5 h, 3 h, 24 h and 48 h p.i. of ⁶⁴Cu-labeled nanoparticles; B) representative MR images acquired before (i) and after 3 h (ii) and 24 h (iii) intravenous injection of nanoparticles in 4T1 tumor-bearing mice; C) representative photoacoustic images of the tumor part in 4T1 tumor-bearing mouse with intravenous injection of nanoparticles. Adapted from Xu et al.

Figure 11

Clinical PET/CT imaging of nanoparticle biodistribution and tumor uptake after systemic administration of ¹²⁴I-cRGDY–PEG–C dots. A) Coronal CT in patient shows a hypodense left hepatic lobe metastasis (arrowhead); B) coronal PET image at 4 h p.i. shows radiolabeled nanoparticle activity along the peripheral aspect of the tumor (arrowhead), in addition to the bladder, gastrointestinal tract (stomach, intestines), gallbladder, and heart; C, D) co-registered PET/CT at 4 h (C) and 24 h (D) p.i. localizes activity to the tumor margin; E) corresponding ¹⁸F-FDG PET-CT image showing the hepatic metastasis in (A) (arrowhead). The color scale represents SUV values. Adapted from Phillips et al.

Figure 12

The size, shape and surface charge of radiolabeled inorganic nanoparticles dictate their biodistribution among different organs including the liver, lungs, spleen and kidneys, which is an important aspect toward their clinical translation. Adapted from Blanco et al.