Positron emission tomography imaging using radiolabeled inorganic nanomaterials

Abstract

CONSPECTUS: Positron emission tomography (PET) is a radionuclide imaging technology that plays an important role in preclinical and clinical research. With administration of a small amount of radiotracer, PET imaging can provide a noninvasive, highly sensitive, and quantitative readout of its organ/tissue targeting efficiency and pharmacokinetics. Various radiotracers have been designed to target specific molecular events. Compared with antibodies, proteins, peptides, and other biologically relevant molecules, nanoparticles represent a new frontier in molecular imaging probe design, enabling the attachment of different imaging modalities, targeting ligands, and therapeutic payloads in a single vector. We introduce the radiolabeled nanoparticle platforms that we and others have developed. Due to the fundamental differences in the various nanoparticles and radioisotopes, most radiolabeling methods are designed case-by-case. We focus on some general rules about selecting appropriate isotopes for given types of nanoparticles, as well as adjusting the labeling strategies according to specific applications. We classified these radiolabeling methods into four categories: (1) complexation reaction of radiometal ions with chelators via coordination chemistry; (2) direct bombardment of nanoparticles via hadronic projectiles; (3) synthesis of nanoparticles using a mixture of radioactive and nonradioactive precursors; (4) chelator-free postsynthetic radiolabeling. Method 1 is generally applicable to different nanomaterials as long as the surface chemistry is well-designed. However, the addition of chelators brings concerns of possible changes to the physicochemical properties of nanomaterials and detachment of the radiometal. Methods 2 and 3 have improved radiochemical stability. The applications are, however, limited by the possible damage to the nanocomponent caused by the proton beams (method 2) and harsh synthetic conditions (method 3). Method 4 is still in its infancy. Although being fast and specific, only a few combinations of isotopes and nanoparticles have been explored. Since the applications of radiolabeled nanoparticles are based on the premise that the radioisotopes are stably attached to the nanomaterials, stability (colloidal and radiochemical) assessment of radiolabeled nanoparticles is also highlighted. Despite the fact that thousands of nanomaterials have been developed for clinical research, only very few have moved to humans. One major reason is the lack of understanding of the biological behavior of nanomaterials. We discuss specific examples of using PET imaging to monitor the in vivo fate of radiolabeled nanoparticles, emphasizing the importance of labeling strategies and caution in interpreting PET data. Design considerations for radiolabeled nanoplatforms for multimodal molecular imaging are also illustrated, with a focus on strategies to combine the strengths of different imaging modalities and to prolong the circulation time.

Figure 1

Schematic drawing of radiolabeled nanoparticles via (a) coordination of radiometal ions with chelators, (b) direct bombardment of nanoparticles with hadronic projectiles, (c) direct synthesis of nanoparticles with radioactive and nonradioactive precursors, and (d) postsynthetic radiolabeling without chelator.

Figure 2

(a) Scheme of phospholipid-PEG-NH₂ functionalized SWCNTs further labeled with DOTA for ⁶⁴Cu chelation. (b) Representative PET images of mice at 6 h postinjection of ⁶⁴Cu-labeled SWCNT-PEG₂₀₀₀, SWCNT-PEG₅₄₀₀, SWCNT-PEG₂₀₀₀-RGD, and SWCNT-PEG₅₄₀₀-RGD, respectively. White arrows indicate the U87MG tumor. Significant differences in the biodistribution and tumor targeting ability were found among the four samples. (c) Biodistribution data at 8 h postinjection of SWCNTs quantified by PET imaging and ex vivo Raman spectrometry. Reproduced with permission from ref . Copyright 2006 Macmillan Publishers Limited. (d) Representative PET imaging of pregnant mice at 0.5 h postinjection of CNTs. Dashed white circle indicates the uterus. (e,f) Ex vivo PET imaging (e) and quantification of the biodistribution (f) of CNTs in fetuses at 48 h postinjection of CNTs. Negligible difference in the fetal liver and placenta uptakes could be found. Reproduced with permission from ref . Copyright 2014 Elsevier Ltd.

Figure 3

(a) Design of self-illuminating ⁶⁴Cu-doped QDs. (b) A typical comparison of photon flux obtained from ⁶⁴Cu, mixture of ⁶⁴Cu and QDs, ⁶⁴Cu-doped QDs, and QDs under different emission filters. ⁶⁴Cu-doped QDs have an increased photon flux at the emission wavelength of the QDs (636 nm) than the mixture of ⁶⁴Cu and QDs, indicating a higher Cerenkov resonance energy transfer efficiency. (c, d) Representative whole-body coronal PET (c) and sagittal luminescence imaging (d) of U87MG tumor-bearing mice at 1, 17, 24, and 42 h postinjection of ⁶⁴Cu-doped QDs. White arrow, tumor area; black arrow, liver area. Reproduced with permission from ref . Copyright 2014 American Chemical Society.

Figure 4

(a) Schematic illustration of the multifunctional HSA-IONPs. (b) Representative in vivo NIR/PET/MRI images of tumor-bearing mice at 18 h postinjection. White arrow, tumor area. Reproduced with permission from ref . Copyright 2010 Elsevier Ltd. (c) Schematic illustration of a mesenchymal stem cell (MSC) labeled with MRI/NIRF/PET trimodality mesoporous silica nano-particles (MSNs). (d) PET imaging of orthotopic U87MG glioblastoma homing ability of HA-MSN-⁶⁴Cu and MSCs labeled with HA-MSN-⁶⁴Cu 24 h postinjection. The MSC platforms displayed a higher tumor uptake than particles without MSCs. Reproduced with permission from ref . Copyright 2013 Elsevier Ltd.