Recent Development of Radiolabeled Nanoparticles for PET Imaging

Figure 2:  (A) A431-bearing nude mice, injected with 89Zr-Df-Bz-NCS-cetuximab (Left), orAuNPs-PPAA-cetuximab-89Zr (Middle) (two tumors per mouse), or AuNPs-PPAA-cetuximab-89Zr 2 h after a blocking dose of unlabeled cetuximabouse (Right) (one tumor per mouse). Coronal (upper) and transaxial (lower) PET images were obtained 48 h after injection. Liver was shown as red arrows and tumors(bilateral) were indicated as green arrows. The bladder is indicated with 'B' and the spleen with 'S'. (B) Tumor uptake and tumor-to-background ratio of 89Zr-Df-Bz-NCS-cetuximab or AuNPs-PPAA-cetuximab-89Zr in A431-bearing nude mice at 6, 24, 48, 72, 96 and 168 h after injection. Reprinted with the permission of the Contrast Media &Molecular Imaging, Karmani et al., 2013.

Metal oxide nanoparticles

Metal oxide nanoparticles have been widely applied in the construction of PET imaging probes. For instance, Perez–Campana and co–workers reported the activation of ¹⁸O–enriched aluminumoxide (Al₂O₃) NPs by irradiation with protons to yield ¹⁸F–labeled NPs via the ¹⁸O(p,n)¹⁸F nuclear reaction [30]. Biodistribution studies were performed in male rats using PET. The ¹⁸F–labeled NPs allowed the determination of the biodistribution pattern in rodents up to 8 h after iv injection. A plateau was reached in the uptake of NPs in most of the organs within 1 h after administration. In addition, another strategy was recently presented from the same group to activate aluminum oxide (Al₂O₃) NPs by direct irradiation with protons via the ¹⁶O(p,α)13N nuclear reaction [31]. PET–CT imaging was utilized for biodistribution assay in male rats after iv administration of the probe. The accumulation of 13N labeled NPs with different size in different organs was measured during the first 68 min after administration. The results showed that the uptake of NPs in the brain was very low irrespective of particle size. Relatively low accumulation of NPs (<2%) was observed in the lung for smaller NPs as compared to NPs with larger sizes. A high proportion of the NPs accumulated rapidly in the liver. More small NPs were trapped in the kidneys compared with larger NPs.

Radio labeled iron oxide is another major class of nanoparticle for PET imaging. The iron oxide NPs (IONPs) are typically classified by their sizes as standard superparamagnetic iron oxide (SSPIO) at 60-150 nm, ultra–small super paramagnetic iron oxide (USPIO) of approximately 5-40 nm, and mono crystalline iron oxide (MION)- a subset of USPIO ranging from 10 to 30 nm [7,32]. Among these IONPs, the SPIONPs have unique properties such as biocompatibility and intrinsic ability to facilitate surface modification, making them attractive as multifunctional imaging agents. Recent applications of radiolabeled iron oxide nanoparticles for PET imaging and multimodality imaging have been previously summarized in comprehensive reviews [33,34].

Micelles

Micelles are self–assembled colloidal nanoparticles with a hydrophobic core and hydrophilic shell [35]. They can passively accumulate in the areas with leaky vasculature such as tumors, inflammation, and infarction. Recently, polymer micelles are gaining an increasing attention for PET imaging due to their high stability and good biocompatibility. A special group of polymeric micelles can be synthesized by the conjugation of water–soluble copolymers with lipids (such as polyethylene glycol–phosphatidyl ethanolamine, PEG–PE). For example, Xiao et al. reported a multifunctional micelle made up with a hyperbranched amphiphilic block copolymer [36]. The unimolecular micelles were conjugated with cRGD peptide (for integrin α_vβ₃ target), NOTA (a macrocyclicchelator for ⁶⁴Cu–labeling), and doxorubicin (DOX; for cancer therapy). In vitro study showed a much higher cellular uptake of cRGD–conjugated micelles in U87MG human glioblastoma cells due to integrin α_vβ₃–mediated endocytosis than non–targeted micelles, thereby leading to a significantly higher cytotoxicity. In vivo PET imaging demonstrated a higher tumor accumulation of ⁶⁴Cu–micelle–DOX–cRGD than non–targeted control (⁶⁴Cu–micelle–DOX). Injection with a blocking dose of cRGD peptide along with ⁶⁴Cu–micelle–DOX–cRGD significantly reduced tumor uptake, indicating integrin α_vβ₃–specific binding of ⁶⁴Cu–micelle–DOX–cRGD.

Dendrimers

Dendrimers are a novel class of artificial macromolecules with a well–defined topological structure [37]. Dendrimers are usually constructed by three major components from the interior to the surface: a central core with two or more reactive groups; repeated units covalently attached to the central core and organized in a series of radially homocentric layers as called ''generations''; peripheral functional groups on the surface which predominantly determine the physicochemical properties of a dendrimer. Based on the molecular "hooks" attached to the surface, dendrimers can be actively targeted to cancer cells, tumor tissues, and abnormal vessels. Additionally the nanosized dendrimers can passively accumulate in tumor tissues via the EPR effect [38]. Dendrimers can be constructed in various sizes, molecular weights, and chemical compositions. Due to the high loading capacity and the flexibility of controlling the polymer structure, dendrimers are favorable scaffolds or vehicles for the construction of imaging probes [39–45]. However, few studies about positron emitting radionuclides labeled dendrimers have been reported to date [46,47]. Recently, the Shi group has reported gadolium–loaded dendrimer–entrapped GNPs (Gd–Au DENPs) for dual mode computed tomography (CT)/magnetic resonance (MR) imaging applications. They successfully modified amineterminated generation five poly(amidoamine) dendrimers(G5. NH2) with gadolinium (Gd) chelator and polyethylene glycol (PEG) monomethyl ether. The multifunctional Gd–Au DENPs were formed by sequential chelation of Gd(III) and acetylation of the remaining dendrimer terminal amine groups [48]. Because the DOTA chelatorin the dendrimers can be readily labeled by positron emitting nuclides, such as ⁶⁴Cu, the newly developed dendrimers could afford a potential platform for PET application.

Radiolabeled nanoparticles for tumor imaging

Cancer imaging is one of major applications of radiolabeled nanoparticles in medical research. As described in the above sections, various radiolabled nanoparticles have been extensively studied for tumor imaging. Rather than focusing on the various types of nanoparticles, this section concentrates on the utilization of radiolabeled nanoparticles for imaging specific tumor biology, such as tumor angiogenesis.

In general, there are two major strategies for accumulating radiolabeled NPs in the tumor tissue. The first one is known as "passive targeting" (or spontaneous accumulation) based on the EPR effect. The second approach is called as "active targeting", meaning that NPs could target specific cancer cells or tissues by attaching with targetspecific molecules. Over the past decade, numerous PET probes have been extensively explored for targeting specific biological processes in cancer biology [6]. For example, angiogenesis is a major biological process in tumor growth and metastatic spread. The characterization of angiogenesis is the formation of new capillaries by cellular outgrowth from existing microvessels [49]. Integrin α_vβ₃, upregulated at the sites of angiogenesis, has been proven to be a vital biomarker for cancer imaging. Linear as well as cyclic RGD peptides have been identified as integrinα_vβ₃–specifice ligands with high binding affinity and selectivity. Liu's group labeled RGD peptide–conjugated SWNTs with ⁶⁴Cu via a DOTA chelator [50]. In vivo PET imaging of U87MG tumor xenografts showed the specific binding of ⁶⁴Cu–DOTA–PEGRGD–SWNTs to integrin α_vβ₃ overexpressed U87MG tumors.

Platelet–derived growth factor receptor (PDGFR) and nonreceptor membrane–associated tyrosine kinases [i.e., Src family kinases (SFKs)] have been identified as attractive candidates for targeted tumor imaging and therapeutic intervention. It is known that Dasatinib is a new generation of ATP–competitive inhibitor for PDGFR and SFKs. Benezra and co–workers reported a novel fluorinated dasatinib derivative (F–SKI249380) conjugated with nanocarriers for microPET imaging in a platelet–derived growth factor B (PDGFB)-driven genetically engineered mouse model (GEMM) [51]. PDGFR receptor status and tumor–specific targeting were non–invasively evaluated using ¹⁸F–SKI249380, and ¹⁸F–SKI249380-containing micellar and liposomal nanoformulations. As shown in Figure 3, the tumor uptake of ¹⁸F–SKI249380–containing micelle formulations was significantly higher than that of ¹⁸F–SKI249380.

Figure 3: (A) Representative axial microPET images at 1 h pi, demonstrating uptake of unencapsulated ¹⁸F-SKI249380 and micelle or liposome-formulated ¹⁸F-SKI249380 in tumor-bearing brains (arrows) as against non-tumor-bearing (control) brain (arrowhead). (B) Graphical summary of tumor uptake values(%ID/g) for treatment and control groups. (C) Representative sagittal microPET brain images from control and tumor-bearing (arrows) animals iv injected with ¹⁸F-SKI249380, before and after blocking with pharmacologic doses of dasatinib. Corresponding 1-hr time-activity curves are shown. Reprinted with the permission of the Neoplasia, Benezra et al., 2012.

Figure 3:  (A) Representative axial microPET images at 1 h pi, demonstrating uptake of unencapsulated 18F-SKI249380 and micelle or liposome-formulated 18F-SKI249380 in tumor-bearing brains (arrows) as against non-tumor-bearing (control) brain (arrowhead). (B) Graphical summary of tumor uptake values(%ID/g) for treatment and control groups. (C) Representative sagittal microPET brain images from control and tumor-bearing (arrows) animals iv injected with 18F-SKI249380, before and after blocking with pharmacologic doses of dasatinib. Corresponding 1-hr time-activity curves are shown. Reprinted with the permission of the Neoplasia, Benezra et al., 2012.

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The development of radio labeled NPs for dual–modality or multimodality tumor imaging, such as PET/fluorescence, PET/MRI, PET/MRI/optical imaging has gained increasing interest in recent years. Each imaging modality has its own advantages and limitations [7]. For instance, radionuclide–based imaging techniques, such as PET, are highly sensitive and quantitative but they have relatively poor spatial resolution; MRI provides high spatial resolution images with exquisite soft tissue contrast yet it suffers from low sensitivity; optical imaging can sensitively and sequentially interrogate cellular and molecular functions in living subjects, however, the energies in the visible to near–infrared region of the spectrum are limited to penetrate the depth of mammalian tissues. Therefore, combinations of imaging techniques, as so–called "multimodality imaging", are being designed to take advantage the strengths of modalities while minimizing its limitations, which as a result may simultaneously provide comprehensive biological information. In one study, integrin α_vβ₃ targeted IO NPs were developed for dual PET and MR tumorimaging [52]. RGD peptides were conjugated on the surface of IO NPs where the DOTA chelators were incorporated for ⁶⁴Cu labeling. PET/ MR imaging was carried out by using ⁶⁴Cu–DOTA–IO–c(RGDyK) NPs to monitor integrin α_vβ₃ expression levels in U87MG tumor bearing mice. Tumor uptakes of ⁶⁴Cu–DOTA–IO–c(RGDyK) NPs at 1 h, 4 h, and 21 h pi were much higher than those of ⁶⁴Cu–DOTAIO NPs without the conjugation of RGD peptide. Pre–injection of a RGD peptide - [c(RGDyK)] significantly reduced the radioactivity uptake in tumors, suggesting the targeting specificity of ⁶⁴Cu–DOTAIO– c(RGDyK) NPs. The T2–weighted MRI also showed integrin specific delivery of DOTA–IO–c(RGDyK) NPs, which was consistent with PET data. In another example, Cai et al. developed a quantum dot (QD)–based probe for dual–function near infrared fluorescence (NIRF) and PET imaging [53]. The QDs with an amine surface were modified with RGD peptides for integrin α_vβ₃ targeting, and DOTA chelator for ⁶⁴Cu labeling. In cell–based binding assay, the DOTA- RGD-QDs exhibited α_vβ₃ integrin specific binding in U87MG humanglioblastoma cells. For in vivo study, the U87MG tumor uptake of ⁶⁴Cu–labeled DOTA-RGD-QDs was significantly higher than that of ⁶⁴Cu–labeled DOTA-QD. Excellent linear correlation was obtained between the results measured by PET imaging and those measured by NIRF imaging as shown in Figure 4. Histological examination further confirmed that the majority of DOTA-RGD-QDs target the tumor vasculature through an RGD-α_vβ₃ integrin interaction.

Figure 4: (A) Schematic illustration of dual-function PET/NIRF probe DOTA-QD-RGD. PEG = polyethylene glycol. (B) Whole-body coronal PET images of mice at 1, 5, 18, and 25 h after injection of 7-14 MBq of ⁶⁴Cu-labeled DOTA-QD or DOTA-QD-RGD. Arrowheads indicate tumors. Images shown are for slices that were 1 mm thick. GI = gastrointestinal tract; L = liver. (C) Left: PET image of harvested tissues at 5 h after injection of ⁶⁴Cu-labeled DOTA-QD-RGD. Right: NIRF image of harvested tissues at 5 h after injection of ⁶⁴Cu-labeled DOTA-QD or DOTA-QD-RGD. Reprinted with the permission of the Journal of Nuclear Medicine, Cai et al., 2007.

Figure 4:  (A) Schematic illustration of dual-function PET/NIRF probe DOTA-QD-RGD. PEG = polyethylene glycol. (B) Whole-body coronal PET images of mice at 1, 5, 18, and 25 h after injection of 7-14 MBq of 64Cu-labeled DOTA-QD or DOTA-QD-RGD. Arrowheads indicate tumors. Images shown are for slices that were 1 mm thick. GI = gastrointestinal tract; L = liver. (C) Left: PET image of harvested tissues at 5 h after injection of 64Cu-labeled DOTA-QD-RGD. Right: NIRF image of harvested tissues at 5 h after injection of 64Cu-labeled DOTA-QD or DOTA-QD-RGD. Reprinted with the permission of the Journal of Nuclear Medicine, Cai et al., 2007.

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In a recent study, Xie and colleagues applied triple functional iron oxide nanoparticles for in vivo PET/NIRF/MRI study [54]. Human serum albumin (HSA)–coated iron oxide nanoparticles (HSAIONPs) were dually labeled with ⁶⁴Cu–DOTA and Cy5.5, and tested in a subcutaneous U87MG xenograft mouse model. PET/NIRF/MR tri–modality imaging, ex vivo study, and histological examinations demonstrated that the constructed nanosystem was suitable for dual encapsulation of IONPs and drug molecules. The HSA–IONPs labeled with ⁶⁴Cu and Cy5.5 manifested a prolonged circulation half–life and massive accumulation in lesions (Figure 5). With a high spatial resolution, MRI offers a better description of the particle distribution pattern than either PET or NIRF. In another hand, PET provides a better signal–to–noise ratio while NIRF can be visualized both ^{in vivo} by an IVIS system and ex vivo by fluorescence microscopy, playing a unique role of bridging the in vivo and histological observations. By combining the information gathered from all the aspects, it is clear that the HSA–IONPs have not only a high retention rate, but also a good extravasation rate and a low macrophage uptake rate at the tumor area.

Figure 5: (A) Schematic illustration of the multi-functional HSA-IONPs. (B) Representative in vivo NIRF images of mouse injected with HSA-IONPs. Images were acquired 1 h, 4 h and 18 h post injection. (C) In vivo PET imaging results of mouse injected with HSA-IONPs. Images were acquired at 1 h, 4 h, and 18 h post injection. (D) MRI images acquired before the injection and at 18 h post injection. Reprinted with the permission of the Biomaterials, Xie et al., 2010.

Figure 5:  (A) Schematic illustration of the multi-functional HSA-IONPs. (B) Representative in vivo NIRF images of mouse injected with HSA-IONPs. Images were acquired 1 h, 4 h and 18 h post injection. (C) In vivo PET imaging results of mouse injected with HSA-IONPs. Images were acquired at 1 h, 4 h, and 18 h post injection. (D) MRI images acquired before the injection and at 18 h post injection. Reprinted with the permission of the Biomaterials, Xie et al., 2010.	

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Radiolabeled nanoparticles for cardiovascular imaging

Cardiovascular diseases include, but are not limited to, arteriosclerosis (general hardening of arteries); atherosclerosis (plaque–associated arterial hardening); thrombotic blockage stenosis and ischemia in coronary, carotid, renal and other peripheral arteries; aneurysms; venous blood clots and varicose veins; dysregulation of hemostasis (e.g., platelets and von Wille brand factor) [55]. Among these diseases, atherosclerosis is one of the most prevalent vascular disease models in which nanomedicine approaches have been studied.

Atherosclerosis, a chronic inflammatory disease of the arterial wall, is the major cause of morbidity and mortality from cardiovascular disease. Macrophages play a central role in the atherogenic process as modulators of lipid metabolism and immune responses [56,57]. Macrophages can enter initial atherosclerotic lesions, ingest modified lipoprotein particles, and convert to foam cells at the early stage of atheroma. The accumulation of foam cells results in the formation of fatty streaks and the deposition of fibrous tissues, indicating the progression of atheroma into an intermediate stage [58]. Nahrendorf et al. developed a dextranated 20–nm nanoparticle labeled with ⁶⁴Cu to yield a PET, MR, and optically detectable imaging agent [59]. The radioactivity peak from PET at 24 hr after iv injection into mice deficient in apolipoprotein E with experimental atherosclerosis mapped to areas of high plaque load identified by CT, such as the aortic root and arch, and correlated with MR and optical imaging. The uptake of ⁶⁴Cu–labeled NPs was further confirmed by the ex vivo fluorescence reflectance imaging and autoradiography conducted on excised aortas.

Angiogenesis, new blood vessel formation, is a characteristic event in ischemic lesions. The overexpression of integrin α_vβ₃ on endothelial cells has been proven in the ischemic tissue. Almutairiet al. reported the efficacy of biodegradable dendritic structures whose surface was modified with a cyclic arginine–glycine–aspartic acid (cyclic RGD) peptide and encapsulating radioactive Bromine (₇₆Br) for PET imaging of hindlimb ischemia in a mouse model [47]. Eight tyrosine residues near the center of the macromolecular structure were functionalized for labeling with ⁷⁶Br. The hetero bifunctional polyethylene oxide (PEO) chains provided extended blood circulation, and cyclic RGD motifs installed at the terminal ends of the PEO chains enhanced the direct binding to α_vβ₃ integrin receptors. The targeted nanoprobes (IC₅₀ = 0.18 nM) exhibited a 50–fold enhancement binding affinity to integrin α_vβ₃ over the monovalent RGD peptide alone (IC₅₀ = 10.40 nM). The cell–based assay using integrin α_vβ₃–positive cells showed a 6–fold increase in α_vβ₃ receptor-mediated endocytosis for the 125I–labeled dendritic nanoprobes as compared to the nontargeted nanoprobe. As shown in Figure 6, in vivo studies of 76Br–labeled dendritic nanoprobes in a murine hindlimb ischemia model revealed highly specific accumulation of the nanoprobesin integrin α_vβ₃ overexpressed ischemic muscles.

Figure 6: (A) Schematic illustration of ⁷⁶Br-arginine-glycine-aspartic dendritic nanoprobes for targeting integrin α_vβ₃. (B) Uptake of the ⁷⁶Br-labeled integrin α_vβ₃- targeted dendritic nanoprobes was higher in ischemic hindlimb (left side of image) than control hindlimb (right side of image).Reprinted with the permission of the Proceedings of the National Academy of Sciences of the United States of America, Almutairi et al., 2009.

Figure 6:  (A) Schematic illustration of 76Br-arginine-glycine-aspartic dendritic nanoprobes for targeting integrin αvβ3. (B) Uptake of the 76Br-labeled integrin αvβ3- targeted dendritic nanoprobes was higher in ischemic hindlimb (left side of image) than control hindlimb (right side of image).Reprinted with the permission of the Proceedings of the National Academy of Sciences of the United States of America, Almutairi et al., 2009.	

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Conclusion and Perspectives

As a highly sensitive imaging tool, PET can assist in the translational application of nanomaterials for early stage disease detection, and monitoring of disease progression, regression, and recurrence. The good examples presented in this review demonstrated that the nanoplatforms with PET imaging could be very useful for diagnosis and treatment in cancer and cardiovascular diseases. Despite the fact that PET is highly sensitive and quantitative, it has relatively poor spatial resolution, which can be compensated by other imaging modalities, such as MRI. The beauty of nanoparticles over other materials is that they can be readily functionalized. The design of multifunctional nanoparticles could significantly improve already existing nanoparticle characteristics. Whereas monofunctional nanoparticles provide a single function, multifunctional nanoparticles can combine different functionalities in a single stable construct, which is well suitable for multimodality imaging.

Although radiolabeled NPs have shown great promise in PET imaging of diseases, several challenges need to be addressed to translate the radiolabeled NPs to clinical applications. One of the major challenges is to develop truly tissue–selective targeting NPs without the significant uptake in the mononuclear phagocytic system (MPS). To resolve this issue, the NPs can be designed with optimal surface modifications. In general, NPs coated with a hydrophilic polymer, such as PEG unit, can reduce the nanoparticle uptake in the MPS and increase circulation time as compared to the uncoated counterparts. In addition, the targeted nanocarriers functionalized with antibodies, peptides or other targeting ligands that recognize specific receptors or antigens have the potential to increase the targetto– background ratio. Considering the toxicity and immunogenicity, the biodegradable nanomaterials would be a better choice. In this regard, the organic nanomaterials are usually better than the inorganic nanoparticles. Furthermore, in vivo biodistribution of nanopariticles is largely dependent on the characteristics of nanoparticles, such as shape, charge, size, surface coating, and dosing [61]. Based on these factors, design considerations can be manipulated to prolong blood circulation, reduce the nonspecific distribution, and enhance imaging contrast. Moreover, in order to achieve optimal target–to–background contrast in PET, good in vivo stability of radiolabeled NPs is also required [8].

In conclusion, radiolabeled NPs have shown great promise in PET imaging. With the development of hybrid imaging technology, we expect that novel radiolabeled NPs with PET along with other imaging modalities will afford accurate and precise assessment of biological signatures in a real–time manner and thus improve disease management.

Acknowledgments

This work was supported by the research fund (#IRG–58–007–51) from the American Cancer Society, the Donald E. and Delia B. Baxter Foundation, USC Department of Radiology, and the Natural Science Foundation of China (Grant No. 81171368).

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Citation: Xing Y, Zhao J, Shi X, Conti PS, Chen K. Recent Development of Radiolabeled Nanoparticles for PET Imaging. Austin J Nanomed Nanotechnol. 2014;2(2): 1016. ISSN:2381-8956

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