Targeted PET/MRI Imaging Super Probes: A Critical Review of Opportunities and Challenges

REVIEW Targeted PET/MRI Imaging Super Probes: A Critical Review of Opportunities and Challenges Anna KastelikHryniewiecka 1,2 Pawel Jewula 3 Karolina Bakalorz 1 Gabriela Kramer-Marek 2,4 Nikodem Kuźnik 1 1 Silesian University of Technology, Faculty of Chemistry, Gliwice, Poland; 2 Radiopharmacy and Preclinical PET Imaging Unit, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice, Poland; 3 Central European Institute of Technology, Brno University of Technology, Brno, Czech Republic; 4 Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, UK Abstract: Recently, the demand for hybrid PET/MRI imaging techniques has increased significantly, which has sparked the investigation into new ways to simultaneously track multiple molecular targets and improve the localization and expression of biochemical markers. Multimodal imaging probes have recently emerged as powerful tools for improving the detection sensitivity and accuracy—both important factors in disease diagnosis and treatment; however, only a limited number of bimodal probes have been investigated in preclinical models. Herein, we briefly describe the strengths and limitations of PET and MRI modalities and highlight the need for the development of multimodal molecularly-targeted agents. We have tried to thoroughly summarize data on bimodal probes available on PubMed. Emphasis was placed on their design, safety profiles, pharmacokinetics, and clearance properties. The challenges in PET/MR probe development using a number of illustrative examples are also discussed, along with future research directions for these novel conjugates. Keywords: medical imaging, bioresponsive probes, targeting, contrast agents, relaxivity, clearance Introduction Efforts to improve the earlier diagnosis of cancer are multifaceted. Standard laboratory tests are beneficial due to their accessibility, relatively low costs, and specificity, but their routine use requires clear guidelines. 1 With the shift to noninvasive disease diagnosis and novel treatment regimens, molecular imaging has gathered remarkable momentum in practical applications over the past few decades and has played a profound role in monitoring disease progression and facilitating drug research. Imaging modalities allow for the non-invasive, real-time visualization and quantification of physiological and pathological processes at the cellular and molecular levels, allowing for the better management of cancer treatment. Currently, molecular imaging uses mainstream technologies such as X-ray computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and single-photon emission computed tomography (SPECT), as well as optical and ultrasound (US) imaging. These techniques require highlysensitive instruments and specific imaging probes that link the imaging signal with a molecular event. Each of these modalities has pros and cons. For example, CT is widely available, has a fast acquisition time and high spatial resolution, but Correspondence: Nikodem Kuźnik; Gabriela Kramer-Marek Tel +48 694 22 00 77; +44 208 722 4412 Fax +48 32 237 13 08; +44 207 370 5261 Email nik[email protected]; [email protected] International Journal of Nanomedicine 2021:16 8465–8483 8465 © 2021 Kastelik-Hryniewiecka et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www. dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). International Journal of Nanomedicine Dovepress open access to scientific and medical research Open Access Full Text Article Received: 27 August 2021 Accepted: 9 November 2021 Published: 1 January 2022 International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) due to its poor sensitivity (10 −2 – 10 −3 mol/L), it is sometimes combined with SPECT or PET to capture biochemical and physiological processes. 2 Moreover, CT is associated with high radiation exposure and provides relatively low-contrast images of soft tissues. MRI does not use ionizing radiation, 3 has a high spatial resolution (~100 µm), 4 and delivers information about soft tissues, but it also has a low sensitivity. In contrast, PET has an extremely high sensitivity (10 −11 – 10 −12 mol/L), limitless depth of penetration, and quantitative capabilities, but it lacks anatomical parameters to identify molecular events. 5 Tremendous improvements have recently been made in the development of imaging modalities (eg, PET/MRI systems) and image reconstruction algorithms, and also in the design of novel imaging agents. Among these are probes that can directly recognize and bind to the targets of interest, as well as probes that are conjugated in a multivalent fashion to the surface of nanoparticles. Some probes may leverage natural processes for uptake or retention, and some be activated by disease-related processes. Our experience in the design and characterization of MRI and PET contrast agents has prompted us to critically review some of the benefits and possible pitfalls of the recently reported bimodal probes. Herein, we discuss how we can use physicochemical properties to predict major in vivo effects such as the clearance route and undesired deposition in various systems and how to assess the dose required to achieve signal enhancement in the region of interest. Imaging Techniques Specificity of MRI and PET MRI is a tomography technique based on nuclear magnetic resonance (NMR). In some atoms (such as 1 H, 13 C, 31 P, or 19 F), nuclides (often miscalled as isotopes) 6 adopt different energy states in a high magnetic field. In medical practice, the field strength ranges from 1.5 to 3.0 T (B 0 ), which is a hundred thousand times stronger than that of the Earth. After the radiofrequency (RF) pulse is applied to excite the nuclei, the nuclear magnetic spins rapidly return to their original equilibrium energy levels in a process called relaxation (Figure 1). There are two types of relaxation— longitudinal and transverse—which are expressed by the time constants, T 1 and T 2 , respectively. Additionally, the intrinsic imperfections of the magnetic field lead to relaxation faster than T 2 recorded as T 2 *. 7 Fortunately, many biogenic substances contain MRI-active nuclides, where 1 H is the most common; therefore, MRI scanners are tuned to 1 H in water, which makes up 73% of the fat-free mass of human bodies, but also in fat, proteins, and sugars. The outlines of tissues, organs, and all abnormalities are revealed in the images due to the specific mobility of 1 H present in these organic molecules. MRI is a superior imaging modality for visualizing soft tissues like the gastric tract, cardiovascular system, and, most commonly, the brain and central nervous system. 8 Some MRI sequences can differentiate between water and fat, which is useful for the evaluation of adrenal tumors. Similar fat-suppression sequences (eg, CHESS, fat-sat) are used to enhance the contrast resolution and improve the visibility of lesions to determine their lipid contents and remove artifacts. Furthermore, MRI’s good temporal resolution allows the monitoring of dynamic changes, eg, angiography and functional MRI (fMRI), which can be used to track blood flow and brain activity as a function of signal change vs time. In PET imaging, the detected signal originates from the radioactive decay of neutron-deficient radionuclides (eg, 11 C, 15 O, 18 F, and 89 Zr). These specific atoms emit positrons from unstable nuclei. When traveling, the particles rapidly lose their kinetic energy by spreading around the tissue before finally being annihilated by a nearby electron. This process leads to the emission of two 511 keV photons emitted in almost opposite directions (180° apart, 9 (Figure 1)). Subsequently, scintillation detectors surrounding the patient convert the electrical signal into sinograms that are subsequently rebuilt into tomographic images. 5 The radiotracers (in this work interchangeably referred to as radioligands, radiopharmaceuticals, and for unification with MRI – contrast agents) used in PET consist of Figure 1 Graphical representation of the principle of the MRI and PET techniques. https://doi.org/10.2147/IJN.S336299 DovePress International Journal of Nanomedicine 2021:16 8466 Kastelik-Hryniewiecka et al Dovepress Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) a radioactive tag bound to an organic ligand (a targeting agent). The ligand of each radiotracer interacts with a target molecule, resulting in a characteristic distribution of the radiotracer throughout the body. From a chemical point of view, radioligands are identical to their nonradioactive equivalents, so they show the same in vivo behavior. In contrast to conventional modalities (eg, US, CT, MRI) PET provides a functional or metabolic assessment of normal tissues or pathological conditions because biochemical changes usually occur before anatomical and structural changes become evident in MRI or CT. 10,11 In the last 20 years, the idea of combining both MRI and PET into a single device that can simultaneously acquire both datasets has raised interest. The potential benefits of PET/MRI compared with PET/CT include an improved detection rate in selected cancers and an overall reduced radiation exposure, which may be particularly beneficial for pediatric patients. In line with this, several groups have focused on the development and characterization of PET/MRI bimodal contrast agents. 12–14 Probe Characteristics MRI Probes The diagnostic value of MRI is enhanced by the possibility of changing signals using contrast agents (CAs). At least 1/3 of all examinations using MRI in the US and Europe are performed by administering magnetically-active substances, which shortens the relaxation times. CAs such as paramagnetic ion complexes or superparamagnetic particles contain lanthanide elements such as gadolinium (Gd 3+ ) or the transition metal manganese (Mn 2+ ). Most paramagnetic contrast agents are positive agents that shorten the T 1 relaxation time, leading to increased signal intensity in T 1 -weighted images (the enhanced region appears brighter). On the contrary, superparamagnetic agents are negative CAs, which reduce the signal intensity in T 2 -weighted images (the enhanced region appears darker). Positive CAs are used to evaluate lesions and tumors because they increase the signal intensity in vessels and tissues, especially where there are perfusions or disruptions. Negative CAs highlight, eg, damages in capillary membranes and gastrointestinal bleedings; 15 however, in this case, the strong magnetization often causes undesired signal disappearance and blurring, known as susceptibility artifacts; therefore, positive contrast agents are generally favored. 16,17 MRI CAs affect the local magnetic field of water protons, leading to a specific acceleration in their relaxation, known as proton relaxation enhancement (PRE); 18 therefore, magnetic species are not directly recorded by the MRI scanner, but rather their consequent interactions with water molecules. Accordingly, understanding the relaxation mechanisms and specific influence of the magnetic species on water is crucial for designing and developing CAs. The relaxation mechanism of water protons accelerated by small-molecule paramagnetic complexes, which constitute the majority of the positive CAs, has been precisely described. 19–21 Two factors are directly related to the interaction of water molecules with CAs: the number of water molecules coordinated to the paramagnetic center q, and the rate of water exchange by the center, expressed as the residence lifetime of coordinated water T M . Two other specific features of the probe contribute to the relaxation mechanism, ie, tumbling, expressed as rotational correlation time T R , and the relaxation of the paramagnet’s electrons, T 1e (Figure 2). Indirect, weaker, more distant interactions have been identified and exploited during the design of CAs, but major efforts have been expended to control the tumbling of paramagnetic species. One of the most spectacular effects has been observed for interactions with protein molecules such as albumin. Tumbling can be limited by anchoring the Figure 2 Solvent molecules (H 2 O) and the Fe(III) and N-methylacetohydroxamate (NMA – ) complex, as well as the specific chemical interactions. The ORTEP view [source: Mercury program 3.10.1 (Build 168220).] of the [Fe(NMA) 3 ] crystal structure 22 was generated using atomic coordinates taken from the CSD database (structure code: CCDC 1538337). International Journal of Nanomedicine 2021:16 https://doi.org/10.2147/IJN.S336299 DovePress 8467 Dovepress Kastelik-Hryniewiecka et al Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) probe onto a large protein globule, leading to a much more efficient acceleration in the water relaxation. This effect greatly brightens the MRI images due to the interactions with macromolecules and is known as receptor-induced magnetization enhancement (RIME, (Figure 3)). Interestingly, the results of interactions are not yet mathematically described and have rather experimental nature. This is the major reason why the observed in vivo effects are not precisely designable yet; 7 however, this review, supported by large amounts of experimental data from the literature, aims to identify the main relationship between the chemical or physical factors of CAs and their visual effects in the imaging techniques. Nanoparticles (NPs), which belong to the negative CAs group, fall into a completely different field of relaxation theory, whose description is much more general, yet suffers from the identification of precise factors. Thus, the features contributing to their relaxation mechanism mainly include the following physical properties: size (often presented as a distribution), shape (mostly globular), and magnetic moment (in the range of superparamagnets). Although size is one of the most important parameters, its determination is often ambiguous. TEM images can visualize single-particles, while the hydrodynamic radius (reaching up to 140 nm) 23 can be used to reveal agglomeration in dispersions. Surface functionalization reduces the description of the mechanism back to the molecular level; therefore, NPs have also been well-studied for molecular imaging applications (Figure 4). 15 An interesting discussion of the complexity of the relaxation mechanism for gadolinium complexes anchored on NPs has been presented by Verwilst. 24 This is an essential approach for understanding the impact of both NPs, as the massive component—which are not limited to the function of a support—and the small molecules introduced on the surface of NPs. The magnetic properties of the probes encompass different factors, which are particularly complex in NPs. In practice, magnetic species accelerate both T 1 and T 2 relaxation times. If the T 1 effects are dominant or at least not overwhelmed by T 2 acceleration, then such a probe is a promising positive contrast agent. Such an assessment might be done using the r 2 /r 1 ratio. 25 When it falls into the range of 1–2, brightened images are observed and are not distorted by T 2 effects; however, a good negative contrast agent should express a ratio of at least 20. Due to the assumption of the universality of the contrast agents with respect to the strength of the magnetic field (B 0 ) and the predictability of the influence of B 0 on r 1 and r 2 , NMRD (nuclear magnetic relaxation dispersion) experimental studies have been performed. 26 Designing new probes with an appropriate r 2 /r 1 ratio should be one of the criteria, which should be validated using experimental data. In radiological practice, susceptibility to artifacts causes a high deviation in this range, particularly for positive contrast agents (Table 1). In a large series of MRI candidates, there are examples of such a well-thought-out design. Kellar proposed iron oxide NPs with an oxidized starch coating as a T 1 CA with r 2 /r 1 = 1.69 (0.47 T, 35 °C). 27 Another relaxometric measurement of Fe 2 O 3 in an aqueous dispersion did not exceed an r 2 /r 1 ratio of 2 in a low magnetic field, 28 but most low-diameter iron oxides have high r 2 /r 1 ratios. 29 An interesting approach was published by Gazeu, where gadolinium was chelated on carbon nanotubes, where the resulting r 2 /r 1 ratio was close to 1 and almost field-insensitive. 30 Carbon nanotubes are known for their strong effect on T 2 . 31 Another factor compared in MRI contrast agent studies is the relaxivity (Table 1). This value is relatively easy to determine in vitro. It is assumed that high relaxivity values will directly cause an explicit, clear image in the region of interest. Most often, it is expressed in units of mM −1 s −1 , which initially came from gadolinium complex Figure 3 RIME (receptor-induced magnetization enhancement) effect. Figure 4 Ideological presentation of an MRI/PET probe based on chelated radionuclides (metal complex for PET imaging) and superparamagnetic iron oxides (SPION for MRI contrast). https://doi.org/10.2147/IJN.S336299 DovePress International Journal of Nanomedicine 2021:16 8468 Kastelik-Hryniewiecka et al Dovepress Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) Table 1 Relaxivity of MRI Contrast Agents Entry r 1 r 1 r 2 r 2 B 0 t [ C] Paramagnet Content [%] Size [nm] Remark, Ref. mM −1 s −1 (mg/ mL) −1 s −1 mM −1 s −1 (mg/ mL) −1 s −1 [T] Discrete complexes GdDOTA-4AMP-F 7.4–3.9 10–19 1.4 37 14% (Mw) [40] Gd-NPep-Fl (MRI or PET probe) 21.2 16 1.4 37 12% (Mw) [41] [GdDO3A-SA–Ga(AAZTA)] − 3.7–10.1 9–24 0.47 25 13% (Mw) [42] Gd-PCTA-Lys(ZW800–1)- OAl 5.47 6 9.4 37 18% (Mw) 0.31 [43] Nanoparticles (NP) Commercial SPIONs Feridex ® 23.9 151.9 3 20 80–150 [36,44] Feraheme TM (ferumoxytol) 10 75 89 667 4.7; 3 37 41.21% Fe 17–35 nm [45,46] New hybrids MnMEIO 321.6 4400 1.5 75.25 Mn+Fe % 32 (hydro) [37] Jarrett2008-ADIO 14.46 129 72.55 659 1.4 37 50% 32.3 [47] Lee2008-PASP-IO 105.5 2134 3 20 72.3% (X-ray Fe 3 O 4 ) 45±10 [36] DOTA-mSPIO 209 0.47 20.3 (hydro) [48] EP-2104R 41 3 Gd 100000 Da protein [41] SPIO_cRGD 101.9 204 4.7 18 11.2%Fe 10 [49] CAN-Magh 0.2 2 72 601 V1.5 64.4% Fe 44– 55(hydro) [50] DIO/Cu 17.1 135.8 1.4 37 45.7 [51] NOTA–OA–IONP 157 4.7 66 [34] SPION@PAA 93.8 4.7 37 [35,52] PEM 265.0 261 3 5.5%Fe 140 [23] Fe3O4@Al(OH)3 3.7 49 121.9 279 3 7.92 49.8 [53] SDIO 18.1 36 95.8 194 1.4 37 11.34%Fe 62.4 [39] DIO 15.7 49 89.2 279 1.4 37 17.53%Fe 38.1 [39] AGuIX 10.3 13.4 1.4 12.42% (ICPMS) 2.5 (hydro) [54] NOTA-IO-Man 449.9 10.12 (hydro) [55] (Continued) International Journal of Nanomedicine 2021:16 https://doi.org/10.2147/IJN.S336299 DovePress 8469 Dovepress Kastelik-Hryniewiecka et al Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) characteristics by measuring their acceleration effect (T 1 or T 2 shortening – T 1/2 (obs)) with units of millimolar concentration ([Gd] - mM). There is also a diamagnetic factor derived from the natural relaxation rate of water T 1/2 (diam) – Equation 1. T1=2obsð Þ¼r1=2�Gd½ � þ T1=2diamð Þ (1) This way of expressing relaxivity is simple, useful, and can be used to directly evaluate a potential candidate. The calculation of the molarity of the paramagnet is necessary, which is not a problem for discrete molecular complexes. Additionally, the impact of the paramagnet is crucial, however even if its content in the final complex is 20– 30% (for example 28% Gd in gadoteric acid) due to the size (<1 nm) the majority of the mass, a kind of securing ballast is not regarded to be a burden the clearance mechanisms. However, when it comes to NPs the size is already 1–2 orders higher, and taking into account their spatial, mostly globular nature, their weight is already a great difference. For example, a 100 nm SPION has a mass of about 2.5*10 −12 g. For comparison, globulin in the blood can reach a size of 50 nm, 10 −18 g, 32 while a red blood cell in humans is about 6000 nm; 33 therefore, it is worth normalizing the relaxation enhancement to the mass of the nanomaterials. This is usually not provided in reports, perhaps due to the assumption that the majority of NPs are responsible for the contrast effects. While this is true for chelator-free, poorly-functionalized SPION particles, it is not valid for advanced decoration. For example, Kim reported the use of 16.1 nm SPION, which after functionalization with oleate acid residues and NOTA chelator, formed 66.3 nm nanoparticles. 34 Very similar size growth was observed in Yang’s models. 35 Another challenge to compare the relaxivity recalculated based on the mass of particles is the lack of a paramagnet percentage. To calculate classic relaxivity expressed in mM −1 s −1 , one must know the real paramagnet (Fe, Gd, Mn, …) content; however, this is not directly provided in most works, or there is often no explanation of how the concentration was determined. Although IC-MS is recommended, it is possible that the researchers assume paramagnets are the main component based only on its mass, such as Fe 3 O 4 . Kim showed that the non-magnetic balance may be huge and, therefore, the results may carry high error; therefore, based on the provided data, as well as the indirect, but very useful and reliable information like thermogravimetric analysis (TGA) that shows the real content of the inorganic matter in probes, we compiled the relaxivity data for comparison and further discussion (Table 1). Most of the reported NPs expressed a higher T 2 relaxivity than the reference iron-containing drugs, Feridex ® and Feraheme™. The high base relaxivity and Table 1 (Continued). Entry r 1 r 1 r 2 r 2 B 0 t [ C] Paramagnet Content [%] Size [nm] Remark, Ref. mM −1 s −1 (mg/ mL) −1 s −1 mM −1 s −1 (mg/ mL) −1 s −1 [T] DOTA-IO-GUL 185 9.4 11.01 [56] 68Ga-C-IONP 5.7 51.7 22.2 201.3 1.5 37 50.6% Fe 20.6 [57] s-SPION25 953 11.7 rt 25 [58] NPs-dopa-PEG-DOTA/RGD 267.5 1609 7.0 32.5%Mn&Fe 26.4 [38] NOTA−FA−FI−PEG−PEI−Ac −Mn3O4 0.57 4.04 0.5 37 40% Mn 476.5 (hydro) [59] AGuIX 13.5 12 18.2 16 1.4 37 14% Gd (Mw) 4.6 [60] SPION−LDOPA−PEG −MANOTA 360 3965 3 61.5% Fe 119 [60] FH 10–20 57–60 [61] Au-Fe3O4@PDA-PEG-DTPA -Gd T1/T2/ dual model 6.14 71.88 3.0 22800 Gd/NP 70.89 [62] https://doi.org/10.2147/IJN.S336299 DovePress International Journal of Nanomedicine 2021:16 8470 Kastelik-Hryniewiecka et al Dovepress Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) significant content of magnetic components (Fe, Mn) resulted in extremely high relaxivities calculated per mass in the range of several thousand, such as in the case of Choi, Shi, and Lee. 36–38 Comparing two of Tu’s NPs SDIO and DIO, it is clear that a similar T 2 relaxivity calculated from the molarity of iron is 40% higher as expressed by the entire mass of the NP due to a higher iron content. 39 Moreover, the smaller size of the more effective species may improve their biocompatibility. The limitation of r 2 comparison calculated by the classical unit mM −1 s −1 is evident in the case of two completely different NP: Aryal’s USPIONs (initially 5 nm), after being covered by poly(lactic-co-glycolic acid), lipids, and polyethylene glycol, had a final size of 140 nm with an r 2 of 265 mM −1 s −1 . The multilayer organic-polymeric shell reduced the iron content to 5%, which led to an r 2 of 261 (mg/ mL) −1 s −1 . In contrast, Shi’s NPs with a similar r 2 [mM −1 s −1 ] were much smaller. They contained 32.5% of the magnetic elements, reaching 1609 (mg/mL) −1 s −1 , which means that its unit mass concentration provided a 6-fold more efficient acceleration of T 2 . There are many ways to compare the available data, but our goal is to investigate how the determined physical properties allow for a preliminary estimation of the intended effect. PET Probes PET imaging agents fall into two categories: i) agents used for metabolic imaging based on small molecules, such as glucose or amino acids, which are rapidly taken up into cells by transporters and metabolized. Many of these are analogs of native small molecules and are designed to undergo limited metabolism and are afterwards retained within particular cells; ii) agents used for receptor imaging based on monoclonal antibodies, antibody fragments, or engineered protein scaffolds. The most commonly used PET radiotracer is [ 18 F]- 2-fluoro-2-deoxy-glucose ( 18 F-FDG). It is a glucose analog that accumulates in tissues with increased glucose metabolism; therefore, increased radiotracer uptake can usually be found in high-grade tumors. 63 A significant drawback of 18 F-FDG is its lack of specificity and high physiological accumulation in organs such as the brain or heart. Receptor-based ligands specifically bind to antigens on the cell membrane. The selection of an optimal targeting agent is based on several characteristics, including its specificity, affinity, metabolism, and clearance of the molecule. Designing a PET imaging probe is a complex process. The choice of a radioisotope, linker, and targeting vector must be carefully selected, as each can alter the radiopharmaceutical properties and, thus, the imaging results. Choosing a specific isotope suitable for a probe depends on its availability, half-life, and the chemical characteristics of the nuclide. The selected radioisotope should decay mostly through positron emission or electron capture, so the annihilation of a positron-electron pair may occur. The most frequently used PET isotopes are 11 C, 18 F, 68 Ga, 89 Zr, 124 I, and 64 Cu, all of which have different chemical properties (Table 2). The radionuclide half-life needs to match the biological half-life of the targeting molecule and should be long enough to allow for radiolabeling and imaging procedures. Finally, depending on the scientific question at hand, the targeting vector’s molecular weight, radiopharmaceutical clearance characteristics, and binding affinity must be optimized. In practice, imaging agents based on intact antibodies suffer due to their large molecular size, slow pharmacokinetics, and long circulation times (up to 3 weeks); therefore, they need to be radiolabeled with longer-lived radionuclides (eg, 89 Zr, 124 I). These are lessideal for clinical imaging due to higher associated radiation doses and longer wait times for imaging. Smaller protein scaffolds have much shorter circulation times (hours rather than weeks), deeper penetration into tissue, and they can be labeled with more clinically-relevant shorter-lived PET radionuclides, which enable same-day imaging; however, they may have lower affinities and typically display lower overall tumor uptake than full antibodies. Real Problems Probe Preparation Obtaining such complex molecules as bimodal probes (Table 3) involves many synthetic steps. The preparation of a nanostructure, surface functionalization, and the attachment of a targeting molecule are often long and multi-stage processes. 34,38–40,49,50,53,57,59,60,62 More Table 2 PET Isotopes and Their Half-Lives Isotope 11 C 68 Ga 18 F 64 Cu 69 Ge 89 Zr 124 I Half-life 20.4 min 68 min 110 min 12.7 h 39.5 h 78 h 100 h International Journal of Nanomedicine 2021:16 https://doi.org/10.2147/IJN.S336299 DovePress 8471 Dovepress Kastelik-Hryniewiecka et al Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) reaction steps require more time from the operator and might affect the reproducibility; therefore, modular and one-pot syntheses are gaining in popularity due to faster tracer preparation times and often lower costs. Moon et al reported shorter one-/two-step encapsulation methods for the synthesis of iron oxide with DOTA-SA and GUL-SA moieties. 56 The first step of the synthesis—the preparation of amphiphiles for the IO core functionalization—gave a yield of 45% (for two steps) and 36% (for one step). The second part involved attaching amphiphiles to SPION, which had a yield of 85%. Another team proposed a one-step modular solution for the synthesis of three matrices based on different nanostructures: SPION, AuNPs, and upconverting nanophosphors (UCNPs), containing aliphatic side chains. 64 Five separate modules based on BSA (bovine serum albumin), with different chelators (DOTA or DFO) or optical imaging dye (Alexa647) and a maleimide moiety, were prepared. By choosing a nanocore and a BSA-based module or modules, one-step functionalization was carried out employing van der Waals interactions between BSA and the functional groups present in the aliphatic chains of the nanostructures. This approach allowed for the creation of a library of thirteen different multimodal probes. Moreover, Yang et al demonstrated the ability of ferritin to reversibly disassemble upon pH changes. 65 At low pH (2–3), melanin NPs (MNPs) and iron ions were added to the unfolded nanostructure. When the mixture was put into an alkaline environment (pH = 8), the ferritin structure encapsulated the MNPs and iron ions. The radiolabeling of 64 Cu was carried out without reopening the structure, and the ions penetrated the interior through pores. The in vivo imaging post-probe injection showed accumulation in the target. The authors highlighted the prospect of using this method to load other ions or targeting motifs; however, a concern is that the low-pH environment of tumor tissues may cause partial disassembly of the probe’s structure. This would be a disadvantageous effect for diagnostics, but it may have therapeutic potential. Other interesting studies confirmed the benefits of using chelator-free microwave-assisted heating for the one-step preparation of dextran-coated SPIONs containing the 64 Cu isotope. 51 The authors demonstrated that the probe was less prone to radionuclide loss than when attaching copper via a chelator. Coating It is common to coat the surface of inorganic nanostructures with various polymers to increase their dispersibility or to incorporate functional groups that can be further modified. Poly(ethylene glycol) (PEG) coatings have been shown to increase the stability of probes in vivo and protect them from undesirable non-specific binding due to stealth effects. There are numerous reports on nanostructures coated with this polymer. 23,34,36,49,50,52,59,62,66 To achieve colloidal stability, the surface of nanostructures was coated with dextran, which increased the probe’s stability in water, its biocompatibility, and its blood retention time. 39,47,51,57,61,67,68 In addition, the PAA (poly(acrylic acid) (PAA), 35 serum albumin, 37 and methoxy-PEG (MPEG) 58 were also used to increase the colloidal stability and water solubility. Radiolabeling Apart from the modular/single-pot syntheses described above, radionuclides can be attached to molecules via both chelator and chelator-free methods. In the first approach, it is necessary to introduce a ligand into the structure or on the surface of the probe. The most commonly used chelators are: DFO for 89 Zr 45,69 and for 64 Cu: DOTA, 23,36,38,39,47,48,56,70 DTCBP, 53,68 NODAGA, 60 MANOTA 66 and NOTA. 49,59 Gallium-68 was chelated with NOTA, 34 NODA, 50,54 and TRAP. 71 In the chelator-free approach, 89 Zr can be directly conjugated to the feraheme (dextran-coated SPIONs) surface using heat-induced radiolabeling. 61,67 The sorption of germanium ions onto the iron oxide surface at pH from 4 to 8 has also been reported. 52 Radiolabeling of bimodal probes with non-metallic radionuclides such as 124 I or 11 C requires the formation of covalent bonds between the molecule and isotope. This can be achieved by surface functionalization with albumin. 37,72 Cytotoxicity MRI is considered to be a relatively safe method compared to other imaging techniques, but MR CAs may have a negative impact on living organisms. For example, iron oxide NPs can lead to local and systemic inflammation, oxidative stress, and genotoxicity. 73,74 The scale of these effects depends on the NP core size, synthesis method, type of coating, and hydrodynamic radius. 75 Moreover, Gd was shown to cause nephrogenic systemic fibrosis. Although this effect was strongly reduced by applying restrictive administration guidelines, 76 the deposition of Gd in the brain and other tissues has been reported. 77–80 Recently proposed MRI-PET bimodal probes (Table 3) display biocompatibility and can possibly synergistically cancel or amplify deleterious effects; therefore, every https://doi.org/10.2147/IJN.S336299 DovePress International Journal of Nanomedicine 2021:16 8472 Kastelik-Hryniewiecka et al Dovepress Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) Table 3 PET/MRI Bimodal Probes Molecule Isotope Paramagnetic Activity per Inj. Dose Target (Targeting Vector) Accumulation a Clearance b Ref Liposome 89 Zr Gd 35–40μCi 2.78 μmol Gd-DTPA -BiSA Neuroendocrine tumor: SSTr2postive transduced cell (OCT) RES – 18% ID/g Bones – 12% ID/g Tumor – 3.5–5%ID/g @ 50 h pi >96 h through RES [45] PLGA/PEG 64 Cu SPION 100 μCi 0.1 mg SPION Breast tumor Tumor - 3.5 ± 0.25% ID/g Liver 22.0 ± 6.0% ID/g Spleen, kidneys - 5% each @ 20 h pi 50 h (from blood) Renal excretion of 64 Cu [23] FH 89 Zr SPION 185–195 μCi ~0.20– 0.21 mg Fe Muscle inflammation Inflamed muscle - 0.95–0.12%ID/g Liver - 101.93%ID/g Spleen 132.96%ID/g @ 120 h pi Inflamed-to-control muscle ratio at 120 h pi: 9.64 ±2.49 >120h [67] PAA modified SPIONs 69 Ge SPION 50 µCi 10 µCi (paw inj.) 7.77 mM Fe SLN Liver - 13%ID/g Spleen 9%ID/g @ 36 h pi SLN – 28%ID/g (paw inj.) @ 20h pi >36 h [52] PAA modified SPIONs *As SPION 148.5 µCi 81 µCi (paw inj.) 40 μL, 7.77 mM of Fe SLN Liver - 25 and 11% ID/g Bladder - 12 and 3.8%ID/g @0.5 h and 20 h pi SLN 12.5 and 13.2% ID/g (paw inj.) @ 2.5 and 15 h pi No data [35] MnMEIO 124 I MnFe 2 O 4 , 110 µCi 335 μCi (paw inj.) 80 µg (Mn +Fe inj.) 229 mg/kg (Mn+Fe) SLN No data > 144 h [37] MnFe2O4 and Fe3O4 18 F Fe 25 µCi 60 mg Fe [53] (Continued) International Journal of Nanomedicine 2021:16 https://doi.org/10.2147/IJN.S336299 DovePress 8473 Dovepress Kastelik-Hryniewiecka et al Powered by TCPDF (www.tcpdf.org) International Journal of Nanomedicine downloaded from https://www.dovepress.com/ by 147.229.97.124 on 04-Jan-2022 For personal use only. Powered by TCPDF (www.tcpdf.org) from optimal for clinical applications; however, if mutual efforts from biologists, medicinal chemists/radiochemists, and engineers/medical physicists can be directed towards improving the characterization of these probes, they might be used in the future in the image-guided delivery of therapeutic agents. When designing these probes, there are still many factors that need to be optimized, including their biocompatibility, pharmacokinetics, targeting efficacy, acute and chronic toxicity, as well as costeffectiveness (Table 6). Designing bimodal probes raises completely new issues that need to be addressed, such as the cytotoxicity of these complex molecules, the ratio of radionuclide to paramagnetic agent, and the clearance of complex molecules. Clinical trials of the proposed probes are still lacking, but there is growing interest in multimodal imaging, which is confirmed by the increasing number of publications on this topic. Although the application of PET radiotracers is necessary, the development of numerical methods and quantum computers might diminish the need for MRI CAs applications; however, the detection of hepatic or stroke-originated lesions, as well as biomarker sensing, molecular imaging, and theranostics should be further investigated in the field of MRI enhancement. 104 Additionally, as specialists have emphasized, future developments should focus on features such as targeting and high efficiencies with low doses and multimodal characteristics. 99,100 Such efforts should hopefully give us an “all-in-one” specific pill. Acknowledgments This publication was supported (KB) by The Excellence Initiative - Research University Program realized at the Silesian University of Technology, Grant No. 04/020/ SDU/10-22-02, year 2020. This review (PJ) was supported by the Czech Science Foundation (GAČR) under the EXPRO 21-20716X project. Disclosure The authors report no conflicts of interest in this work. 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