Cancer is a disease of continual, unregulated proliferation of cells, which may spread to distant organs in the body abruptly [1]. It continues to be the leading cause of death worldwide, despite the large number of studies and great advances seen during the past decade [2]. The coronavirus disease 2019 (COVID-19) pandemic has negatively affected the diagnosis and treatment of cancer in 2020 [3]. In fact, increased mortality was seen because of delays in diagnosis and treatment of cancers. Fear of COVID-19 exposure and reduced access to care because of health care setting closures were the most common causes of cancer deaths [4].

Since the early 1990s, molecular imaging has been developed as a non-invasive tool to visualize the biological functions and mechanisms of living organisms at molecular and cellular levels. Molecular imaging methods facilitate diagnosing the progress of different diseases, the biodistribution of drugs, in vivo molecular events, and evaluating metabolic processes in real time [5]. Various imaging techniques can be divided into two groups: anatomic/structural imaging and functional imaging. Anatomical imaging depicts the exact location and area of interest in the body, with particular properties related to the imaging method employed. On the contrary, functional imaging provides details on the molecular conditions of specific organs or tissues and represents the spatial distribution of physiological processes based on the particular imaging modality employed. Magnetic resonance imaging (MRI) with outstanding soft tissue contrast and x-ray computed tomography (CT) with high spatial resolution produce three-dimensional anatomic imaging without penetration depth concerns. Optical imaging (OI) and nuclear imaging (SPECT and PET) provide quantitative functional information on biological events at the molecular level [6,7,8,9,10]. Molecular imaging modalities have distinct advantages as well as inherent limitations (refer to Fig. 1). For instance, OI provides high sensitivity and fast data acquisition with low-cost contrast, yet it suffers from low penetration depth and high spatial resolution; MRI and CT have high spatial resolution but often achieve low sensitivity; SPECT and PET offer high sensitivity and strong penetration depth, but they have poor spatial resolution. Furthermore, clinical applications of CT, PET, and SPECT are limited due to the risks associated with ionizing radiation [11]. Table 1 summarizes the characteristics of each imaging modality.

A schematic representation depicting various molecular imaging modalities is provided, along with their corresponding advantages and disadvantages

Multimodality imaging with two or more imaging techniques enables the combination of the strengths of individual modalities while overcoming their limitations. In particular, integration of structural and functional images with the utilization of incorporated single photon emission computed tomography/computed tomography (SPECT/CT) and positron emission tomography/computed tomography (PET/CT) has been indicated to be highly effective and useful [13,14,15]. A multimodal imaging approach ideally has the purpose of precisely visualizing the exact localization, metabolic activity of the target organ or tissue, and pathological mechanisms at the molecular level. Thus, it ensures enormous benefits for improving the diagnosis and therapeutic assessment of a disease [16].

Nanotechnology can generate new materials that act as valuable platforms for a wide range of applications, such as biosensing, bioimaging, nanomedicine, drug delivery, and nanotheranostics [17,18,19,20,21,22]. Nanoparticles propose great advantages to the field of multimodal imaging owing to their special features, including nanometer dimensions (1–100 nm), tunable imaging characteristics, and multifunctionality [23]. Based on the chemical compositions of nanoparticles, they are mainly classified into three categories: inorganic, organic, and carbon-based [24], as demonstrated in Fig. 2 Among all the properties of nanoparticles, size has a significant impact on tumor imaging. Nanoparticles show enhanced permeability and retention (EPR) effects in tumors due to their small size (see Fig. 3) [25]. These effects increase the local tumor concentrations of imaging agents. Moreover, blood circulation half-life, biodistribution, tumor targeting, and cellular uptake are remarkably associated with the size of nanoparticles [26]. One of the proposed procedures to gain quantitative information on the whole-body biodistribution is incorporating appropriate radionuclides in the nanoparticles [27, 28]. This approach is called "radiolabeling," and radioisotopes used for nuclear imaging and therapeutic purposes are listed in Table 2. The applications of radiolabeled nanoparticles as imaging probes have numerous benefits [28]. These nanoparticles amplify signals and improve contrast and sensitivity indices more than common radiotracers. Moreover, they can be easily conjugated with various biomolecules due to their large surface area for targeted cancer detection [29]. Furthermore, the novel concept of "nanotheranostics" emerged from the incorporation of both diagnostic and therapeutic moieties into one nanoplatform for improved targeted cancer management [30]. Generally, procedures used for radiolabeling nanoparticles are divided into four categories: a) chelator-based radiolabeling (indirect); b) direct bombardment of nanoparticles; c) chelator-free radiolabeling; d) mixture of nonradioactive and radioactive precursors used for the synthesis of nanoparticles [31]. Among these methods, chelator-free radiolabeling is a favorable choice because it can preserve the native physical features of nanoparticles, such as in vivo pharmacokinetics, surface charge, and particle size. Also, complicated conjugation chemistry is not required in chelator-free radiolabeling [32].

Classification of nanoparticles based on the chemical composition in three division. 1) Organic nanomaterials; 2) Inorganic nanomaterials; 3) Carbon-based nanomaterials

Illustration of passive and active tumor targeting used in the field of nanomedicine. Passive targeting is achieved by unique properties of tumor tissues, in which blood vessels are commonly leaky due to their unorganized structure and ineffective lymphatic drainage. The key factor driving this strategy is EPR effect. Hence, nanoparticles enter to the tumor tissue more easily than other healthy tissues. Active targeting involves surface functionalization of the nanoparticles with targeting moiety that have high affinity and specificity to recognize and bind to receptor and markers on the surface of cancer cells. In this approach, actively guiding the nanoparticles to the desired tissues improves the efficiency of drug delivery and therapeutic effect, as well as, minimizing side effects

Cancer therapy includes various treatment strategies such as surgery, chemotherapy, radiotherapy, and immunotherapy. Different factors (i.e., cancer type, grade, and stage) influence the therapeutic approaches, either alone or in combinations, used for cancer patients [35]. Engineered smart nanocarriers for tumor diagnosis and therapy, known as theranostic agents, find great potential, particularly in radiopharmaceutical therapy (RPT). Primarily, β-emitting and mostly potent α-emitting radionuclides are used in targeted delivery of radiation [36]. RPT is a new therapeutic technique offering several advantages over other approaches for the treatment of cancer. In comparison to radiotherapy, in targeted RPT, the radiation is delivered systematically inside the body, and cytotoxic radiation directly influences tumor cells and their microenvironment. Moreover, unlike other existing therapeutic approaches, targeting therapeutic agents is possible by using PET and SPECT imaging modalities for precise detection of RPT delivery. Minimal cytotoxicity and acceptable efficacy were observed for RPT [37]. Also, fast responses, a single or at most five injection doses, and less severe side effects are associated with the administration of RPT compared to the chemotherapy approach.

In this review, we present the latest progress in the design and synthesis of radiolabeled nanomaterials (with at least one dimension below 100 nm) for in vivo dual/multimodality cancer imaging and nanotheranostic applications (Fig. 4). Moreover, we discuss toxicity issues, challenges, and opportunities for future trends in developing desirable radiolabeled nanoparticles for multimodal imaging and nanotheranostic, as cutting-edge technologies, in preclinical and clinical purposes of cancer diagnosis and therapy.

Development of multifunctional nanoparticles for targeted multimodal cancer imaging and theranostic application. Nanoparticles are functionalized with multiple contrast agents, therapeutic agent, targeting moiety (e.g., small molecules, aptamers, peptide, and antibodies), and then radiolabeled with radionuclide for multimodal cancer imaging and therapy

Radiolabeling procedures are strategies used to attach radionuclides to nanoparticles. Many purposes can be achieved by this technique, such as understanding the biological behavior and pharmacokinetics of nanoparticles, non-invasive, real-time, and whole-body imaging, targeted therapy, and cancer image-guided therapy [38, 39]. The successful development of a radiolabeled nanoplatform basically relies on three divisions: 1) surface functionalization of the nanoparticle, 2) selection of an appropriate radioisotope, and 3) applying an efficient and reproducible radiolabeling procedure to combine Sections 1 and 2. An ideal radiolabeling method must be able to provide high radiochemical purity, good stability, and a simple, fast, low-cost, and robust strategy with minimal changes in the pharmacokinetic properties of nanoparticles. A radiation safety principle of "as low as reasonably achievable (ALARA)" represents guidelines for personal protection while working with radioactive materials [40], so it is preferred to do the radiolabeling process at the final step of construction. Here, we divide the radiolabeling strategies of nanoparticles for multimodality imaging and theranostic applications into two main categories, according to the use of chelators or not: 1) chelator-based radiolabeling 2) chelator-free radiolabeling (see Fig. 5).

Radiolabeling of nanoparticles through two main strategies: chelator-based and chelator-free radiolabeling. Radionuclides and chelators typically used in radiolabeling of nanoparticles for multimodal cancer imaging and theranostic applications are depicted

Generally, most of the organic or inorganic nanoparticles were radiolabeled with chelator-based methods. Hence, the surface of the nanoparticles should first be covalently conjugated to an appropriate chelator [41, 42]. Different factors are associated with the selection of a particular chelator; the most important ones include the oxidation state and the physical properties of the radiometal ion [43]. The most common bifunctional chelators, which are linear or macrocyclic, are depicted in the Fig. 5. The formation of a stable coordination complex between nanoparticles and radiometal ion is required to avoid the detachment of radiometals from the nanoparticles, and it is possible via a strong binding of the radioisotope to the surface of the nanoparticles. Typically, this technique is applicable for nanoparticles, in which their surfaces are well-functionalized [44]. The considerable concerns in chelator-based radiolabeling are related to the multistep process needed for surface modification of nanoparticles with an appropriate bifunctional chelator, the increased time of production, as well as the alternation of physiochemical properties (i.e., the size, surface charge, and hydrophilicity of nanoparticles) after chemical modification with the chelator. Moreover, detachment of radiometal from the surface of nanoparticles might still be possible [31].

Chelator-free radiolabeling is a state-of-the-art approach that exploits the intrinsic physicochemical properties of nanoparticles. The revolution of this surface-based radiochemistry offers a great opportunity for the construction of radiopharmaceuticals for targeted multimodal imaging. In surface chemistry, the term "chemisorption" refers to the chemical binding of radioisotopes with functional groups on the surface of nanoparticles directly. Therefore, the chelator-free technique is a simple, fast, specific, and desirable alternative in which the physicochemical properties of nanoparticles are maintained without requiring a complicated surface-conjugated process with chelators [45]. Despite its advantages, chelator-free radiolabeling also presents certain limitations. Firstly, chelator-free methods avoid covalently linked chelators, but this means relying on the intrinsic properties of nanoparticles for radiolabeling. Surface modifications of nanoparticles significantly impact labeling yield. Some radioisotopes lack reliable molecular chelators, making it challenging to achieve stable labeling without them. The stability of chelator-free labeling varies across different radioisotope-nanoparticle combinations. Also, radiolabeling often requires harsh conditions (e.g., high temperatures, low or high pH) that may compromise nanoparticle stability. Maintaining stability during radiolabeling is crucial to prevent detachment of surface-bound labels. These issues can lead to inaccurate biodistribution imaging, affecting the reliability of results [42, 46].

Positron emission tomography-computed tomography (PET/CT) is a reliable method used for the diagnostic imaging of multiple types of human cancers. In 1998, PET/CT imaging was first introduced and integrated anatomical data obtained by CT with functional data from PET, increasing sensitivity and allowing more efficient disease detection [47].

Most early studies have focused on the use of prostate-specific membrane antigen (PSMA) or gastrin-releasing peptide (GRP) receptors, as small-molecule based targeted probes, for prostate cancer [48, 49]. These agents indicated rapid body elimination through renal clearance and led to limited tumor penetration. Therefore, a polymeric nanoparticle has gained attention from Pressly et al. to prepare a PET/CT tracer for prostate cancer [50]. An amphiphilic comb-like nanoparticle was prepared and loaded with C-atrial natriuretic factor to target the natriuretic peptide clearance receptor. For radiolabeling of the complex with 64Cu, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator was used. The results of PET/CT imaging and biodistribution of the targeted and nontargeted 64Cu-Comb nanoparticles on the CWR22 prostate cancer tumor model revealed low renal clearance, prolonged blood pool retention, and improved tumor penetration and tumor uptake. The tuned physiochemical properties and biological behavior of this targeted radiolabeled polymeric nanoparticle make it a promising candidate for prostate cancer PEC/CT scans.

Recently, a PET/CT probe based on amphiphilic polymer nanoparticles that were radiolabeled with 68Ga was synthesized for sentinel lymph node metastasis imaging [51]. The enhanced stability and radiolabeling yield of nanoparticles were associated with the increased rigidity of the used ligands. In this work, the importance of regulating the chelation efficiency and rigidity of the coordination structure of 68Ga-labeled nanoparticles in comparison with small-molecule probe-based 68Ga was investigated. The PET/CT scans demonstrated that the best differentiation of normal lymph nodes from tumor-metastasized sentinel lymph nodes was only feasible with the strongest rigidity of coordination structure. In 2019, Miedema et al. reported the application of PET/CT imaging based on radiolabeled nanoparticles in patients with advanced solid tumors for the first time [52]. They used CPC634, which is composed of docetaxel entrapped in a stabilized nanosized core-cross linked polymeric micelles by a covalent bond. CPC634 improved the EPR effect and tumor accumulation of the drug in comparison to typically administered docetaxel. Five patients with solid tumors received 89Zr-desferal-CPC634 and whole-body PET/CT scans were acquired at certain time intervals. Information gained from biodistribution studies indicated consistent and high retention of 89Zr-desferal-CPC634 in tumors and confirmed the EPR effect of CPC634 in humans, which is important to develop therapeutic agents for targeted tumor treatment. Another clinical study of radiolabeled nanoparticles for PET/CT scans in patients with esophageal cancer was reported in 2022 [53]. 89Zr-labeled high-density lipoprotein nanoparticle (HDL) was intravenously administered to nine patients with adenocarcinoma or squamous cell carcinoma. The findings proved safe administration of 89Zr-HDL and demonstrated accumulation of the radiotracer in tumors. HDL nanoparticles might have a potential opportunity for the delivery of anti-cancer drugs in the future. 89Zr-HDL nanoparticles were also investigated as a PET/CT tracer to monitor the response to immunotherapy in mice [54].

Lung ventilation-perfusion PET/CT offers useful information for the evaluation of regional lung function. This approach has revealed hopeful potential in different clinical strategies such as pulmonary embolism, radiotherapy, and pre-surgical assessment in patients with lung cancer [55]. In this regard, the chemical composition and physical properties of 68Ga-carbon nanoparticles as ventilation PET/CT probes were investigated and compared to Technegas®, a common clinical method used in the analysis of regional lung ventilation function [56]. Other nanoparticles (i.e., gold and platinum) were radiolabeled with 2-Deoxy-2-[18F] fluoro-D-glucose (18F‐FDG) and 89Zr for PET/CT imaging of tumor-bearing mice through active and passive targeting [57, 58].

SPECT/CT dual-modal imaging was introduced in 1977 to combine the advantages and overcome the limitations of each technique. This well-established procedure has been extensively used for clinical diagnosis applications. Because of the slow speed of developing SPECT/CT imaging probes, it is necessary to develop novel and efficient SPECT/CT contrast agents to improve the diagnosis of various diseases and clinical decision-making strategies [59]. For this purpose, a poly(lactic acid)-polyethylene glycol copolymer nanoparticle was conjugated to PSMA and radiolabeled with 111In through a chelator-based strategy (111In-DOTA-PEG-alkyne) [60]. The in vivo SPECT/CT scans of 111In-labeled targeted nanoparticles and 111In-labeled untargeted nanoparticle in tumor bearing mice revealed a modest positive impact on prostate cancer localization due to active targeting made by conjugating PSMA to nanoparticles than untargeted nanoparticles. Moreover, Li et al. reported the synthesis of a cost-effective nanoprobe for targeted tumor SPECT/CT scan [61]. They used low generation dendrimers, which their surface was covalently functionalized with PEGylated folic acid and DTPA chelator. Then the complex entrapped gold nanoparticles and radiolabeled with 99mTc. This dual-contrast agent was tested for in vivo SPECT/CT imaging of cell-surface overexpressed folate receptor cancer in a mouse model.

Compared to PET/CT and SPECT/CT modalities, PET/MRI and SPECT/MRI, as the next generation of dual-modality imaging, have considerably improved the diagnostic process [62]. High spatial resolution, specificity, sensitivity, low dose of radiation, and soft-tissue penetration of MR imaging provide much more comprehensive information in comparison with CT [63]. Numerous magnetic materials, including Gd, Cu, Mn, Zr, and iron oxide, were used in the fabrication of PET/MRI probes [64,65,66,67,68]. Recently, Xie et al. developed a PET/MRI nanoprobe based on biocompatible melanin nanoparticles and 124I radionuclides [69]. WL12, a cyclic peptide with high affinity for programmed death protein ligand-1 (PD-L1), was selected for active targeting of cancer cells. PET/MRI imaging using this radiotracer in a mouse model with an A549 tumor demonstrated high tumor uptake and PD-L1-targeting, providing an excellent opportunity for PD-L1 therapy in patients with lung cancer.

Another PET/MRI and PET/CT modality of nanoprobes based on organic nanoparticles was constructed by Wen et al. [70]. Dopamine-melanin nanoparticles, which included biocompatible and biodegradable natural-produced dopamine, were used as a novel nanoplatform. The surface of nanoparticles was pegylated and loaded with a monoclonal antibody, trastuzumab. This antibody has a high affinity to target human epidermal growth factor 2 (HER2). The in vivo behavior and pharmacokinetics of this radiolabeled nanoprobe-(124I/64Cu, Mn)-Her-PEG-dMNPs were evaluated by PET/MRI and PET/CT imaging in patient-derived xenograft mouse models with gastric cancer. The valuable findings of this study indicated enhanced retention time of trastuzumab in tumors, low cardiac toxicity, and the possibility of following the therapeutic effect in real time via dual-modality imaging.

Radiolabeled superparamagnetic iron oxide nanoparticles (SIONPs) with various radionuclides have been greatly investigated for passive and active targeting with SPECT or PET/MRI imaging, particularly over the past decade [67, 71,