key: cord-0750470-2825digl
authors: Phua, Vanessa Jing Xin; Yang, Chang-Tong; Xia, Bin; Yan, Sean Xuexian; Liu, Jiang; Aw, Swee Eng; He, Tao; Ng, David Chee Eng
title: Nanomaterial Probes for Nuclear Imaging
date: 2022-02-09
journal: Nanomaterials (Basel)
DOI: 10.3390/nano12040582
sha: c8e2b9ad2f15267608362b082f113235f2001d7f
doc_id: 750470
cord_uid: 2825digl

Nuclear imaging is a powerful non-invasive imaging technique that is rapidly developing in medical theranostics. Nuclear imaging requires radiolabeling isotopes for non-invasive imaging through the radioactive decay emission of the radionuclide. Nuclear imaging probes, commonly known as radiotracers, are radioisotope-labeled small molecules. Nanomaterials have shown potential as nuclear imaging probes for theranostic applications. By modifying the surface of nanomaterials, multifunctional radio-labeled nanomaterials can be obtained for in vivo biodistribution and targeting in initial animal imaging studies. Various surface modification strategies have been developed, and targeting moieties have been attached to the nanomaterials to render biocompatibility and enable specific targeting. Through integration of complementary imaging probes to a single nanoparticulate, multimodal molecular imaging can be performed as images with high sensitivity, resolution, and specificity. In this review, nanomaterial nuclear imaging probes including inorganic nanomaterials such as quantum dots (QDs), organic nanomaterials such as liposomes, and exosomes are summarized. These new developments in nanomaterials are expected to introduce a paradigm shift in nuclear imaging, thereby creating new opportunities for theranostic medical imaging tools.

Molecular imaging is a non-invasive medical imaging technique capable of providing detailed images and information at molecular and cellular levels. Molecular imaging enables the visualization of cellular function through the different imaging modalities such as Positron Emission Tomography (PET) and Single-photon Emission Computed Tomography (SPECT). Imaging probes or biomarkers are used for tracking specific molecular pathways in particular targets in a living system [1, 2] . The molecular imaging techniques offer possibilities of early detection and treatments of diseases through molecular imaging. Through a variety of novel molecular imaging applications, understanding of pathological development is expected to be enhanced, facilitating drug discovery and development in tackling diseases [3] .

Bionanomaterials including organic and inorganic materials can be easily assimilated in living systems. These small-sized nanomaterials can penetrate into tiny capillaries and propagate across biological barriers, enabling detection of changes occurring at molecular levels. Combining these unique properties with being biocompatible has accelerated the application of nano-biomaterials for molecular imaging [4] . Nanomaterials can be applied as a probe for various imaging modalities such as PET/SPECT, Computed tomography used in clinical practices. Development of multimodal imaging probes can help in the identification and positioning of abnormal tissues accurately via complementary physiological and anatomical information attained from PET or SPECT and MRI, respectively.

In this review, we discuss some key factors of nanomaterial modification for their applications as nuclear imaging probes in preclinical and potential clinical uses. We summarize the recent progress in the development of nanomaterials including organic nanomaterials such as peptides, antibodies, liposomes, and inorganic nanomaterials as nuclear imaging probes ( Table 1 ). The development of exosomes as nuclear imaging probes is highlighted (Scheme 1). Most of the nanomaterial nuclear imaging probes selected and described in this review were reported in the past five years. 68 Ga-NOTA-MSA (human) 68 Ga NPs, SCN-mannose modified HSA, NOTA Diagnostic PET imaging for SLN [16] [ 64 Cu]DO3A-KRAS PNA-peptide 64 Cu NPs, DO3A

Diagnostic PET imaging, specific genetic characteristics of radiolabeled-PNA-peptide NPs [17] HDL 89 Zr NPs, PL or apoA-I conjugated, 8.6 ± 1.3 nm Diagnostic PET imaging, 89 Zr-labeled TAM imaging using HDL, specific for macrophages, quantitative macrophage PET [18] DFB 89 Zr Nanocarriers, PEGylated,~15 nm Diagnostic PET imaging,~15 nm PEG 40kDa - 89 Zr-radiolabeled surrogates of PEG-prodrugs of SN-38 (PLX038) [19] BPT-DPP 64 Cu NPs, spherical, PEGlyated, NOTA, 31.3 ± 2.8 mm PET/PAI dual modality imaging probe [20] SNs and SNs-RPM 18 F Nanometric emulsions, [ 18 F]FBEM conjugated, PEGylated,~130-150 nm Diagnostic PET imaging, 18 F-radiolabeled technique for lipid-based nanocarriers [21] MNPs 64 Cu NPs, PEGylated,~11 nm Diagnostic PET imaging, good imaging, therapeutic effects on A431 tumors, potential in targeted radiotherapy [22] CBT- 68 Ga-NPs 68 Ga NPs, 258.3 ± 127.85 nm Diagnostic PET imaging, tumor-targeted imaging probe [23] Micelles 67 Ga Nanocarriers, α-alkyl chain, NOTA or DOTA Diagnostic PET imaging, higher uptake in liver of micelles due to increased lipophilicity of Ga(III) chelates [24, 25] Nano-GO sheets 66 Ga 64 Cu PEGlylated, NOTA, 10-50 nm Diagnostic PET imaging, site-specific tumor neovasculature targeting through functionalization of the TRC105 antibody [26, 27] Zeolite Y 68 Ga Nanocrystalline, azide functionalized, µm tõ 55 nm

Diagnostic PET imaging, incorporation of 68 Gato pores of azide-functionalized NaY zeolite as a bifunctional molecular targeting vector [28] QDs 64 Cu Amine functionalized, DOTA,~20-25 nm PET/NIRF, dual modality imaging QD-based nanoprobe for tumor VEGFR expression [29] Metal oxides 89 Zr Nanorods, nanospheres, NPs, PEGylated, 140 nm

Diagnostic PET/MRI imaging, chelator-free radiolabeling of 89 Zr-on metal oxide for multimodal imaging [30] Dendrimer-based single molecular platform 67/68 Ga NPs, NOTA and DOTA PET/MRI or SPECT/MRI dual modality imaging probe with quantifiable radioisotopes chelated in NOTA or DOTA [31] MDIO- 64 Cu-DOTA 64 Cu IONPs, dextran coated, DOTA,~62.7 nm PET/MRI dual-modality imaging probe, Anionic charges on surface of nanoparticulate MDIO- 64 Cu-DOTA to facilitate recognition by SR-A on macrophages for VAP [32] 

A key challenge faced in current nuclear imaging is the design of an imaging probe that is suitable for clinical application. An ideal imaging probe includes but is not limited to the following properties: biocompatible, easily excreted from the body, enables robust imaging signal and sensitivity, site-specific targeting to area of interest, physiochemical behavior of probe in relation to radioisotope, low toxicity, and good biodistribution [1] . Additionally, the selection of a radioisotope for radiolabeling is also crucial in the design of the probe. There are certain criteria to consider in the development and design of an optimal probe. Sufficient half-life and optimal energy of the radioisotopes have to be complementary to the selected probes for quality imaging [44] . For example, 68 Ga and 18 F for PET are radioisotopes with a short half-life utilized for imaging purposes with drugs that have fast distribution kinetics. On the other hand, longer half-life radioisotopes such as 64 Cu are commonly utilized with antibodies for site-specific targeting, which requires a period of time to reach. Small molecules such as FDG are currently used as imaging probes in PET imaging. However, small molecules tend to exhibit non-specific distribution and poor uptake in certain tumors, which could lead to deviation from diagnostic results [2, 10, 45] . Single biomolecules can only transport one radioisotope to targeted sites [46] . Large molecules and more than 98% of small molecules, imaging probes or drugs do not have the ability to propagate across the blood-brain barrier to target neurological or intracranial diseases [47] .

Nanomaterials can potentially overcome these limitations due to their advantageous size and physiochemical properties [4] . The nanosized feature allows localization of probes at disease sites and reduction in renal excretion and metabolism in the liver due to the unique properties of EPR, enabling prolonged circulation in the body [46] . The pharmacokinetic behavior and biodistribution of the nanomaterial probes allow their theranostic applications with regard to various preclinical and clinical objectives. Effective radiotherapy requires an efficient amount of radiopharmaceutical payload to be delivered to the targeted sites (high payload). For a single nanoparticle, multiple radioisotopes can be labeled, thereby transporting hundreds of radionuclides to the targeted sites. The increase in therapeutic payloads makes nanomaterials effective radiotherapy probes. Moreover, the potential in integrating multiple complementary radioisotopes and signal reporters on a single nanoparticle allows the usage of multimodal molecular imaging. Additionally, quantitative imaging can be performed through the incorporation of radioisotopes onto nanoparticles using PET or SPECT for in vivo biodistribution studies, which are essential for the evaluation and validation of potential clinical therapeutics.

The limitations of crossing biological barriers such as the blood-brain barrier (BBB) and small capillaries can also be overcome using nanomaterials. These nanosized vessels are small enough to propagate across the barriers, delivering drugs to targeted sites [4] . For example, Dalargin, an antineoplastic drug, is unable to propagate across the BBB when administered systematically [48] . However, the conjugation of [ 3 H]Dalargin to poly(butylcyanoacrylate) nanoparticles injected systematically showed accumulations in the brain, indicating that the nanoparticle complex had crossed the BBB. The development of nanomaterials for specific targeting of the Central Nervous System (CNS) still remains extremely challenging due to the safety and efficacy concerns. However, there has been great advancement in the design of nanoparticle as carriers, drugs or probes to efficiently and safely propagate across the BBB. With more knowledge and better understanding of nanomaterials and their mechanisms, more success in the design of a nanomaterial probe may be achieved in targeting neurological diseases in the near future, creating more opportunities in therapeutics and diagnostic clinical applications.

Bionanomaterials in particular have been widely investigated for theranostic applications due their natural ability to assimilate easily in body systems. These natural nanoparticles are equipped with unique properties such as biocompatibility, biodegradability, and stability in blood circulation, thereby overcoming some of the limitations that need to be considered in the design and development of a novel imaging probe [49] . For example, metallic bionanomaterials and their oxides such as gold, silver, copper, and iron are easily engineered and synthesized and have shown low toxicity for both living cells and the environment, making these a favorable drug or imaging probe to be used in diagnosis and therapeutic applications. Enhancement of molecular imaging can also be achieved as bionanomaterials not only provide biocompatibility but also have a high surface area per volume, resulting in a high payload and selective binding to targets via passive or active targeting that enables specific pathway signals to be elicited for detection using imaging modalities at molecular levels. With these unique features of bionanomaterials, more accurate diagnosis of diseases can be attained and treatments can be tailored accordingly.

To improve their biocompatibility, targeting specificity, and easily controllable properties, nanomaterial-based nuclear imaging probes require necessary surface modifications such as coating and targeting moiety attachments, which include conjugation with peptides, antibodies, and many other targeting molecules (Scheme 2). The modifications promote various advantageous properties such as site-specific targeting, higher affinity to biomolecules, enhanced uptake into cells, improved biocompatibility, and longer circulation time that are essential for theranostic applications. Scheme 2. Various modifications of nanomaterials as nuclear imaging probes for their multifunctional theranostic applications.

The nanomaterial probe administered intravenously into the living system is assimilated either by the hepatobiliary system or by the renal system. To improve the biocompatibility, the nanoparticles are coated with hydrophilic polymers that include linear chain polymers of polyethylene glycol (PEG) and branched copolymers [50, 51] . The hydrophilic nature of the coating polymer prevents 'opsonisation', as the hydroxyl (-OH) group offers steric hindrance to the approaching protein. It has been shown that the particles coated with PEG have a tendency to evade opsonisation by the immune system [52] . It was found that an increase in the molecular weight of PEG resulted in nanoparticles with longer blood circulation time but also resulted in reduced tumor accumulation [53] [54] [55] . Both the concentration and morphology of the PEG chains affect the targeting capability of the nanomaterial imaging probe. At a moderate concentration, PEG chains presented a brush conformation due to the lateral pressure between these PEG chains while the PEG chains would tangle themselves into a random-coil conformation known as the mushroom conformation when PEG density was too high [56] . The brush conformation PEG chains grafted on targeting moieties would have more chance to interact with receptors [57] . To achieve specific targeting capability, the concentrations and morphology of PEG chains need to be carefully optimized.

Apart from PEG, several other coating polymers including polyvinyl pyrrollidone (PVP) [58] , polyvinyl alcohol (PVA) [59] , polylactide, polycaprolactone, polaxomers of polyethylene oxide (PEO), and polypropylene oxide (PPO) have been developed. Cyclodextran, a natural polysaccharide with an inert property, is most commonly used for coating iron oxide nanoparticles (IONPs), enabling longer circulation in living systems [60] [61] [62] . The liposomes with amphiphilic long-chain lipid molecules form a lipid-bilayer around the signaling molecule and mimic the plasma membrane of the blood corpuscles, thereby overcoming the reticuloendothelial (RES) system and providing a long circulation time in the blood [63] [64] [65] . Apart from linear chain polymers, branched amphiphilic copolymers such as dendrimers show superior biocompatibility with improved blood circulation time. The smaller size (~20 nm) dendrimers show higher efficiency of ghost drug encapsulation [66] .

Normally, nanomaterials are conjugated with functional linkers for further improved pharmacokinetics and biodistribution. Linkers bound with "targeting ligands" have high affinity. The most commonly used system is biotin-avidin. Biotin a water-soluble vitamin that can bind to streptavidin molecules with a very high affinity, defined by the dissociation constant K D . Dissociation constants determine the affinity with which the molecules can bind to each other. Melamide, succinimide, and other carbodiimide reactions are exploited to form covalent ester bond to link typically an alcohol group-carboxylic group to create an ester bond. Many such reactions are useful in molecular imaging for functionalizing the surface of the nanoparticles [67] [68] [69] .

Nanomaterial itself in which the radiolabeled isotopes are packed and delivered to the living system is essential for non-specific uptake and ideal distribution behavior for molecular imaging. The nano-sized particles offer a greater surface area per volume of the particle, giving accessibility for functionalization of the surface with ligands including biological peptides, antibodies, vitamins, and other biological molecules. These nanoparticles can selectively bind to cell surface receptors and cause specific "signal" changes that can be detected. The "signals" are due to the behavior of the nanoparticle. Targeting moieties have been designed to bind to receptors that are over-expressed in pathological cells but much less expressed in normal cells [70, 71] . The targeting moieties differentiate pathological cells from healthy cells, actively enhancing the specific cell binding. The targeting moieties can facilitate the nanoparticle localization in lesions [72] . Targeting moieties are normally conjugated or loaded onto the outer surface of nanomaterials to achieve maximum receptor binding. Commonly used targeting moieties are peptides such as somatostatin and cyclic arginylglycylaspartic acid (cRGD), antibodies such as Traztuzumab, and small molecules. Somatostatin is a targeting poly-peptide as it binds to the over-expressed somatostatin receptors (SSTRs) presented on the neuroendocrine tumors. Its analog poly-peptides such as octreotide bind to SSTR with very high affinity, leading to a combined targeting and therapeutic effect. Cetuximab, an epidermal growth factor receptor inhibitor showed therapeutic effects in metastatic cancer [73] . Cyclic arginylglycylaspartic acid peptide (cRGD) is another small peptide that binds to α v β 3 integrins, which are over-expressed during neovascularization in cancer. cRGD has been used as a molecular imaging target to evaluate neovascularization in tumors. cRGD conjugated superparamagnetic iron oxides (SPIOs) as MRI contrast agents showed excellent distribution in the tumor vasculature, which was not observed in control tumors. cRGD functionalized SPIO conjugated 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-chelated Cu-64 has been explored as a PET probe, and a study showed accumulation of the probe in tumors, indicating targeting to the ligand. Neuronal stem cell-labeled SPIOs were implanted into a brain trauma patient. MR images showed the labeled cells proliferated and migrated throughout the brain tissue post-implantation [74] . The cardiomyocyte-labeled SPIOs have been used for treating plaques in atherosclerosis in which the viability of the cardiomy-ocytes was assessed [75] . Traztuzumab is an antibody targeting human epidermal growth factor receptor 2 (HER2) associated with breast cancer. When the HER2 antibody was functionalized into different nanoparticles of approximately 200 nm, the specific binding of the HER2 receptor to cancerous breast tissue was enhanced, and this can thus be used as a theranostic probe. The shape of the nanoparticles also impacts the targeting ability of Traztuzumab, with nanorods showing almost twice the binding affinity to HER2 receptors in a breast cancer cell line in comparison to nanospheres [76] . Antibodies targeting intracellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) have been used for studying inflammation related to atherosclerosis and plaques, respectively [77, 78] . Nano-biomaterials have been widely used in cell tracking and regenerative medicine. For cell labeling, the nano-biomaterials need to be inert, be easily taken up by the cells, and provide a platform for sensitive signal imaging. Thus, nano-biomaterials are usually coated with inert coating agents such as cyclodextran, followed by further functionalization with cell-penetrating peptides such as the transactivator of transcription (TAT) peptide to enhance the uptake of the nanoparticles by the cells [79] .

Monoclonal antibodies used as targeting moieties for several cancer therapies have been reported [80] . Efforts have been emphasized in the research on engineering of monoclonal antibodies for the targeting. For example, antibodies can be broken down into smaller fragments that retain the receptor-binding capabilities but are easier to manipulate. The targeting efficacy generally depends on the quantity of targeting moieties and the conjugation mode. Nanomaterials that are conjugated with targeting moieties with multiple sites such as multivalency normally possess enhanced affinity, slower disassociation, and better biodistribution when compared to monovalency [81] . Some small nucleic acids such as aptamers have been attracting interest as targeting moieties. Several reports showed aptamers have a high affinity binding with various receptors, with applications in a variety of therapeutics [82, 83] . Moreover, the aptamers have advantages of synthesis across a large scale and high batch-to-batch consistency, even in vitro chemical techniques [84] .

Some over-expressed receptors have been chosen as targets in certain tumors for molecular imaging. Folic acid as a water-soluble vitamin has been studied as an active targeting moiety for some rodent tumor models such as ovarian cancer and prostate cancer because it binds with the Frα receptors that are over-expressed in these tumors [85] . As Frα receptors are constantly replenished on the surface of the tumors [86] , folic acid has been bound to fluorescent isothiocyanate (FITC) for clinical surgeons to resect the tumors precisely [87] .

Radiolabeled peptide or antibody can be incorporated onto nanoparticles or nanomaterials as PET (SPECT) imaging probes for cancer diagnostics as these nanoparticles demonstrated high affinity and selectivity for receptors that are over-expressed by various human cancers such as breast, lung, and prostate tumors [10, 88, 89] . Radiolabeled particulate nanocarriers such as 99m Tc-labeled colloidal nanoparticles can be used for the imaging and localization of sentinel lymph nodes [90] . In order to improve the resolution and sensitivity, 68 Ga-labeled mannosylated human serum albumin (MSA) has been developed as a PET probe for lymph node imaging [16, 91] . Peptides targeting galectin-3, beta-galactoside-binding animal lectins overexpressed by a variety of human cancers, especially breast cancer, have been successfully radiolabeled with 68 Ga in gelatin nanoparticles (GNPs) using phage display techniques [92] . The 68 Ga-labeled GNPs showed high radiochemical purity and stability in serum over a 4-h time. GNPs demonstrated promising results as colloidal carrier systems for drug delivery due to their biocompatibility and biodegradability. In addition, radiolabeling showed little impact on the characteristics of the GNPs. Peptide Nucleic Acid (PNA) peptide nanoparticles containing Kirsten rat sarcoma viral oncogene homolog (KRAS) mRNA and insulin-like growth factor 1 (IGF1) receptor were conjugated with DOTA-chelated 64 Cu for tumor targeting in human pancreas cancer xenograft mice with higher tumor uptake in PET images [93] .

Liposomes, especially PEGylated long-circulating liposomes, have been widely used as nanocarriers for drug delivery. Ranging from 50-1000 nm, these sphere vessels composed of lipid bilayers surrounding the aqueous core have shown great potential as theranostic nuclear imaging probes [17] . Manipulations can be applied to both the aqueous core and phospholipid bilayer, making liposomes a versatile candidate as drug carriers and imaging probes in multimodal imaging reporters and therapeutic drugs. Since liposomes and lipid nanoparticles have potential as drug carriers, evaluation of the biodistribution, pharmacokinetics, and stability in vivo is necessary, which can be achieved through nuclear imaging. Radiolabeling of lipid nanoparticles includes direct labeling of radionuclides on the surface of lipid nanoparticles and/or via chelator-based radiolabeling in which the chelator normally conjugates to the phospholipid at the surface of liposomes [94, 95] . A comparison study using PEGylated liposomes/micelles with DTPA derivative was shown to be suitable for radiolabeling with various radiometals such as 68 Ga, 111 In, 99m Tc, and 177 Lu for different imaging modalities along with specific targeting activity [96] . Solid lipid nanoparticles (SLNs) have also been employed as potential drug carriers. The in vivo evaluations were carried out using PET imaging via radiolabeled 64 Cu through the incorporation of lipid-PEG-BAT chelator into SLNs [97] . SLNs were shown to be compatible with 64 Cu radiolabeling, enabling biodistribution studies to be quantitatively evaluated. Through the ability to evaluate in vivo studies through nuclear imaging, potential theranostic systems using liposome drug carriers can be discovered to target more diseases.

As the structures of liposomes can be easily manipulated, radiolabeling of liposomes and lipoproteins has been explored further in the functionalization of multiple imaging reporters and/or therapeutic drugs. Natural high-density lipoprotein (HDL) nanoparticle is specific for macrophages. The reconstituted HDL was developed and radiolabeled with 89 Zr for PET-based imaging of tumor-associated macrophages (TAM) in a breast cancer model [18] . PEG-conjugated desferroxamine B (PEG-DFB) nanocarriers were developed as a diagnostic surrogate to investigate tumor accumulation susceptibility for a cancer drug [19] . PEG-DFB nanocarriers were radiolabeled with 89 Zr for tumor imaging using microPET/CT. Interestingly, the PEG-DFB nanocarriers exhibited passive tumor targeting properties and longer serum stability and retention time in tumors, enabling higher tumor exposure. The EPR effect of PEG-conjugated nanocarriers (15 nm) led to a long elimination half-life of the 89 Zr-radiolabeled nanocarriers, resulting in remarkably high tumor uptake. The benzodithiophene-diketopyrrolopyrrole (BDT-DPP) conjugated polymer by Stille coupling of diketo-pyrrolopyrrole (DPP) and benzo-dithiophene (BDT) was used to synthesize biocompatible nanoparticles by self-assembly of phospholipid-PEG (DSPE-mPEG5000), followed by non-covalent binding of DOTA-chelated 64 Cu [20] . The resulting 64 Cu-labeled nanosystem was evaluated for its accumulation in HepG2 tumors. Both PET imaging and biodistribution studies showed high uptake in tumors 4 h post injection. The strong NIR absorption and photoacoustic imaging (PAI) sensitivity of the nanosystem indicated it can be used as dual-mode imaging probe for PET and PA. Chelator-free radiolabeling of organic lipid-based nanosystems containing PEG-lipid functionalized sphingomyelin nanometric emulsions was coupled to 18 F-labeled fluorobenzamide-n-ethylmaleimide ([ 18 F]FBEM) for in vivo biodistribution and PET imaging studies [21] . Apart from enhancing signals, sensitivity, and specificity to targets, radiolabeled nanocarriers can also be manipulated to achieve stability in plasma and long blood half-life. Radiolabeled nanosystems demonstrated high potential as targeted PET/SPECT imaging probes in cancer diagnosis Highly specific vascular targeting by radiolabeled polymeric liposomes nanocarriers for biomedical applications was also achieved through the conjugation of clickable monoclonal antibodies (mAb) and single-chain variable fragments (scFv) [98] . 111 In radionuclide was incorporated into the click immunoliposomes, and in vivo imaging was carried out via microSPECT/CT. Natural melanin has an inherent ability to chelate various metal ions. This property allows radiometals to be chelated on melanin, enabling the usage of nuclear medicine and imaging for theranostic applications. Water-soluble melanin nanoparticles (MNPs) have the ability to retain chelating characteristics without the need for surface modifica-tions [22] . PEGylated melanin nanoparticles (PEG-MNPs) were radiolabeled with 64 Cu for PET/CT imaging. With the advantage of the EPR property, 64 Cu-PEG-MNPs, tumor accumulation was monitored, and the evaluation of 64 Cu-PEG-MNPs as a potential targeted thernostic drug for cancer therapy was carried out. Similarly, dopamine melanin nanoparticles (DMNs) also exhibit metal-chelating properties. DMNs were used to chelate to various radiometals ( 64 Cu, 89 Zr, and 177 Lu) for tumor PET imaging [99] . Radionuclide 124 I was also radiolabeled to DMNs through an electrophilic substitution reaction instead of a chelation reaction. To enhance tumor targeting, folic acid was conjugated on the surface of PEG-DMNs. In order to achieve deeper tissue penetration without macrophage recognition, biocompatible melanin nanoparticles of less than 20 nm were synthesized and functionalized with PEG. To tap into the pH-induced aggregation properties, citraconic amide was coated on PEG-MNPs under mildly acidic conditions to form pH-triggered MNP aggregates that accumulated at tumor sites [100] . Through PET imaging using radiolabeled 68 Ga radiolabeled PEG-MNPs, an enhanced tumor signal was observed in the H22 tumor-bearing mice, indicating targeted tumor imaging. Intracellular 68 Ga-labeled nanoparticles CBT- 68 Ga were reported as a furin-responsive radiopharmaceutical for the PET imaging of furin-overexpressing cancer cells [23] (Figure 1 ). Incorporation of tumor-overexpressing protein convertase into intracellular nanoparticles could enhance tumor targeting and improve the cancer diagnosis. A furin-responsive Ga-labeled 2-cyano-benzothiazole (CBT-Ga) underwent furin-initiated condensation to form nanoparticles (CBT-Ga-NPs) by self-assembly. The 68 Ga-labeled nanoparticles (CBT-68 Ga-NPs) were used for in vivo mcroPET imaging of tumors in MDA-MB-468 breast tumor xenografts. The results showed enhanced tumor uptake in both mice, one with co-injection of CBT-68 Ga and CBT-Ga and the other with injection of CBT-68 Ga only. Micelles can be employed as colloidal nanocarriers for drug delivery with improved pharmacokinetics and target-to-background ratio. Micelles can be labeled with radioisotopes as a PET/SPECT imaging probe by aggregation of amphiphilic ligands comprising NOTA or DOTA coupled to an α-alkyl chain via acetate pendant arms, followed by chelation with the radionuclide [24, 25] . Based on the in vivo biodistribution study, there was a directly proportional relationship between uptake of 67Ga-micelle in rat liver and the length of the pendant α-alkyl chain and lipophilicity of the amphiphilic ligand. Inorganic nanomaterials such as mesoporous silica-based nanostructures, graphene oxide (GO), and zeolites have been explored as PET/SPECT imaging probes. Various radioisotopes such as 64 Cu, 68 Ga, 89 Zr, 18 F, and 124 I have been reported to radiolabel silica-based nanostructures or nanoparticles through different methods including chelator-based and chelator-free labels [101] . Nano-graphene oxide (GO) sheets were modified by covalent conjugation to PEGylated chains, subsequently coupled to NOTA for radiolabeling with 66 Ga and 64 Cu for PET imaging in respective studies [26, 27] . To enable specific targeting for CD105, a vascular target marker in tumor, the. TRC 105 antibody, was conjugated to the radiolabeled GO sheets. Accumulation of the radiolabeled-GO-TRC105 sheets was observed in tumors of 4T1 murine breast tumor-bearing mice, with steady tumor uptake over a period of time. The specificity in tumor uptake of radiolabeled-GO-TRC105 sheets indicates the potential of such nanoplatforms for targeted CD105 tumor vasculature imaging. Attachment of targeting moieties such as peptides or aptamers to zeolite Y via chloro-propyl-trimethoxysilane and azide-functionalization been reported [28] . The modified azide-functionalized zeolite nanoplatform exhibited high affinity for 68 Ga radiolabeling for PET imaging, showing promising potential as a targeting application in imaging.

PET radioisotopes can be incorporated into quantum dots (QDs) to produce optical/PET bimodal probes. These nanomaterials with quantum confinement present unique properties for in vivo imaging studies such as biodistribution of QDs to image cancer [29, 102] . Organic CdSe/ZnS QDs can be encapsulated by amphiphile polysorbate 60 for specific binding to target cells such as RGD-C18 for angiogenesis imaging. The QDs were further functionalized with 2-(p-isothiocyanatobenzyl)-NOTA ([NOTA]-C18) and then labeled with 68 Ga for specifical accumulation in U87MG human glioma xenografts in mice by PET imaging [103] . Ultrasmall gold nanoparticles (AuNPs) have been extensively used as imaging probes such as CT, Raman or photoacoustic imaging (PAI) due to their intrinsic physicochemical properties. AuNPs with homogeneous size have been manipulated into desired shapes or tailored to be tumor-specific for theranostic applications. Radiolabeling of AuNPs with 64 Cu ( 64 Cu-AuNPs) was evaluated as a diagnostic PET imaging probe based on favorable in vivo biodistribution and clearance of 64 Cu-AuNPs [104] . The 64 Cu-labeled palladium-gold core-shell tripod nanomaterial 64 Cu-doped PdCu@Au was synthesized with 64 Cu directly doped into the crystal lattice and functionalized with D-Ala1-peptide T-amide (DAPTA) for CCR5 breast tumor PET imaging in 4T1 mice. Due to the bimodal characteristics of 64 Cu-doped PdCu@Au, the imaged-guided photothermal cancer treatment was promising [105] . Copper sulfide-ferritin nanocage CuS-Fn NCs were prepared via a novel biomimetic method for incorporation of ultrasmall CuS nanoparticles within the cavity of ferritin nanocages (Fn NCs). 64 Cu-labeled 64 CuS-Fn NCs demonstrated considerable tumor uptake in human glioblastoma U87MG-bearing nude mice in PET imaging [106] . CuS-Fn NCs have potential in cancer photothermal therapies. Cornell dots ("C dots") were the first ultrasmall inorganic hybrid nanoparticles for clinical trials. Functionalization of C-dots with a 124 I containing peptide ( 124 I-cRGDY-PEG-C) could be used as hybrid imaging probe for translational and clinical cancer diagnostics [107] . PAI demonstrates the advantages of both of high sensitivity of optical imaging and high resolution of ultrasonic imaging. Besides that, it can be used for cancer treatment by photothermal therapy. Molybdenum-based poly oxometalates were used for redox-activated PAI-guided photothermal therapy. The PAI imaging probe was labeled with 89 Zr to investigate its biodistribution study by PET [108] .

MRI/PET multimodal nanomaterial probes are promising for tumor imaging [109] [110] [111] . There two types of MRI/PET multimodal nanomaterial probes are based on classifications of MRI contrast agents: magnetic nanoparticles such as superparamagnetic iron oxide [112, 113] and gadolinium containing nanomaterials [114] . Chelator-free radiolabeling of 89 Zr to a variety of metal oxide (M x O y , x = 1-2, y = 2-5) nanomaterials with a PEGylated surface were reported as PET/MR probes for in vivo lymph node (LN) mapping [30] (Figure 2) . The high-labeling yield M x O y nanomaterials showed stability in serum due to the strong bonding between oxyphilic 89 Zr 4+ with the oxygen atom on the M x O y surface. The nanostructures or different morphologies of metal oxides affect the target-ligand affinity. A dendrimer-based single molecular platform for merging MRI and PET probe moieties to facilitate colocation and cross-validation from each modality in targeted regions of interest was reported [31] . The platform contained NOTA for specific chelation with 67/68 Ga and DOTA for Gd. The platform also carried three amine groups to attach targeting moieties for enhanced targeting [32] . Conjugation of the 64 Cu-DOTA complex with dextran-coated iron oxide nanoparticles was specially modified with maleic anhydride to obtain a high negative surface charge. The increased anionic charge enhanced the scavenger receptor type A (SR-A) targeting in which SR-A is expressed in macrophages. Polymeric micelle nanoparticles were modified with Fe-deferoxamine (Fe-DFO) as an MR contrast agent to avoid Gd-related toxicity such as nephrogenic systemic fibrosis and were labeled with 89 Zr as a dual modality probe for tumor imaging through EPR effects [33] . Human serum albumin (HSA)-encapsulated IONPs were labeled with 64 Cu-DOTA and NIR dye Cy5.5 as an optical/PET/MRI triple modal nanoprobe [34] . Prolonging the NPs' blood circulation of the HSA matrices led to significant accumulation of NPs in the lesion of a U87MG (glioblastoma cell)-xenografted mouse model by in vivo trimodal imaging. Thermally cross-linked IONPs as a triple modal optical/microPET/MRI probe were synthesized by a facile preparation method through single labeling with positron-emitting 124 I [35] . The β + decays of 124 I with a mean energy led to strong Cerenkov radiation for Cerenkov luminescence imaging.

Radioiodination of bio-nanomaterials can be easily carried out due to the abundance of tyrosine and histidine amino acid groups inside liposomes, polymers, antibodies, peptides, and extracellular vesicles [10] . Similarly, methods of radiolabeling of nanomaterials with iodine are through encapsulation and/or surface attachment depending on the type of nanomaterial and its applications. By combining the uses of nanomaterials as drug carriers and nuclear imaging, iodine-containing radiopharmaceuticals can be developed as therapeutic and diagnostic medicines for various diseases [101, 115, 116] . 131 I was radiolabeled on a polyethylenimine (PEI)/doxorubicin (DOX) complex, forming radiolabeled nanoparticles with pH-response for cellular uptake by conjugating alkoxyphenyl acylsulfonamide (APAS) functional groups to the surface of the complex. APAS in the radiolabeled APAS-131 I-PNPs/DOX nanoparticles changed their surface charges from neutral charge at physiological pH (pH~7.4) to positive charge at slightly acidic pH (pH~5.5-6.0), which allows cellular uptake of nanoparticles through electrostatic interaction tumor cell membranes. In vitro SPECT imaging showed enhanced signal of C6 cancer cells with APAS-131 I-PNPs/DOX compared to that of cells with 131 I-PNPs/DOX at tumor pH, while at physiological pH~7.4, lowered signals were found in both cells. Similarly, in vivo SPECT imaging of xenograft tumors showed enhanced signal at 4-, 6-, 8-, and 12-h post-injection in tumor-bearing mice injected with APAS-131 I-PNPs/DOX compared to low signals of tumor-bearing mice injected with 131 I-PNPs/DOX throughout the same time intervals. The results suggest that APAS promotes cellular uptake of the nanoparticles under slightly acidic conditions (i.e., tumor pH) [36] .

Shikonin, a napthoquinone often used in traditional Chinese medicine for wound healing, is able to suppress tumor cell growth and induce apoptosis of cancer cells [117, 118] . The synergistic effect of shikonin and silver nanoparticles (AgNPs) was investigated for theranostics in lung cancer. Shikonin was not only used as anti-tumor treatment for A549 cells (human lung carcinoma cell line) but also acted as a reducing and stabilizing agent for the synthesis of spherical shikonin-AgNPs, enabling a more environmentally friendly synthesis reaction. Through radioiodination of 131 I to the synthesized shikonin-AgNPs, biodistribution studies by gamma counting showed their highest preferential retention time in the lung tissues at all-time points compared to other organs, indicating specific targeting in lungs. Moreover, shikonin-AgNPs also showed inhibitory effects for A549 cells in cell viability and proliferation [37] . AuNPs were used as delivery cargos to deliver boron atoms to cancer cells for boron neutron capture therapy (BNCT). PEGylated AuNPs were under surface modified to conjugate an anti-HER2 antibody 61 IgG for specific tumor targeting. The resulting AuNP-boron cage assemblies (B-AuNPs) were radiolabeled with 123 I as a SPECT imaging probe for N87 gastric cancer xenograft model targeting [38] . Both biodistribution and microSPECT/CT imaging studies showed high uptake of 123 I-61-B-AuNPs in tumors, indicating the probe's promising theranostic applications for BNCT in clinical settings. HSA has a target-specific binding ability for glycoprotein60, which is commonly found on the surface of cancer cells. HSA containing nanoparticles thus can be used as a sitespecific drug cargo to deliver drugs to targeted sites [119] . HSA containing metabolizable nanomaterial was reported to track tumor variation under X-ray exposure. The SPECT/CT imaging demonstrated prolonged retention time of radiolabeled 125 I-HSA nanoparticles in the tumor due to X-ray exposure compared with the control tumor imaging without X-ray effects [39] .

Exosomes were first discovered in the 1980s when it was hypothesized that the debris of these nanosized vesicles was secreted into the extracellular space from cells during blood reticulocyte maturation to remove unwanted transferrin receptors [120] [121] [122] [123] [124] [125] . Until 1996, these exosomes were considered debris, but since then, studies have reported the role of exosomes in immune responses such as antigen presentation in immune-modulating activity of B cell-derived vesicles and their potential in immunotherapy [123, [126] [127] [128] . Extensive research has been done in recent years to gain a deeper understanding of these complex vesicles and their involvement in the cellular system, as well as exploration for potential clinical diagnosis and therapeutics in nanomedicine [125, 129, 130] . Currently, there are studies to investigate the effects of exosomes on SARS-CoV-2 coronavirus and potential development of exosome-based therapeutic approaches to tackle this deadly virus [131] [132] [133] . Evidently, exosomes play a crucial role not only in elimination of unwanted proteins out of the cell but also in other important cellular communications and functions [122, 123, 126, 127, 129, [134] [135] [136] .

There are three main subgroups of extracellular vesicles (EVs) that are classified based on their biogenesis origin: (a) exosome (30-100 nm), (b) microvesicles (100 nm-1 µm), and (c) apoptotic bodies (1-5 µm) . In this review, only exosomes will be explained as the focus is on nanosized materials. Exosomes are a subgroup of EVs secreted as nanosized particulates into the extracellular space when multivesicular bodies fuse with the cell membrane. Many types of cells found throughout the body produce exosomes including mesenchymal stromal cells (MSCs), nervous system cells (Schwann cells), neurons, epithelial cells, dendritic cells, fibroblasts, and cells of the immune system such as T-cells, B-cells, and macrophages. Furthermore, these nanoparticulate vesicles can be found in bodily fluids such as blood, breast milk, urine, sperm, amniotic fluid, saliva, cerebrospinal fluid, and many more [122, 124, 127, 128] . Exosomes play a vital role in intercellular communication, acting as a "transporter" in carrying bioactive materials such as proteins, lipids, RNAs, and DNAs that will be taken up by target cells to elicit signals important for regulation, regeneration, and protection in the body systems. Additionally, the involvement of exosomes in cancer progression has also been evidently reported; tumor-derived exosomes (TDEs) are known to be involved in cancer progression [124] [125] [126] 130] . One of the greatest advantages of these exosomes is the ability to cross biological barriers such as the blood-brain barrier easily, and therefore, bypassing potential side effects arising from traditional cell-based therapy [40, 125, 129, 137] . For example, pulmonary embolism that could potentially arise from MSC transplantation in the brain could be avoided [132, 133] . Making use of the advantageous properties of exosomes may provide endless potential applications in both clinical diagnostic and therapeutic tools.

Since exosomes encapsulate many bioactive materials important for paracrine factors, tumor growth, and suppression, these vesicles can serve as biomarkers for diagnosis and prognosis for diseases [124, 128, 129, 138] . Studies have shown that exosome concentrations were found to be higher in the blood of patients with cancer [124, 127, 128] . Additionally, radiolabeled exosomes can also be used for tracking of pharmacokinetics via different routes of administration, which is important in biodistribution studies in determining the design of the drug [40, 138, 139] for clinical translation.

The radioisotope can be labeled through two main techniques: (a) surface labeling and (b) intraluminal labeling. The surface labeling methods for exosomes that have been investigated so far include modifications of genetic materials, direct labeling of radioisotopes, and attachment with the help of a bifunctional chelator. Intraluminal radiolabeling encapsulates the radioisotope with the help of a radiometal complex into the intravesicular space of the exosomes. There are two methods currently known, remote loading and ionophore-chelator binding. Further elaborated details for each labeling method can be found [129, 140] . The versatility of exosomes provides a platform for new discoveries in theranositcs. Even so, a current challenge faced by scientists in labeling exosomes is maintaining the integrity of the exosomes. Any type of modification, for example, surface labeling, could affect the properties of the exosome, which can nullify the potential use of the radiolabeled exosome as a diagnostic or therapeutic tool in clinical application [130, 138, 139] . In addition, the exact location where the radionuclide binds in the exosome is still uncertain which may compromise imaging [129] . Nonetheless, it is worth investigating methods in modifying exosomes to improve the uptake or physiochemical properties, creating novel techniques for diagnosis and therapeutics. By labeling a radionuclide on an exosome, nuclear imaging such as SPECT and PET can be utilized, which is particularly useful in acquisition of whole-body imaging in clinical translation. Despite the superior sensitivity and deep tissue penetration capacities, there are only few studies reporting the use of radiolabeled exosomes [40, 140, 141] . 131 I-exosomes are potentially used for disease prognosis, exosome-based therapies, and monitoring binding ability to target tissues via SPECT/CT. In vivo tumor model mice imaging showed higher tumor uptake of 131 I-tumor-derived exosomes ( 131 I-TDE) compared to the tumor uptake of free 131 I in the same tumor model [141] . The biodistribution studies showed unlike 131 I-HEK293 exosomes (human embryonic kidney 293 cells that are non-cancerous), 131 I-MDSCs exosomes (myeloid derived suppressor cells) and 131 I-EPCs exosomes (endothelial progenitor cells) accumulated in the primary tumor site in breast cancer and metastatic site in lung cancer, indicating target-specific TDEs accumulation in tumors, enabling the potential uses of the specific derived exosomes.

A novel radiolabeling approach was reported for 131 I-labeled EVs for two different cell lines, thyroid cancer cell (Cal62) and natural killer cells (NK92-MI). Instead of direct labeling the radioiodine on the EV surfaces, sulfosuccinimidyl-3-(4-hydroxypheynyl) propionate (SULFO-SHPP) was employed to modify the surface of EVs to increase the number of available sites for radioiodination on the EV surfaces. In terms of morphology and size, the SEM images showed little differences between normal EVs in comparison to 131 I-labeled surface modified EVs. A gamma camera was initially used for in vivo tracking to quantify the levels of free and radiolabeled exosomes. Due to the low resolution of gamma camera, it was unable to perform imaging of the thyroid gland, but limitations can be overcome by using SPECT/PET imaging [41] (Figure 3 ). Through modification of the surface of EVs, increased labeling sites can be labeled with radioiodine for in vivo studies and eventually clinical potentials. Similarly, the glycosylated moieties on EV surfaces were modified followed by conjugation of 124 I-for in vivo studies using different routes of administration. By PET-CT imaging and biodistribution studies, the radioactivity in different organs was quantified at different time intervals with a gamma counter. The glycosylated EV surface affected the biodistribution of 124 I-EVs in different organs after 72 h. Glycosylated 124 I-EVs by neuraminidase showed higher accumulation of radioactivity in the lungs than unmodified 124 I-EVs. Interestingly, the presence of glycosylated 124 I-EVs was detected in the brain. This offers an example of how surface modification of EVs for radiolabeling could affect the distribution and how different routes of administration could lead to different biodistributions of the radiolabeled EVs [40] . 64 Cu-and 68 Ga-radionuclides chelated by a bifunctional chelator, 1,4,7-triazacyclononanetriacetic acid (NOTA), were used to label exosomes via the conjugation of NOTA to amine groups on the exosome surfaces. 64 Cu-or 68 Ga-labeled exosomes showed similar accumulation results at the target sites in PET imaging. Due to the difference of half-life and labeling efficiency of the two radioisotopes, 64 Cu-was superior, with a half-life of 12.7 h and a labeling efficiency of 13.3% for 100 ug of exosomes, compared to 68 Ga-, with a half-life of 68 min and a labeling efficiency of 2.22% for 100 µg exosomes. The study also highlighted the superiority of PET imaging having better sensitivity and depth penetration over optical imaging where accumulation of radiolabeled exosomes was found in the lungs and liver using PET imaging but was not found in optical imaging. The radiolabeling of exosomes using bifunctional chelators such as NOTA enables less dependency on the cell type since most cells contain amine functional groups for interaction [42] . With less dependency on cell type, more exosomes derived from different tumors and cells could be used as nanomaterials for radiolabeling in nuclear medicine and imaging. Intraluminal labeling of radionuclides to exosomes was demonstrated through the use of a metastable lipophilic [ 89 Zr]Zr(oxinate) 4 neutral complex. The radiometal complex was encapsulated into the exosomes and ensured that the surfaces of the exosome were not affected. The lipophilic complex [ 89 Zr]Zr(oxinate) 4 was able to pass through the lipid bilayer of the vesicles where 89 Zr dissociated from the oxine ligands; dissociated free 89 Zr then bound to intravesicular metal-chelating ligands, such as proteins and nucleic acids within the exosomes. Biodistribution studies using exosomes derived from pancreatic cancer cells (PANC1) via PET-CT displayed 89 Zr-PANC1 exosomes accumulated in the liver, spleen, bladder, lymph nodes, and brain within 1 h of intravenous (iv.) injection [43] . As exosomes are involved in cellular communication, the integrity of the surface of exosomes is crucial. Modifications could result in impacts on the distribution and functions of the exosomes. This work has shown a radiolabeling method that could prevent alterations of the surface of exosomes, expanding routes to radiolabel exosomes. The possibilities of discovering new probes to label these nanosized vesicles could potentially help in creating novel clinical diagnostic and therapeutic tools in nuclear medicine to tackle different targets and diseases.

With the development of nuclear imaging probes using nanomaterials, pathological processes at molecular levels can be revealed that could potentially help in early detection and interventions of various diseases. Enhancement of nanomaterial targeting capabilities as imaging probes has been explored through various approaches such as surface modifications and targeting moieties attachment. In this review, we summarized developments of nanomaterials as nuclear imaging probes through various modifications. The applications of nanomaterials have been extensively exploited for biocompatibility, in vitro stability, and in vivo biodistribution and animal imaging. Despite promising results from in vivo studies, there are still challenges that need to be overcome before nanomaterials can be applied as diagnostic and/or therapeutic nuclear medicine and imaging tools in clinical applications. For example, the reproducibility of various nanomaterials needs to be systematically determined, and the synthetic methods need to be standardized to ensure their biocompatibility so that theoretical modelling of nanomaterial integration can be guided for cell tracking and cell internalization. The review provides some future research directions to those with expertise in radiochemistry, nuclear imaging engineering, and other bio-imaging research. It is envisaged that the research thrust area combining these nanomaterials including exosomes can lead to a new generation of nuclear imaging probes and introducing a paradigm shift in theranostics. 

Design and development of molecular imaging probes

Molecular imaging for cancer diagnosis and surgery

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

Engineering precision nanoparticles for drug delivery

Combined 18 F-FDG PET-CT and DCE-MRI to Assess Inflammation and Microvascularization in Atherosclerotic Plaques

Clinical evaluation of contrast-enhanced digital mammography and contrast enhanced tomosynthesis-Comparison to contrast-enhanced breast MRI

Instrumentation in molecular imaging

Limits of Tumor Detectability in Nuclear Medicine and PET

The Evolving Role of 18F-FDG PET/CT in Diagnosis and Prognosis Prediction in Progressive Prostate Cancer

Radiolabelling of nanomaterials for medical imaging and therapy

Cellular internalization of bystander nanomaterial induced by TAT-nanoparticles and regulated by extracellular cysteine

Gadolinium-based bimodal probes to enhance T1-Weighted magnetic resonance/optical imaging

Nano based drug delivery systems: Recent developments and future prospects

Nanoparticulate Contrast Agents for Multimodality Molecular Imaging

Recent development of nanoparticles for molecular imaging

Development of 68 Ga-labeled mannosylated human serum albumin (MSA) as a lymph node imaging agent for positron emission tomography

Radiolabeled liposomes and lipoproteins as lipidic nanoparticles for imaging and therapy

PET imaging of tumor-associated macrophages with 89 Zr-labeled high-density lipoprotein nanoparticles

Imaging of the EPR Effect in Tumor Xenografts Using Small 15 nm Diameter Polyethylene Glycols Labeled with Zirconium-89

The Novel DPP-BDT Nanoparticles as Efficient Photoacoustic Imaging and Positron Emission Tomography Agents in Living Mice

Radiolabelling of lipid-based nanocarriers with fluorine-18 for in vivo tracking by PET

64Cu-labeled melanin nanoparticles for PET/CT and radionuclide therapy of tumor

Furin-Guided Intracellular 68Ga Nanoparticle Formation Enhancing Tumor MicroPET Imaging

Triaza-based amphiphilic chelators: Synthetic route, in vitro characterization and in vivo studies of their Ga(III) and Al(III) chelates

III) chelates of amphiphilic DOTA-based ligands: Synthetic route and in vitro and in vivo studies

In vivo targeting and positron emission tomography imaging of tumor vasculature with 66Ga-labeled nano-graphene

Vivo Targeting and Imaging of Tumor Vasculature with Radiolabeled

Preparation of a Versatile Bifunctional Zeolite for Targeted Imaging Applications

Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots

Chelator-Free Labeling of Metal Oxide Nanostructures with Zirconium-89 for Positron Emission Tomography Imaging

Molecular Platform for Design and Synthesis of Targeted Dual-Modality Imaging Probes

Multimodality PET/MRI agents targeted to activated macrophages

89 Zr-and Fe-Labeled Polymeric Micelles for Dual Modality PET and T1-Weighted MR Imaging

PET/NIRF/MRI triple functional iron oxide nanoparticles

Facile Preparation of a Hybrid Nanoprobe for Triple-Modality Optical/PET/MR Imaging

131I-Labeled Multifunctional Polyethylenimine/Doxorubicin Complexes with pH-Controlled Cellular Uptake Property for Enhanced SPECT Imaging and Chemo/Radiotherapy of Tumors

Synergistic Cytotoxicity of Shikonin-Silver Nanoparticles As An Opportunity For Lung Cancer

Development of theranostic active-targeting boron-containing gold nanoparticles for boron neutron capture therapy (BNCT)

X-rays-optimized delivery of radiolabeled albumin for cancer theranostics

Modification of the glycosylation of extracellular vesicles alters their biodistribution in mice

Radioiodine labeling and in vivo trafficking of extracellular vesicles

Identification of Lymphatic and Hematogenous Routes of Rapidly Labeled Radioactive and Fluorescent Exosomes through Highly Sensitive Multimodal Imaging

Zr(oxinate) 4 allows direct radiolabelling and PET imaging of small extracellular vesicles

Challenges in Nuclear Medicine: Innovative Theranostic Tools for Personalized Medicine

The Repertoire of Small-Molecule PET Probes for Neuroinflammation Imaging: Challenges and Opportunities beyond TSPO

An overview of nanoscale radionuclides and radiolabeled nanomaterials commonly used for nuclear molecular imaging and therapeutic functions

Blood-brain barrier delivery

Nanotechnology approaches for drug and small molecule delivery across the blood brain barrier

Introduction to Bionanomaterials: An Overview

Superparamagnetic iron oxide-Loaded poly (lactic acid)-d-α-tocopherol polyethylene glycol 1000 succinate copolymer nanoparticles as MRI contrast agent

Facile synthesis of water-stable fine magnetite nanoparticles for MRI and magnetic hyperthermia applications

Nanoparticles disguised as red blood cells to evade the immune system

Effect of Folate-Targeted Nanoparticle Size on Their Rates of Penetration into Solid Tumors

Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers

Her2-targeted pegylated liposomal doxorubicin: Retention of target-specific binding and cytotoxicity after in vivo passage

Influence of poly(ethylene glycol) grafting density and polymer length on liposomes: Relating plasma circulation lifetimes to protein binding

PEGylation of microspheres generates a heterogeneous population of particles with differential surface characteristics and biological performance

Manipulating the surface coating of ultra-small Gd2O3 nanoparticles for improved T1-weighted MR imaging

Magnetic and hydrogel composite materials for hyperthermia applications

Novel magnetic multicore nanoparticles designed for MPI and other biomedical applications: From synthesis to first in vivo studies

Synthesis of iron-oxide magnetic nanoparticles coated with dextran of varied molecular mass using a facile ball-milling method

Highly sensitive magnetite nano clusters for MR cell imaging

LipoCEST and cellCEST imaging agents: Opportunities and challenges

Development of a novel microbubble-liposome complex conjugated with peptide ligands targeting IL4R on brain tumor cells

Peptide-conjugated nanoparticles for targeted imaging and therapy of prostate cancer

Synthesis and in vivo magnetic resonance imaging evaluation of biocompatible branched copolymer nanocontrast agents

Streptavidin-biotin technology: Improvements and innovations in chemical and biological applications

Kraeber-Bodéré, F. Improvement of Radioimmunotherapy Using Pretargeting

Chemoaffinity capture of pre-targeted prostate cancer cells with magnetic beads

Targeted drug delivery to tumors: Myths, reality and possibility

Nanoparticle and targeted systems for cancer therapy

Targeting Strategies for Multifunctional Nanoparticles in Cancer Imaging and Therapy

Targeting strategies for improving the efficacy of nanomedicine in oncology

Tracking Neural Stem Cells in Patients with Brain Trauma

Death: Insights from Molecular and Microstructural Magnetic Resonance Imaging

Particle shape enhances specificity of antibodydisplaying nanoparticles

Antibody-labeled liposomes for CT imaging of atherosclerotic plaques: In vitro investigation of an anti-ICAM antibody-labeled liposome containing iohexol for molecular imaging of atherosclerotic plaques via computed tomography

VCAM-1-targeted magnetic resonance imaging reveals subclinical disease in a mouse model of multiple sclerosis

Cell-Penetrating Peptides: A Useful Tool for the Delivery of Various Cargoes Into Cells

Monoclonal Antibodies in Cancer Therapy

The hallmark of antibodies used for optimization of tumor targeting by design

Aptamers as therapeutics

A Nucleolin-Targeted Multimodal Nanoparticle Imaging Probe for Tracking Cancer Cells Using an Aptamer

Applications of Aptamers as Sensors

Folate-targeted therapeutic and imaging agents for cancer

The Folate Receptor α Is Frequently Overexpressed in Osteosarcoma Samples and Plays a Role in the Uptake of the Physiologic Substrate 5-Methyltetrahydrofolate

Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: First in-human results

Prospective of 68Ga-Radiopharmaceutical Development

Imaging cancer cells with nanostructures: Prospects of nanotechnology driven non-invasive cancer diagnosis

Sentinel lymph node excision with or without preoperative hybrid single-photon emission computed tomography/computed tomography (SPECT/CT) in melanoma: Study protocol for a multicentric randomized controlled trial

Labelling of commercially available human serum albumin kits with Ga-68 -as surrogates for 99 mTc-MAA microspheres

Nanoparticles and Phage Display Selected Peptides for Imaging and Therapy of Cancer. Recent Results Cancer Res

Radiohybridization PET imaging of KRAS G12D mRNA expression in with [ 64 Cu]DO3A-peptide nucleic acid-peptide nanoparticles

Emerging role of radiolabeled nanoparticles as an effective diagnostic technique

Nuclear imaging of liposomal drug delivery systems: A critical review of radiolabelling methods and applications in nanomedicine

Radiolabeling of lipid-based nanoparticles for diagnostics and therapeutic applications: A comparison using different radiometals

Novel Method to Label Solid Lipid Nanoparticles with 64 Cu for Positron Emission Tomography Imaging

Vascular Targeting of Radiolabeled Liposomes with Bio-Orthogonally Conjugated Ligands: Single Chain Fragments Provide Higher Specificity than Antibodies

Melanin-based nanoparticles in biomedical applications: From molecular imaging to treatment of diseases

pH-triggered assembly of natural melanin nanoparticle for enhanced PET imaging

Radiolabeling Silica-Based Nanoparticles via Coordination Chemistry: Basic Principles, Strategies, and Applications

Imaging prostate cancer lymph node metastases with a multimodality contrast agent

Nanoparticles Modified by Encapsulation of Ligands with a Long Alkyl Chain to Affect Multispecific and Multimodal Imaging

Targeted 64 Cu-labeled gold nanoparticles for dual imaging with positron emission tomography and optical imaging

Tripods: A Multifunctional Nanomaterial for Positron Emission Tomography and Image-Guided Photothermal Cancer Treatment

Biomineralization-Inspired Synthesis of Copper Sulfide-Ferritin Nanocages as Cancer Theranostics

Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe

Bioresponsive Polyoxometalate Cluster for Redox-Activated Photoacoustic Imaging-Guided Photothermal Cancer Therapy

Radiolabeled PET/MRI Nanoparticles for Tumor Imaging

Application of Nanomaterials in Biomedical Imaging and Cancer Therapy

Simultaneous Preclinical Positron Emission Tomography-Magnetic Resonance Imaging Study of Lymphatic Drainage of Chelator-Free Cu-64-Labeled Nanoparticles

Liposomes for PET and MR Imaging and for Dual Targeting (Magnetic Field/Glucose Moiety): Synthesis, Properties, and in Vivo Studies

Hybrid core shell nanoparticles entrapping Gd-DTPA and 18F-FDG for simultaneous PET/MRI acquisitions

Solid Tumor-Targeting Theranostic Polymer Nanoparticle in Nuclear Medicinal Fields

Nuclear molecular imaging with nanoparticles: Radiochemistry, applications and translation

Shikonin derivatives for cancer prevention and therapy

Shikonin Inhibits Cancer Through P21 Upregulation and Apoptosis Induction

Human Serum Albumin Nanoparticles for Use in Cancer Drug Delivery: Process Optimization and In Vitro Characterization

Exosomes: Looking back three decades and into the future

Electron microscopic evidence for externalization of the transferrin receptor in vesicular form in sheep reticulocytes

The Messengers of Health and Disease

B lymphocytes secrete antigen-presenting vesicles

Exosomes: Key players in cancer and potential therapeutic strategy

Exosomes as Smart Nanoplatforms for Diagnosis and Therapy of Cancer

Eradication of established murine tumors using a novel cell-free vaccine: Dendritic cell derived exosomes

Exosomes-based biomarker discovery for diagnosis and prognosis of prostate cancer

Exosomes in cancer development and clinical applications

Radiolabelling of Extracellular Vesicles for PET and SPECT imaging

Advances in Analysis of Biodistribution of Exosomes by Molecular Imaging

Circulating exosomes are strongly involved in SARS-CoV-2 infection

Mesenchymal stem cell-based therapy and exosomes in COVID-19: Current trends and prospects

Diverse Effects of Exosomes on COVID-19: A Perspective of Progress from Transmission to Therapeutic Developments

Exosomes in developmental signalling

Extracellular Vesicles and Their Role in Urologic Malignancies

Emerging role of exosomes in liver physiology and pathology

Current Perspectives on Clinical Use of Exosomes as a Personalized Contrast Media and Theranostics

Towards Therapeutic Delivery of Extracellular Vesicles: Strategies for In Vivo Tracking and Biodistribution Analysis

In Vivo Tracking of Extracellular Vesicles by Nuclear Imaging: Advances in Radiolabeling Strategies

Differential in vivo biodistribution of 131 I-labeled exosomes from diverse cellular origins and its implication for theranostic application