Abstract
The armamentarium of approved radiopharmaceuticals for either diagnosis or therapy is at the core of the clinical practice of today’s nuclear medicine. Nevertheless, both because the currently approved agents do not meet all the clinical needs for radionuclide targeting and because advancing knowledge in the pathophysiology of tissues/organs open in turn new opportunities, investigations continue at the preclinical and clinical validation level for the development of new radiopharmaceuticals, most of which are not approved yet for commercial use. Concerning in particular the diagnostic applications of nuclear medicine to oncology, ongoing investigations in the search for tumor-targeting agents with better specificity and sensitivity are countless, possibly within the scenario of theranostics – that is, with the dual potential for imaging and for therapy, depending on the specific radionuclide employed for radiolabeling. We will focus this chapter on the most promising imaging agents labeled with single-photon-emitting radionuclides based on some of the mechanisms that are typical for tumor cells/tissues.
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Introduction and Background
The armamentarium of approved radiopharmaceuticals for either diagnosis or therapy is at the core of the clinical practice of today’s nuclear medicine. Nevertheless, advancing knowledge in the pathophysiology of tissues/organs opens new opportunities, for the development of new radiopharmaceuticals, most of which are not approved yet for commercial use. There is an ongoing search for tumor-targeting agents with better specificity and sensitivity. There are many new developments of agents with the dual potential for imaging and for therapy, depending on the specific radionuclide employed for radiolabeling [1–3].
Tumor cells and tissues exhibit different characteristics compared to normal cells and due to the altered physiology, tissue composition, and expression of intra- and extracellular molecules [4, 5]. These attributes can be the basis for developing new imaging targets for diagnostic applications as well as for developing new anticancer drugs and for assessing tumor response to treatment [6–9] (see also Chaps. 1, “Cancer Biology of Molecular Imaging,” and 2, “Principles of Molecular Targeting for Radionuclide Therapy” of this book).
Single-photon-emitting radiopharmaceuticals can be classified according to different properties, such as their biodistribution and targeting characteristics, their different chemical and physical properties, and their specific interaction with a target. Tumors are known to display an aberrant vascular network and microcirculation, which in turn influence an increase in interstitial pressure, as well as hypoxia and acidosis; all these features contribute to the expression of malignant phenotypes and to resistance to various treatments [10]. Within this environment, tumor cells can also display altered energy metabolism, as reflected, for example, in increased glucose uptake and shifted balances in metabolic products.
Thus, at the preclinical level, a variety of single-photon-emitting tracers are under evaluation for use as markers for (neo)angiogenesis [11–13], hypoxia [14, 15], acidosis [16], metabolic activity [17], and proteolytic activity [18, 19]. Besides metabolic tracers, efforts are being directed also toward the development and validation of single-photon probes specific for tumor target molecules such as cell surface antigens, receptors, or other molecules similarly overexpressed in tumor tissues [20]. The use of peptides interacting with receptors [21], of antibodies or antibody fragments targeting different epitopes of tumor-associated antigens [22], of vitamin-based radiopharmaceuticals [23], and of nucleoside analogs [24–27] significantly increases the possibilities for tumor detection, localization, and staging. Specific issues of interest in translational preclinical imaging studies include efforts directed at improving specificity for tumor types [28], tumor uptake/retention [29], yet with minimal pharmacological effects of the imaging probes.
The successful choice of a target molecule potentially leads to the development not only of a molecular imaging probe but also of a therapeutic agent capable to inhibit the disease process – according to the approach of theranostics . Receptor targeting with small radiolabeled peptides for receptor-targeted tumor imaging (PET and SPECT) as well as for radionuclide therapy provides good examples of such theranostics potential.
Peptide Receptor Targeting
The best-known examples of this tumor-targeting mechanism are based on the use of somatostatin analogs. For imaging purposes either single-photon-emitting radionuclides (chiefly 111In) or positron-emitting radionuclides (chiefly 68Ga) are used in the clinical routine. For therapeutic purposes, different β−-emitting radionuclides (chiefly 90Y and 177Lu) are currently being used clinically or undergoing extensive validation; although the chief indications for the use of these radiopharmaceuticals regard neuroendocrine neoplasms (see Chaps. 29, “Diagnostic Applications of Nuclear Medicine: Neuroendocrine Tumors,” and 43, “Neuroendocrine Tumors: Therapy with Radiolabeled Peptides” of this book), the indications for the use of these tracers, with either diagnostic or therapeutic purposes, are expanding to other tumors as well. Thus, the radiolabeled somatostatin analogs are prototypes for a whole spectrum of other peptide receptor systems that are overexpressed in a variety of tumors. The common feature shared by all these systems is that they are members of the so-called G-protein-coupled receptor superfamily and play a major role in the progression and angiogenesis of a number of malignancies.
Briefly, the peptide ligands that have yielded the most promising results so far are the analogs of bombesin, of cholecystokinin, of the vasoactive intestinal peptide, of gastrin, of glucagon, of substance P, of exendin, and of the α-melanocyte-stimulating hormone [30–36]. The use of the so-called RGD-based peptides for targeting the integrin receptor system (another member of the G-coupled family) is discussed further below in this chapter.
Apoptosis
Apoptosis is a process of regulated or programmed cell death, which in its classic form, does not cause inflammation. The mitochondria and ribosomes of the cells undergoing apoptosis remain intact, and surrounding cells internalize them along with the other components of the post-apoptotic cell. Necrotic cells, in contrast, lose membrane integrity, swell, and then release their contents to the surrounding tissue, causing inflammation and possibly initiating an immune response.
Lipid composition of the outer and inner leaflets of the plasma membrane is normally not symmetrical; for instance, some molecules such as phosphatidylserine and phosphatidylethanolamine are normally retained on the intracellular face of the cell membrane. When cells undergo apoptosis, this distribution is altered, so that these molecules are rapidly exposed to the outside of the cell membrane. The most promising single-photon-emitting radiopharmaceuticals targeting phosphatidylserine and phosphatidylethanolamine are represented by radiolabeled annexin and duramycin, respectively.
99mTc-Annexin V
The discovery of phosphatidylserine externalization as the event initiating apoptosis has opened the way to the search for compounds that have an affinity for phosphatidylserine and could therefore be used to localize in sites of apoptosis. To date, the compound that has received major interest in both the preclinical and clinical arena is annexin V, a non-glycosylated single-chain protein physiologically involved in the inhibition of hemostasis [37]. Annexin V, which is part of a protein family that binds to negatively charged phospholipids in a Ca2+-dependent manner, is distributed ubiquitously in the human body. Complete functional details of the annexin V pathway have yet to be clarified, but a large body of evidence suggests that annexin acts as a specific ligand for phosphatidylserine, and it is able to prevent activation of the immune response when cells undergo apoptosis [38].
In translational research, annexin V labeled with radionuclides has been used for studying, localizing, visualizing, and measuring apoptosis in vitro as well as in vivo, both in preclinical animal models and in patients [39, 40]. Radiolabeled annexin was first proposed to image blood clots in patients with atrial fibrillation; subsequently this compound gained attention for imaging of apoptosis in tumors [41]. Annexin V used for development of radiolabeled imaging agents is produced by the expression of annexin V complementary DNA in Escherichia coli . Several radiolabeled probes and other agents bearing different moieties have been explored preclinically to image annexin V uptake by means of SPECT, PET, MRI, and near-infrared fluorescence (NIRF).
As single-photon imaging probes, numerous methods for labeling annexin with 99mTc have been identified through the use of chelators such as the bifunctional N2S2 chelate to form 99mTc-4,5-bis(thioacetamido)pentanoyl-annexin V (or 99mTc-BTAP-annexin V, also known as 99mTc-Apomate) or hydrazinonicotinamide (HYNIC) to form 99mTc-HYNIC-annexin V. The former formulation is also available as a good manufacturing practice (GMP) product in a radiolabeling kit [42].
Moreover, animal experiments suggest an improved protocol for annexin labeling via the use of self-chelating annexin V mutants. In this case, the radiotracer exhibits reduced abdominal background and decreased renal radiation dose [43]. At the clinical level, various studies support the notion that 99mTc-annexin V SPECT allows for noninvasive, reproducible, quantitative apoptosis imaging and for assessing tumor response as early as 24 h after the start of treatment, with the goal of monitoring the effectiveness of therapy in cancer patients. With pioneering work, Belhocine et al. used 99mTc-BTAP-annexin V to monitor chemosensitivity in a variety of cancer types (e.g., lung cancer, lymphoma, and breast cancer), demonstrating that 99mTc-BTAP-annexin V uptake after chemotherapy was significantly related to survival and progression-free survival in cancer patients [44].
More recently 99mTc-annexin V has been probed in clinical studies to assess the efficacy of chemotherapy and radiotherapy [45, 46]. The promising results so far obtained offer the possibility also in this scenario to develop a personalized medicine approach, now primarily explored in genome-based medicine, applicable to all cancer patients.
However, the main problems in a wide clinical application remain the absence of ideal biological properties; experiences with radiolabeled annexin V have indicated that issues such as biodistribution and target-to-background ratio require further improvement [47]. In an attempt to reduce renal uptake, annexin V was also labeled with 123I. 123I-annexin V does indeed show good imaging features for imaging the abdominal region compared to 99mTc compounds (no liver nor renal radioactivity accumulation 12-h post-injection) but is subject to rapid in vivo dehalogenation and is more expensive, and the labeling procedure is more complex [48].
99mTc-Duramycin
Duramycin, a 19-amino acid peptide cross-linked by a disulfide bond, has been found to be capable of binding to phosphatidylethanolamine with high affinity and high selectivity; therefore, the radiolabeled 99mTc-duramycin represents now a novel molecular compound for apoptosis imaging [49].
Similar to phosphatidylserine (the target marker of the earliest apoptosis probe, annexin V), phosphatidylethanolamine is a major component of the inner leaflet of the cell membrane, and its expression on the surface of normal viable cells is extremely low [50–52]. When apoptosis occurs, phosphatidylethanolamine is exposed on the cell surface [53], because of redistribution of phospholipids across the bilayer. Phosphatidylethanolamine becomes accessible to the extracellular milieu during necrosis, because of the compromised plasma membrane integrity. Thus, phosphatidylethanolamine constitutes a potential target molecule for cell death imaging in general.
Phosphatidylethanolamine expressed on the apoptotic cell surface appears to play a regulatory role in the so-called blebbing and formation of apoptotic bodies. In these constitutive processes of apoptosis, intracellular components are discretely packaged and earmarked for engulfment by scavenger cells without causing inflammation. As one of the morphologic hallmarks of apoptosis, blebbing includes profound membrane structural remodeling. The trans-bilayer movement of phosphatidylethanolamine is especially enhanced on the blebs of apoptotic cells. These morphologic changes are in part attributed to the phosphatidylethanolamine-mediated reorganization of actin filaments [54, 55].
As a novel molecular probe to target apoptosis imaging, duramycin is produced by Streptoverticillium cinnamoneus [56, 57]. Biologic activities of duramycin have been well characterized, and their phosphatidylethanolamine binding activity explored with in vitro biologic studies [58–62]. In particular, duramycin binds the head group of phosphatidylethanolamine with high affinity at a molar ratio of 1:1 [63–65]. Duramycin has a compact cyclic configuration, with a single binding pocket that specifically interacts with phosphatidylethanolamine. Stabilized by three internal thioether bonds, duramycin is the smallest known polypeptide that has a defined three-dimensional binding site [56, 57].
In 2008, Zhao et al. originally described the preparation of 99mTc-labeled duramycin, using a HYNIC ligand with tricine and phosphine as coligands [66]. The low molecular weight of duramycin (∼2 kDa) confers favorable pharmacokinetics and biodistribution properties for in vivo imaging of apoptosis. However, in the original formulation, HPLC purification after radiolabeling was a prerequisite for intravenous injection in humans, a cumbersome procedure that limited clinical investigations. The goal to produce high-quality 99mTc-curamycin in a single-step kit formulation, without additional purification steps, was achieved in 2012 by Zhao and coworkers, with the development of a single-step kit formulation for 99mTc-labeling of HYNIC-duramycin [67]. An optimal formulation with tricine-to-TPPTS molar ratio of 10:1 was determined, which led to consistent production of high radiochemical purity 99mTc-duramycin without the need for further purification. The radiopharmaceutical so produced retained phosphatidylethanolamine binding affinity and specificity, while its clearance properties and in vivo biodistribution were consistent with those obtained in prior studies using radio-HPLC-purified preparation.
In a rat model of myocardial ischemia/reperfusion injury, 99mTc-duramycin showed specific higher uptake in apoptotic cells than in viable control cells, with favorable pharmacokinetic and biodistribution profiles. The tracer was rapidly cleared from the circulation via the renal system with a blood half-life of less than 4 min in rats and a very low liver and gastrointestinal uptake [67, 68]. Similar favorable targeting and biodistribution properties have been observed also in a porcine model of myocardial ischemia/reperfusion, showing high accumulation of 99mTc-duramycin in tissue sites of injury with high apoptotic activity [69]. In addition, 99mTc-duramycin has been evaluated for imaging ischemia/reperfusion injury in the brain using the rat model of middle cerebral artery occlusion [70], as well as in a model of oxidative lung injury [71–73], and finally in susceptible tissues after exposure to high-dose radiation [74].
Taken altogether, these investigations suggest the high potential of 99mTc-duramycin for use in oncology, an assumption that has recently been confirmed by preclinical studies demonstrating high specific uptake of 99mTc-duramycin in apoptotic cells of colon cancer or breast cancer xenografts responding to chemotherapy [75–77], thus supporting the hypothesis that 99mTc-duramycin is a potential candidate in cancer patients to assess response to therapy.
Angiogenesis
The formation of the new vessels (“angiogenesis”) is an essential process in the growth of solid tumors. Once tumors have reached a size of >1 mm3, diffusion alone from the capillary bed is no longer sufficient to supply the tumor cells with adequate amounts of oxygen and nutrients. Further tumor growth is only possible when new blood vessels are formed. Nevertheless, while normal angiogenesis is orderly and highly regulated, tumor angiogenesis is chaotic and irregular. Angiogenesis represents an interesting molecular target not only for imaging but also for targeted forms of therapy. Examples for target antiangiogenic therapies currently used in the clinical practice are cilengitide (that inhibits integrin receptors αvβ3 and αvβ5) and bevacizumab, an antibody targeting the vascular endothelial growth factor (VEGF).
Different potential molecular targets to monitor angiogenesis are potentially available for imaging purposes. At the moment the most suitable candidates for tracer development are represented by integrin antagonists, expressed extracellular matrix protein inhibitors or matrix metalloproteinase, as well as by tracers binding to tyrosine kinases or growth factor receptors.
Integrins
Integrins are heterodimeric membrane receptors constituted by α and β subunits that mediate interactions between cells and the extracellular matrix and soluble molecules (such as growth factors). So far 18 different α and 8 different β subunits have been identified, corresponding to 24 different integrin receptors. Integrin αvβ3 is one of the most studied in oncology, because it is highly expressed on the cell surface of activated endothelial cells in newly formed blood vessels. In the preclinical setting, a large variety of imaging strategies have been successfully employed for imaging integrin expression.
All the tracers that are used for imaging of integrin expression are based on the tripeptide sequence arginine-glycine-aspartic acid (or RGD in the single letter code) [78]. RGD binds to the integrin containing the αv subunit, which represents an abundant physiologic integrin-binding ligand in proteins of the extracellular matrix. Accordingly, a variety of radiolabeled RGD-based peptides have been developed for noninvasive imaging of integrin αvβ3 expression with either SPECT or, in most of the cases, PET. The 99mTc-labeled RGD peptides have been the subject of few investigations, and few peptides have been translated into clinical use, such as 99mTc-NC100692 and 99mTc-labeled RGD dimeric peptides with PEG4 and Gly3.
99mTc-αP2
This 10-amino acid 99mTc-peptide first described in 1988 contains two copies of the RGD motif for integrin-specific binding. It has been tested in a clinical study in a patient with malignant melanoma, resulting in a good detection rate of metastases in the neck, axilla, abdomen, and soft tissue 60–120 min after injection; however, sensitivity was somewhat lower for lesions located in the thorax, due to high blood pool activity in the heart and large vessels [79].
99mTc-NC100692 (or 99mTc-Maraciclatide)
99mTc-NC100692 is a new RGD-containing peptide labeled with 99mTc that binds to integrin αvβ3 with high affinity [80]. Clinical studies in patients with breast and lung cancer showed a good detection rate for malignant lesions greater than 1 cm, in the breast, brain, and lung, whereas the detection rate was considerably lower for bone and liver metastases [81–83].
On the other hand, in the scenario of theranostics , some investigators confirm that 99mTc-NC100692 does target the αvβ3 integrin in mice bearing glioma tumors and may, therefore, be useful for identifying patients prior to anti-αvβ3 therapy as well as for monitoring tumor response to antiangiogenetic therapy in these patients [84].
99mTc-3PRGD2
99mTc-PEG4-E[PEG4-c(RGDfK)]2 (or 99mTc-3PRGD2) is a new single-photon tracer targeting the integrin αvβ3-receptor and has been used preclinically for tumor imaging, for evaluating angiogenesis, and for monitoring antiangiogenic drug efficacy [85, 86].
The new types of RGD peptides show much higher in vitro integrin αvβ3-binding affinity than the single RGD tripeptide sequence and exhibit significantly increased tumor uptake and improved in vivo kinetics in animal models. 99mTc-3PRGD2 is excreted predominantly by the kidneys and has a rapid blood clearance, with less than 1% of the initial radioactivity remaining in the blood circulation at 60 min after injection. No adverse reactions have been observed in animal models or in humans to date. 99mTc-3PRGD2 can easily be prepared in a kit formulation and has shown excellent in vivo patterns of biodistribution in nonhuman primates [87].
Recently, 99mTc-3PRGD2 has been used in patients, in particular for characterizing solitary pulmonary nodules [88], as well as palpable and nonpalpable breast lesions [89]. It has also been used with satisfactory results in patients with lung cancer [90], in patients with iodine-refractory thyroid cancer [91], for imaging bone metastases in patients with lung cancer (versus the conventional 99mTc-MDP bone scan) [92], and for monitoring the response to treatment with antiangiogenetic therapy in a mouse model of glioma [93].
99mTc-RGD-BBN
A dual receptor-targeted probe, integrin αvβ3 and gastrin-releasing peptide receptor (GRPR)-targeted peptide, Glu-c(RGDyK)-bombesin (RGD-BBN) labeled with technetium-99m (99mTc-RGD-BBN), has been tested with promising results in an animal model [94] and then with pilot studies in humans. In particular, its biodistribution has been evaluated in healthy volunteers (exhibiting a safe profile) and in patients with breast cancer as a novel agent for scintimammography. In this clinical setting, 99mTc-RCD-BBN has shown excellent properties for tumor detection [95], with the potential of avoiding surgical biopsy in patients with equivocal breast lesions, thanks to its very high negative predictive value for malignancy [96].
Hybrid Radioactive/Fluorescent RGD
111In-labeled RGD has been coupled with a fluorescent dye to produce a hybrid tracer, with the purpose of allowing visualization of tumor margins during surgery as well as the in vivo detection of the tumor and its distant metastases. Only very preliminary preclinical studies have been performed so far with this new hybrid tracer, which appears to exhibit optimal properties for targeted αvβ3 integrin detection, with very high tumor-non-tumor ratios [97].
Extracellular Matrix
Fibronectin is a polymorphic matrix protein belonging to the widely distributed family of universal cell-adhesion molecules. Fibronectin can exist in several isoforms implied in a variety of processes such as cell migration, wound healing, and oncogenic transformation. A particular isoform (the splicing variant ED-B) is important in vascular proliferation and is widely expressed in neoplastic tissues while showing a highly restricted distribution in normal tissues [98].
99mTc-AP39
The 99mTc-anti-ED-B fibronectin L19-(Gly)3-Cys-Ala scFv antibody fragment (99mTc-AP39) is a radiolabeled molecular imaging agent developed for single-photon emission imaging of tumor angiogenesis and for guidance during antiangiogenic treatment for tumors.
The single-chain antibody fragment (scFv) derived from the L19 monoclonal antibody (with a high affinity to ED-B fibronectin) was developed by Pini et al. [99] and initially labeled with radioiodine for biodistribution in different animal models, where it exhibited excellent targeting to tumor vessels, without selective accumulation in the vessels of other organs [100].
In order to prepare a stable 99mTc-labeled L19 fragment, Berndorff et al. [101] inserted the amino acid sequence (Gly)3-Cys-Ala at the C terminus of L19 to produce the recombinant protein, AP39. These authors demonstrated that the 99mTc-labeled compound so formed (99mTc-AP39) has favorable biodistribution and imaging properties in mice bearing a murine embryonal teratocarcinoma. Since high levels of ED-B expression have been found in a variety of cancers including primary and metastatic breast, colorectal, and non-small cell lung cancers [102–104], this anti-fibronectin tracer has the potential of being useful for noninvasive imaging of tumor angiogenesis in all such cancers, virtually as a pancarcinoma-targeting agent.
Besides the potential for tumor targeting with imaging purposes as described above, the very high uptake of the anti-fibronectin ED-B monoclonal constructs in tumor tissues opens promising perspectives for developing new agents for radioimmunotherapy, as described in details in Chap. 8, “Novel Radiopharmaceuticals for Therapy” of this book.
Matrix Metalloproteinases
Due to their involvement in tumor metastasis and angiogenesis, the matrix metalloproteinases (MMP) are potential targets for molecular imaging. The MMP family consists of more than 18 different members, with levels in tissues that are controlled by a balance between synthesis of the proenzyme and expression of endogenous MMP inhibitors [105]. Increased proenzyme production causes degradation of the basement membrane and of the extracellular matrix, thus preparing the structural requirements for migration of endothelial cells and formation of vessels [106]. In particular, the MMP-2 and MMP-9 gelatinases are often detected in malignant tissue, and their overexpression correlates with tumor aggressiveness and metastatic potential. Ongoing investigations aim at developing synthetic compounds for targeting MMPs.
Although most studies are in a preliminary phase, some hydroxamate-based tracers with promising binding properties have been identified. In particular, among single-photon-emitting agents, the peptidomimetics [111In]-DTPA-RP782 and [99mTc]-(HYNIC-RP805)(tricine)(TPPTS) and the picolyl-benzenesulfonamide [123I]I-HO-CGS 27023A appear to specifically target the enzymatic action of MMPs in animal models of various diseases. Nevertheless, preclinical studies in animal models prove that these imaging agents might be more successful for investigating atherosclerosis than for tumor targeting [ 107].
Epidermal Growth Factor Receptor (EGFR)
The EGFR family consists of four transmembrane receptors, respectively, EGFR properly said (HER1/erbB-1), HER2 (erbB-2/neu), HER3 (erbB-3), and HER4 (erbB-4). EGFR is a glycosylated transmembrane protein composed of an extracellular ligand-binding region, a transmembrane region, and an intracellular tyrosine kinase domain. The extracellular domain binds endogenous growth factors, like epidermal growth factor (EGF) or transforming growth factor alpha (TGF-α). Binding of one of these endogenous ligands triggers erbB receptor aggregation, thus resulting in the formation of receptor homodimers and/or heterodimers, and internalization. Dimer formation leads to activation of the intrinsic receptor tyrosine kinase domain and to a cascade of intracellular signaling pathways.
This mechanism is involved in the regulation of cell growth, as well as in differentiation and survival of cells. These properties have attracted the interest of investigators especially in oncology, and EGFR has been investigated as a major target for the treatment of uncontrolled tumor growth [108]. In fact, EGFR is often overexpressed in human malignancies such as head and neck squamous cell carcinoma, gastrointestinal and abdominal carcinomas, lung carcinomas, carcinomas of the reproductive tract, melanomas, glioblastomas, and thyroid carcinomas [109]. Although data are heterogeneous in this regard, overexpression is often associated with an aggressive tumor phenotype and poor prognosis . To target tumor cell proliferation or growth via EGFR, monoclonal antibodies (mAbs) against this receptor have been developed for therapeutic purpose. One of these agents, cetuximab, has been approved by the Food and Drug Administration (FDA) in 2004 for treatment of colorectal cancer.
Two predominant classes of EGFR inhibitors have been developed including mAbs that target the extracellular domain of EGFR, such as cetuximab (Erbitux) or trastuzumab (Herceptin), and small molecule tyrosine kinase inhibitors (TKIs) that target the receptor catalytic domain of EGFR, such as gefitinib (Iressa) and erlotinib (Tarceva) [110]. Several SPECT single-photon radiopharmaceuticals have been developed in preclinical trials, such as 99mTc-Cetuximab as stable complex with ethylenedicysteine [111,112]. Besides an unexpected high kidney uptake observed in rates bearing a human breast tumor, the 6-h physical half-life of 99mTc was too short for imaging, considering that mAb preparations like cetuximab the highest tracer accumulation in the tumor is expected 2–3 days post-injection. In a pilot clinical study, high uptake of this cetuximab conjugate in tumors was observed, however, without a sufficiently high target-to-background ratio and without a clear correlation with other clinical features in patients with head and neck cancer.
With its relative longer physical half-life (2.8 days), 111In-labeled mAb conjugates obtained using the chelators DOTA or DTPA are in principle more suitable for tumor imaging than the 99mT-labeled counterparts. Accordingly, these have been investigated in animal models [113, 114] and in humans [115]. Radiolabeled pertuzumab, a HER2 dimerization inhibitor that binds to an epitope different from that of trastuzumab, was also evaluated to image HER2 downregulation after 3 days of treatment with trastuzumab in human breast cancer xenografts. 111In-diethylenetriaminepentaacetic acid-pertuzumab (111In-DTPA-pertuzumab [116]) demonstrated a reduction in viable, HER2-positive tumor cells after 3 weeks of therapy [117].
Folate Receptor Overexpression
Due to their increased metabolic and structural requirements, tumor cells usually consume high amounts of folate, a compound involved in many biosynthetic processes including DNA synthesis. The folate transporter is usually overexpressed on the surface of tumors such as ovarian cancer and lung cancer, thus representing a possible target for molecular imaging, both for therapeutic [118] and for diagnostic purpose (99mTc-Etarfolatide or 111In-DOTA-folate) [119]. Interference by important accumulation of this tracer in normal tissues, particularly in the kidneys, makes it difficult to analyze the results of clinical trials with 99mTc-etarfolatide. To prevent such problem, folic acid or pemetrexed combined with thymidine was administered in patients before tracer injection as an antidote to the potential toxicity [120]. The results of trials with this combination are promising, particularly in patients with ovarian cancer [121–123], and the compound is currently under review by the European Medicines Agency.
Abbreviations
- BTAP:
-
Bis(thioacetamido)pentanoyl
- DOTA:
-
2-(4-Isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (macrocyclic coupling agent to label compounds of biological interest with metal radionuclides)
- DTPA:
-
Diethylenetriaminepentaacetic acid
- EGF:
-
Epidermal growth factor
- EGFR:
-
Epidermal growth factor receptor
- FDA:
-
United States Food and Drug Administration
- GMP:
-
Good manufacturing practice
- HER:
-
Human epidermal growth factor receptor
- HPLC:
-
High-performance liquid chromatography (formerly known as high-pressure liquid chromatography)
- HYNIC:
-
6-Hydrazinopyridine-3-carboxylic acid, also known as hydrazidonicotinic acid/hydrazinonicotinamide (a chelating agent)
- MMP:
-
Metalloproteinases, a family of matrix enzymes
- MRI:
-
Magnetic resonance imaging
- NIRF:
-
Near-infrared fluorescence
- PET:
-
Positron emission tomography
- RGD:
-
Tripeptide composed of L-arginine, glycine, and L-aspartic acid (a sequence that is a common element in cellular recognition)
- SPECT:
-
Single-photon emission tomography
- TGF:
-
Transforming growth factor
- TKI:
-
Tyrosine kinase inhibitor
- TPPTS:
-
3,3,3”-Phosphanetriyltris(benzenesulfonic acid) trisodium salt, a ligand also known as sodium triphenylphosphine trisulfonate
- VEGF:
-
Vascular endothelial growth factor
References
Ravdin P. The use of HER2 testing in the management of breast cancer. Semin Oncol. 2000;27 Suppl 9:33–42.
Roses AD. Pharmacogenetics and the practice of medicine. Nature. 2000;405(6788):857–65.
Cornelissen B. Imaging the inside of a tumour: a review of radionuclide imaging and theranostics targeting intracellular epitopes. J Label Compd Radiopharm. 2014;57:310–6.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–74.
Cavallo F, De Giovanni C, Nanni P, Forni G, Lollini PL. The immune hallmarks of cancer. Cancer Immunol Immunother. 2011;60:319–26.
James ML, Gambhir SS. A molecular imaging primer: modalities, imaging agents, and applications. Physiol Rev. 2012;92:897–965.
Mariani G, Bruselli L, Duatti A. Is PET always an advantage versus planar and SPECT? Eur J Nucl Med Mol Imaging. 2008;35:1560–5.
Pauwels EKJ, Bergstrom K, Mariani G, Kairemo K. Microdosing, imaging biomarkers and SPECT: a multi-sided tripod to accelerate drug development. Curr Pharm Des. 2009;15:928–34.
Mariani G, Strauss HW. Positron emission and single-photon emission imaging: synergy rather than competition. Eur J Nucl Med Mol Imaging. 2011;38:1189–90.
Vaupel P. Pathophysiology of solid tumors. In: Molls M, Vaupel P, Nieder C, Anscher MS, editors. The impact of tumor biology on cancer treatment and multidisciplinary strategies. Heidelberg: Springer; 2009. p. 51–92.
Bredow S, Lewin M, Hofmann B, Marecos E, Weissleder R. Imaging of tumour neovasculature by targeting the TGF-beta binding receptor endoglin. Eur J Cancer. 2000;36:675–81.
Zhou Y, Chakraborty S, Liu S. Radiolabeled cyclic RGD peptides as radiotracers for imaging tumors and thrombosis by SPECT. Theranostics. 2011;1:58–82.
Tsiapa I, Loudos G, Varvarigou A, Fragogeorgi E, Psimadas D, Tsotakos T, et al. Biological evaluation of an ornithine-modified 99mTc-labeled RGD peptide as an angiogenesis imaging agent. Nucl Med Biol. 2013;40:262–72.
Kimura S, Umeda IO, Moriyama N, Fujii H. Synthesis and evaluation of a novel 99mTc-labeled bioreductive probe for tumor hypoxia imaging. Bioorg Med Chem Lett. 2011;21:7359–62.
Umeda IO, Tani K, Tsuda K, Kobayashi M, Ogata M, Kimura S, et al. High resolution SPECT imaging for visualization of intratumoral heterogeneity using a SPECT/CT scanner dedicated for small animal imaging. Ann Nucl Med. 2012;26:67–76.
Weerakkody D, Moshnikova A, Thakur MS, Moshnikova V, Daniels J, Engelman DM, et al. Family of pH (low) insertion peptides for tumor targeting. Proc Natl Acad Sci U S A. 2013;110:5834–9.
von Forstner C, Zuhayra M, Ammerpohl O, Zhao Y, Tiwari S, Jansen O, et al. Expression of L amino acid transport system 1 and analysis of iodine-123-methyltyrosine tumor uptake in a pancreatic xenotransplantation model using fused high-resolutionmicro-SPECT-MRI. Hepatobiliary Pancreat Dis Int. 2011;10:30–7.
Kondo N, Temma T, Shimizu Y, Watanabe H, Higano K, Takagi Y, et al. Miniaturized antibodies for imaging membrane type-1 matrix metalloproteinase in cancers. Cancer Sci. 2013;104:495–501.
LeBeau AM, Duriseti S, Murphy ST, Pepin F, Hann B, Gray JW, et al. Targeting uPAR with antagonistic recombinant human antibodies in aggressive breast cancer. Cancer Res. 2013;73:2070–81.
Cai J, Li F. Single-photon emission computed tomography tracers for predicting and monitoring cancer therapy. Curr Pharm Biotechnol. 2013;14:693–707.
Schottelius M, Wester HJ. Molecular imaging targeting peptide receptors. Methods. 2009;48:161–77.
Heskamp S, van Laarhoven HW, Molkenboer-Kuenen JD, Bouwman WH, van der Graaf WT, Oyen WJ, et al. Optimization of IGF-1R SPECT/CT imaging using 111In-labeled F(ab′)2 and Fab fragments of the monoclonal antibody R1507. Mol Pharm. 2012;9:2314–21.
Muller C. Folate based radiopharmaceuticals for imaging and therapy of cancer and inflammation. Curr Pharm Des. 2012;18:1058–83.
Kassis AI, Adelstein SJ, Mariani G. Radiolabeled nucleoside analogs in cancer diagnosis and therapy. Q J Nucl Med. 1996;40:301–19.
Mariani G, Bodei L, Adelstein SJ, Kassis AI. Emerging roles for radiometabolic therapy of tumors based on Auger electron emission. J Nucl Med. 2000;41:1519–21.
Adelstein SJ, Kassis AI, Bodei L, Mariani G. Radiotoxicity of iodine-125 and other Auger-electron emitting radionuclides: background to therapy. Cancer Biother Radio-Pharm. 2003;18:301–16.
Bodei L, Kassis AI, Adelstein SJ, Mariani G. Radionuclide therapy with iodine-125 and other Auger-electron-emitting radionuclides: experimental models and clinical applications. Cancer Biother Radiopharm. 2003;18:861–77.
Aloj L, Aurilio M, Rinaldi V, D’Ambrosio L, Tesauro D, Peitl PK, et al. Comparison of the binding and internalization properties of 12 DOTA-coupled and 111In-labelled CCK2/gastrin receptor binding peptides: a collaborative project under COST Action BM0607. Eur J Nucl Med Mol Imaging. 2011;38:1417–25.
Forrer F, Valkema R, Bernard B, Schramm NU, Hoppin JW, Rolleman E, et al. In vivo radionuclide uptake quantification using a multi-pinhole SPECT system to predict renal function in small animals. Eur J Nucl Med Mol Imaging. 2006;33:1214–7.
Behr TM, Béhé M, Becker W. Diagnostic applications of radiolabeled peptides in nuclear endocrinology. Q J Nucl Med. 1999;43:268–80.
Behr TM, Béhé MP. Cholecystokinin-B/Gastrin receptor-targeting peptides for staging and therapy of medullary thyroid cancer and other cholecystokinin-B receptor-expressing malignancies. Semin Nucl Med. 2002;32:97–109.
Quinn T, Zhang X, Miao Y. Targeted melanoma imaging and therapy with radiolabeled alpha-melanocyte stimulating hormone peptide analogues. G Ital Dermatol Venereol. 2010;145:245–58.
Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR. Radiopeptide imaging and therapy in Europe. J Nucl Med. 2011;52:42S–55.
Graham MM, Menda Y. Radiopeptide imaging and therapy in the United States. J Nucl Med. 2011;52:56S–63.
Tang B, Yong X, Xie R, Li QW, Yang SM. Vasoactive intestinal peptide receptor-based imaging and treatment of tumors. Int J Oncol. 2014;44:1023–31.
Hubalewska-Dydejczyk A, Sowa-Staszczak A, Tomaszuk M, Stefańska A. GLP-1 and exendin-4 for imaging endocrine pancreas. A review. Labelled glucagon-like peptide-1 analogues: past, present and future. Q J Nucl Med Mol Imaging. 2015;59:152–60.
Yang MY, Chuang H, Chen RF, Yang KD. Reversible phosphatidylserine expression on blood granulocytes related to membrane perturbation but not DNA strand breaks. J Leukoc Biol. 2002;71:231–7.
Bouter A, Carmeille R, Gounou C, Bouvet F, Degrelle SA, Evain-Brion D, et al. Review: annexin-A5 and cell membrane repair. Placenta. 2015;36 Suppl 1:S43–9.
Gottlieb RA. Part III: molecular and cellular hematology apoptosis. In: Lichtman MA, Beutler E, Kipps TJ, editors. Williams’ hematology. 7th ed. New York: McGraw-Hill Book; 2007. p. 125–30.
Ogawa K, Aoki M. Radiolabeled apoptosis imaging agents for early detection of response to therapy. Sci World J. 2014;2014:732603. doi:10.1155/2014/732603. Epub 2014 Oct 14.
Blankenberg FG. In vivo detection of apoptosis. J Nucl Med. 2008;49 Suppl 2:81S–95.
Kemerink GJ, Liu X, Kieffer D, Ceyssens S, Mortelmans L, Verbruggen AM, et al. Safety, biodistribution, and dosimetry of 99mTc-HYNIC-annexin V, a novel human recombinant annexin V for human application. J Nucl Med. 2003;44:947–52.
Tait JF, Smith C, Blankenberg FG. Structural requirements for in vivo detection of cell death with 99mTc-annexin V. J Nucl Med. 2005;46:807–15.
Belhocine T, Steinmetz N, Hustinx R, Bartsch P, Jerusalem G, Seidel L, et al. Increased uptake of the apoptosis-imaging agent 99mTc recombinant human annexin v in human tumors after one course of chemotherapy as a predictor of tumor response and patient prognosis. Clin Cancer Res. 2002;8:2766–74.
Schaper FLWVJ, Reutelingsperger CP. 99mTc-HYNIC-annexin A5 in oncology: evaluating efficacy of anti-cancer therapies. Cancers. 2013;5:550–68.
Vangestel C, Peeters M, Mees G, Oltenfreiter R, Boersma HH, Elsinga PH, et al. In vivo imaging of apoptosis in oncology: an update. Mol Imaging. 2011;10:340–58.
Vangestel C, Van de Wiele C, Van Damme N, Staelens S, Pauwels P, Reutelingsperger CP, Peeters M. 99mTc-(CO)3 His-annexin A5 micro-SPECT demonstrates increased cell death by irinotecan during the vascular normalization window caused by bevacizumab. J Nucl Med. 2011;52:1786–94.
Lahorte CM, van de Wiele C, Bacher K, van den Bossche B, Thierens H, van Belle S, et al. Biodistribution and dosimetry study of 123I-rh-annexin v in mice and humans. Nucl Med Commun. 2003;24:871–80.
Marconescu A, Thorpe PE. Coincident exposure of phosphatidylethanolamine and anionic phospholipids on the surface of irradiated cells. Biochim Biophys Acta. 1778;2008:2217–24.
Bevers EM, Comfurius P, Dekkers DWC, Zwaal RFA. Lipid translocation across the plasma membrane of mammalian cells. Biochim Biophys Acta. 1999;439:317–30.
Alberts B, Johnson A, Lewis J, et al. Molecular biology of the cell. 4th ed. New York: Garland Science; 2002.
Spector AA, Yorek MA. Membrane lipid composition and cellular function. J Lipid Res. 1985;26:1015–35.
Emoto K, Toyama-Sorimachi N, Karasuyama H, Inoue K, Umeda M. Exposure of phosphatidylethanolamine on the surface of apoptotic cells. Exp Cell Res. 1997;232:430–4.
Umeda M, Emoto K. Membrane phospholipid dynamics during cytokinesis: regulation of actin filament assembly by redistribution of membrane surface phospholipid. Chem Phys Lipids. 1999;101:81–91.
Mills JC, Stone NL, Erhardt J, et al. Apoptotic membrane blebbing is regulated by myosin light chain phosphorylation. J Cell Biol. 1998;140:627–36.
Hayashi F, Nagashima K, Terui Y, et al. The structure of PA48009: the revised structure of duramycin. J Antibiot (Tokyo). 1990;43:1421–30.
Zimmermann N, Freund S, Fredenhagen A, et al. Solution structures of the lantibiotics duramycin B and C. Eur J Biochem. 1993;216:419–28.
Aoki Y, Uenaka T, Aoki J, et al. A novel peptide probe for studying the transbilayer movement of phosphatidylethanolamine. J Biochem. 1994;116:291–7.
Machaidze G, Ziegler A, Seelig J. Specific binding of Ro 09-0198 (cinnamycin) to phosphatidylethanolamine: a thermodynamic analysis. Biochemistry. 2002;41:1965–71.
Guder A, Wiedemann I, Sahl HG. Posttranslationally modified bacteriocins: the lantibiotics. Biopolymers. 2000;55:62–73.
Hosoda K, Ohya M, Kohno T, et al. Structure determination of an immunopotentiator peptide, cinnamycin, complexed with lysophosphatidylethanolamine by 1H-NMR1. J Biochem. 1996;119:226–30.
Kaletta C, Entian KD, Jung G. Prepeptide sequence of cinnamycin (Ro 09-0198): the first structural gene of a duramycin-type lantibiotic. Eur J Biochem. 1991;199:411–5.
Marki F, Hanni E, Fredenhagen A, et al. Mode of action of the lanthioninecontaining peptide antibiotics duramycin, duramycin B and C, and cinnamycin as indirect inhibitors of phospholipase A2. Biochem Pharmacol. 1991;42:2027–35.
Iwamoto K, Hayakawa T, Murate M, et al. Curvature-dependent recognition of ethanolamine phospholipids by duramycin and cinnamycin. Biophys J. 2007;93:1608–19.
Seelig J. Thermodynamics of lipid-peptide interactions. Biochim Biophys Acta. 1666;2004:40–50.
Zhao M, Li Z, Bugenhagen S. 99mTc-labeled duramycin as a novel phosphatidylethanolamine-binding molecular probe. J Nucl Med. 2008;49:1345–52.
Zhao M, Li Z. A single-step kit formulation for the 99mTc-labeling of HYNIC-Duramycin. Nucl Med Biol. 2012;39:1006–11.
Audi S, Li Z, Capacete J, Liu Y, Fang W, Shu LG, Zhao M. Understanding the in vivo uptake kinetics of a phosphatidylethanolamine-binding agent 99mTc-Duramycin. Nucl Med Biol. 2012;39:821–5.
Wang L, Wang F, Fang W, et al. The feasibility of imaging myocardial ischemic/reperfusion injury using 99mTc-labeled duramycin in a porcine model. Nucl Med Biol. 2015;42:198–204.
Zhang Y, Stevenson GD, Barber C, et al. Imaging of rat cerebral ischemia-reperfusion injury using 99mTc-labeled duramycin. Nucl Med Biol. 2013;40:80–8.
Clough AV, Audi SH, Haworth ST, Roerig DL. Differential lung uptake of 99mTc-hexamethylpropyleneamine oxime and 99mTc-duramycin in the chronic hyperoxia rat model. J Nucl Med. 2012;53:1984–91.
Audi SH, Jacobs ER, Zhao M, Roerig DL, Haworth ST, Clough AV. In vivo detection of hyperoxia-induced pulmonary endothelial cell death using 99mTc-duramycin. Nucl Med Biol. 2015;42:46–52.
Medhora MM, Haworth S, Liu Y, Narayanan J, Gao F, Zhao M, et al. Biomarkers for radiation pneumonitis using non-invasive molecular imaging. J Nucl Med. 2016;57:1296–301.
Johnson SE, Li Z, Liu Y, Moulder JE, Zhao M. Whole-body imaging of high-dose ionizing irradiation-induced tissue injuries using 99mTc-duramycin. J Nucl Med. 2013;54:1397–403.
Elvas F, Vangestel C, Rapic S, Verhaeghe J, Gray B, Pak K, et al. Characterization of [99mTc]duramycin as a SPECT imaging agent for early assessment of tumor apoptosis. Mol Imaging Biol. 2015;17:838–47.
Luo R, Niu L, Qiu F, Fang W, Fu T, Zhao M, et al. Monitoring apoptosis of breast cancer xenograft after paclitaxel treatment with 99mTc-labeled duramycin SPECT/CT. Mol Imaging. 2016;29:15. doi:10.1177/1536012115624918.
Elvas F, Boddaert J, Vengestel C, Pak K, Gray B, Kumar-Singh S, et al. 99mTc-Duramycin SPECT imaging of early tumor response to targeted therapy: a comparison with 18F-FDG PET. J Nucl Med. 2017;58:665–70.
Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science. 1987;238:491–7.
Sivolapenko GB, Skarlos D, Pectasides D, Stathopoulou E, Milonakis A, Sirmalis G, et al. Imaging of metastatic melanoma utilising a technetium-99m labelled RGD-containing synthetic peptide. Eur J Nucl Med. 1998;25:1383–9.
Hua J, Dobrucki LW, Sadeghi MM, Zhang J, Bourke BN, Cavaliere P, et al. Noninvasive imaging of angiogenesis with a 99mTc-labeled peptide targeted at alphavbeta3 integrin after murine hindlimb ischemia. Circulation. 2005;111:3255–60.
Bach-Gansmo T, Danielsson R, Saracco A, Wilczek B, Bogsrud TV, Fangberget A, et al. Integrin receptor imaging of breast cancer: a proof-of-concept study to evaluate 99mTc-NC100692. J Nucl Med. 2006;47:1434–9.
Bach-Gansmo T, Bogsrud TV, Skretting A. Integrin scintimammography using a dedicated breast imaging, solid-state gamma-camera and 99mTc-labelled NC100692. Clin Physiol Funct Imaging. 2008;28:235–9.
Axelsson R, Bach-Gansmo T, Castell-Conesa J, McParland BJ, Study Group. An open-label, multicenter, phase 2a study to assess the feasibility of imaging metastases in late-stage cancer patients with the alphav beta3-selective angiogenesis imaging agent 99mTc-NC100692. Acta Radiol. 2010;51:40–6.
Dearling JL, Barnes JW, Panigrahy D, Zimmerman RE, Fahey F, Treves ST, et al. Specific uptake of 99mTc-NC100692, an αvβ3-targeted imaging probe, in subcutaneous and orthotopic tumors. Nucl Med Biol. 2013;40:788–94.
Shi J, Wang L, Kim YS, et al. Improving tumor uptake and excretion kinetics of 99mTc-labeled cyclic arginine-glycine-aspartic (RGD) dimmers with triglycine linkers. J Med Chem. 2008;51:7980–90.
Liu Z, Jia B, Shi J, et al. Tumor uptake of the RGD dimeric probe 99mTc-G3-2P4-RGD2 is correlated with integrin αVβ3 expressed on both tumor cells and neovasculature. Bioconjug Chem. 2010;21:548–55.
Zhou Y, Kim YS, Chakraborty S, Shi J, Gao H, Liu S. 99mTc-labeled cyclic RGD peptides for noninvasive monitoring of tumor integrin αVβ3 expression. Mol Imaging. 2011;10:386–97.
Ma Q, Ji B, Jia B, et al. Differential diagnosis of solitary pulmonary nodules using 99mTc-3P4-RGD2 scintigraphy. Eur J Nucl Med Mol Imaging. 2011;38:2145–52.
Liu L, Song Y, Gao S, Ji T, Zhang H, Ji B, et al. 99mTc-3PRGD2 scintimammography in palpable and nonpalpable breast lesions. Mol Imaging. 2014;13:1–7. doi:10.2310/7290.2014.00010.
Zhu Z, Miao W, Li Q, Dai H, Ma Q, Wang F, et al. 99mTc-3PRGD2 for integrin receptor imaging of lung cancer: a multicenter study. J Nucl Med. 2012;53:716–22.
Zhao D, Jin X, Li F, Liang J, Lin Y. Integrin αvβ3 imaging of radioactive iodine-refractory thyroid cancer using 99mTc-3PRGD2. J Nucl Med. 2012;53:1872–7.
Miao W, Zheng S, Dai H, Wang F, Jin X, Zhu Z, Jia B. Comparison of 99mTc-3PRGD2 integrin receptor imaging with 99mTc-MDP bone scan in diagnosis of bone metastasis in patients with lung cancer: a multicenter study. PLoS One. 2014;9(10):e111221.
Ji S, Zhou Y, Voorbach MJ, Shao G, Zhang Y, Fox GB, et al. Monitoring tumor response to linifanib therapy with SPECT/CT using the integrin αvβ3-targeted radiotracer 99mTc-3P-RGD2. J Pharmacol Exp Ther. 2013;346:251–8.
Liu Z, Huang J, Dong C, et al. 99mTc-labeled RGD-BBN peptide for small-animal SPET/CT of lung carcinoma. Mol Pharm. 2012;9:1409–17.
Chen Q, Ma Q, Chen M, et al. An exploratory study on 99mTc-RGDBBN. Peptide scintimammography in the assessment of breast malignant lesions compared to 99mTc-3P4-RGD2. PLoS One. 2015;10(4):e0123401.
Ji T, Sun Y, Chen B, Ji B, Gao S, Ma Q, et al. The diagnostic role of 99mTc-dual receptor targeted probe and targeted peptide bombesin (RGD-BBN) SPET/CT in the detection of malignant and benign breast tumors and axillary lymph nodes compared to ultrasound. Hell J Nucl Med. 2015;18:108–13.
Bunschoten A, van Willigen DM, Buckle T, van den Berg NS, Welling MM, Spa SJ, Wester HJ, et al. Tailoring fluorescent dyes to optimize a hybrid RGD-tracer. Bioconjug Chem. 2016;27:1253–8.
Castellani P, Viale G, Dorcaratto A, Nicolò G, Kaczmarek J, Querze G, Zardi L. The fibronectin isoform containing the ED-B oncofetal domain: a marker of angiogenesis. Int J Cancer. 1994;59:612–8.
Pini A, Viti F, Santucci A, Carnemolla B, Zardi L, Neri P, Neri D. Design and use of a phage display library. Human antibodies with subnanomolar affinity against a marker of angiogenesis eluted from a two-dimensional gel. J Biol Chem. 1998;273:21769–76.
Tarli L, Balza E, Viti F, Borsi L, Castellani P, Berndorff D, Dinkelborg L, Neri D, Zardi L. A high-affinity human antibody that targets tumoral blood vessels. Blood. 1999;94:192–8.
Berndorff D, Borkowski S, Moosmayer D, Viti F, Muller-Tiemann B, Sieger S, et al. Imaging of tumor angiogenesis using 99mTc-labeled human recombinant anti-ED-B fibronectin antibody fragments. J Nucl Med. 2006;47:1707–16.
Kaczmarek J, Castellani P, Nicolò G, Spina B, Allemanni G, Zardi L. Distribution of oncofetal fibronectin isoforms in normal, hyperplastic and neoplastic human breast tissues. Int J Cancer. 1994;59:11–6.
Pujuguet P, Hammann A, Moutet M, Samuel JL, Martin F, Martin M. Expression of fibronectin ED-A+ and ED-B+ isoforms by human and experimental colorectal cancer. Contribution of cancer cells and tumor-associated myofibroblasts. Am J Pathol. 1996;148:579–92.
Santimaria M, Moscatelli G, Viale GL, Giovannoni L, Neri G, Viti F, et al. Immunoscintigraphic detection of the ED-B domain of fibronectin, a marker of angiogenesis, in patients with cancer. Clin Cancer Res. 2003;9:571–9.
Gomez DE, Alonso DF, Yoshiji H, Thorgeirsson UP. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997;74:111–22.
Foda HD, Zucker S. Matrix metalloproteinases in cancer invasion, metastasis and angiogenesis. Drug Discov Today. 2001;6:478–82.
Matusiak N, van Waarde A, Bischoff R, Oltenfreiter R, van de Wiele C, Dierckx RA, et al. Probes for non-invasive matrix metalloproteinase-targeted imaging with PET and SPECT. Curr Pharm Des. 2013;19:4647–72.
Sihver W, Pietzsch J, Krause M, Baumann M, Steinbach J, Pietzsch HJ. Radiolabeled cetuximab conjugates for EGFR targeted cancer diagnostics and therapy. Pharmaceuticals (Basel). 2014;7:311–38.
Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol. 1995;19:183–232.
Harari PM. Epidermal growth factor receptor inhibition strategies in oncology. Endocr Relat Cancer. 2004;11:689–708.
Schechter NR, Yang DJ, Azhdarinia A, Kohanim S, Wendt R, Oh CS, et al. Assessment of epidermal growth factor receptor with 99mTc-ethylenedicysteine-C225 monoclonal antibody. Anticancer Drugs. 2003;14:49–56.
Schechter NR, Wendt RE, Yang DJ, Azhdarinia A, Erwin WD, Stachowiak AM, et al. Radiation dosimetry of 99mTc-labeled C225 in patients with squamous cell carcinoma of the head and neck. J Nucl Med. 2004;45:1683–7.
Price EW, Zeglis BM, Cawthray JF, Ramogida CF, Ramos N, Lewis JS, et al. H4octapa-trastuzumab: versatile acyclic chelate system for 111In and 177Lu imaging and therapy. J Am Chem Soc. 2013;135:12707–21.
Razumienko EJ, Scollard DA, Reilly RM. Small-animal SPECT/CT of HER2 and HER3 expression in tumor xenografts in athymic mice using trastuzumab Fab-heregulin bispecific radioimmunoconjugates. J Nucl Med. 2012;53:1943–50.
Divgi CR, Welt S, Kris M, Real FX, Yeh SD, Gralla R, et al. Phase I and imaging trial of indium-111 labeled anti-epidermal growth factor receptor monoclonal antibody 225 in patients with squamous cell lung carcinoma. J Natl Cancer Inst. 1991;83:97–104.
Lam K, Scollard DA, Chan C, Levine MN, Reilly RM. Kit for the preparation of 111In-labeled pertuzumab injection for imaging response of HER2-positive breast cancer to trastuzumab (Herceptin). Appl Radiat Isot. 2014;95:135–42.
McLarty K, Cornelissen B, Cai Z, Scollard DA, Costantini DL, Done SJ, Reilly RM. Micro-SPECT/CT with 111In-DTPA-pertuzumab sensitively detects trastuzumab-mediated HER2 downregulation and tumor response in athymic mice bearing MDA-MB-361 human breast cancer xenografts. J Nucl Med. 2009;50:1340–8.
Müller C, Mindt TL, de Jong M, Schibli R. Evaluation of a novel radiofolate in tumour-bearing mice: promising prospects for folate-based radionuclide therapy. Eur J Nucl Med Mol Imaging. 2009;36:938–46.
Müller C, Forrer F, Schibli R, Krenning EP, de Jong M. SPECT study of folate receptor-positive malignant and normal tissues in mice using a novel 99mTc-radiofolate. J Nucl Med. 2008;49:310–07.
Reber J, Struthers H, Betzel T, Hohn A, Schibli R, Müller C. Radioiodinated folic acid conjugates: evaluation of a valuable concept to improve tumor-to-background contrast. Mol Pharm. 2012;9:1213–21.
Maurer AH, Elsinga P, Fanti S, Nguyen B, Oyen WJ, Weber WA. Imaging the folate receptor on cancer cells with 99mTc-etarfolatide: properties, clinical use, and future potential of folate receptor imaging. J Nucl Med. 2014;55:701–4.
Morris RT, Joyrich RN, Naumann RW, Shah NP, Maurer AH, Strauss HW, et al. Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide). Ann Oncol. 2014;25:852–8.
Yamada Y, Nakatani H, Yanaihara H, Omote M. Phase I clinical trial of 99mTc-etarfolatide, an imaging agent for folate receptor in healthy Japanese adults. Ann Nucl Med. 2015;29:792–8.
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Orsini, F., Guidoccio, F., Puta, E., Mariani, G. (2017). Novel Single-Photon-Emitting Radiopharmaceuticals for Diagnostic Applications. In: Strauss, H., Mariani, G., Volterrani, D., Larson, S. (eds) Nuclear Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-26236-9_3
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