Imaging hypoxia in tumors

doi:10.1053/snuc.2001.26191

Seminars in Nuclear Medicine

Volume 31, Issue 4, October 2001, Pages 321-329

https://doi.org/10.1053/snuc.2001.26191 Get rights and content

For many years, it has been known that hypoxia affects the response to radiotherapy in human cancers. Hypoxic regions can develop as a tumor grows beyond the ability of its blood supply to deliver oxygen to the full extent of the tumor, exacerbated by vascular spasm or compression caused by increased interstitial fluid pressure. However, hypoxia is heterogeneous, and tumors that appear identical by clinical and radiographic criteria can vary greatly in their extent of hypoxia. Several invasive procedures to measure hypoxia in tumors have been developed and are predictive of response to therapy, but none of these is in routine clinical use because of technical complexity, inconvenience, and inability to obtain repeated measures. Noninvasive imaging with a hypoxia-directed radiopharmaceutical could be of great clinical utility. Most such radiopharmaceuticals under development use 2-nitroimidazole as the targeting moiety. 2-Nitroimidazole, which is selectively reduced and bound in hypoxic tissues, has been labeled with F-18, Cu-64/67, I-123, and Tc-99m. Of these, F-18-fluoromisonidazole and I-123-iodoazomycin arabinoside (IAZA) have been most widely studied clinically. Non-nitro-containing bioreductive complexes, such as the Cu-60/62/64 thiosemicarbazone ATSM and Tc-99m butylene amineoxime (BnAO or HL91), have also been evaluated. In particular, I-123-IAZA and Cu-60-ATSM have shown correlation with response to radiotherapy in preliminary clinical studies. However, more preclinical studies comparing imaging with validated invasive methods and clinical studies with outcome measures are required. Nuclear medicine is poised to play an important role in optimizing the therapy of patients with hypoxic tumors.

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Though growing evidence has been collected in support of the concept of dose escalation based on the molecular level images indicating hypoxic tumor sub-volumes that could be radio-resistant, validation of the concept is still a work in progress. Molecular imaging of tumor hypoxia using radiopharmaceuticals is expected to provide the required input to plan dose escalation through Image Guided Radiation Therapy (IGRT) to kill/control the radio-resistant hypoxic tumor cells. The success of the IGRT, therefore, is heavily dependent on the quality of images obtained using the radiopharmaceutical and the extent to which the image represents the true hypoxic status of the tumor in spite of the heterogeneous nature of tumor hypoxia. Available literature on radiopharmaceuticals for imaging hypoxia is highly skewed in favor of nitroimidazole as the pharmacophore given their ability to undergo oxygen dependent reduction in hypoxic cells. In this context, present review on nitroimidazole radiopharmaceuticals would be immensely helpful to the researchers to obtain a birds-eye view on what has been achieved so far and what can be tried differently to obtain a better hypoxia imaging agent. The review also covers various methods of radiolabeling that could be utilized for developing radiotracers for hypoxia targeting applications.
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We report herein, an azo-derivative (AzP1) of FDA approved antineoplastic drug SN-38 (irinotecan analogue) as a theranostic agent with a potential for both tumor hypoxia-specific activation and therapy. The theranostic AzP1 was found to be stable within a biologically relevant pH scale and was chemically inert towards other competitive biological analytes. However, upon treatment with rat-liver microsomes, AzP1 showed a self-calibrated fluorescence enhancement at λ_em = 560 nm. The cytotoxicity profile of AzP1 was tested in various cancer lines. Under hypoxic conditions, prodrug AzP1 exhibited activation to release the parent drug (SN-38) and enhanced cytotoxicity in cancer cells with concomitant fluorescence enhancement at 560 nm, which served to monitor both the drug activation and tracing purposes. The therapeutic potential of AzP1 for both tumor-specific activation and suppression of tumor weights was validated in xenograft mouse model. Collectively, the synthetic ease and hypoxia-sensitive activation along with promising therapeutic properties highlight the potential of theranostic AzPI in future cancer treatment programs.
Kit formulation for preparation and biological evaluation of a novel <sup>99m</sup>Tc-oxo complex with metronidazole xanthate for imaging tumor hypoxia
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Up to now, much effort has been made to develop radiolabeled hypoxia imaging agents. Among them, nitroimidazole derivates are thought to undergo bioreduction reaction in the hypoxic cell and thus can be retained in hypoxic tissue [2,3]. Thus, different kinds of PET and SPECT tracers containing nitroimidazole group have been evaluated as hypoxia imaging agents [4–24].
Achieving an ideal ^99mTc labeled nitroimidazole hypoxia marker is still considered to be of great interest. Metronidazole xanthate (MNXT) ligand was synthesized and radiolabeled with ^99mTc-glucoheptonate (GH) to form the ^99mTcO-MNXT complex, for the potential use as a novel probe for imaging tumor hypoxia.
For labeling, ^99mTcO-MNXT was prepared by ligand-exchange reaction with ^99mTc-GH. The radiochemical purity of the ^99mTcO-MNXT complex was measured by thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). The distribution coefficient and stability of the complex was investigated. The structure of the ^99mTcO-MNXT complex was verified by preparation and characterization of the corresponding stable rhenium complex. The cellular uptake of the ^99mTcO-MNXT complex was determined in murine sarcoma S180 cell lines under hypoxic and aerobic conditions. The biodistribution and single photon emission computed tomography (SPECT) image studies of the ^99mTcO-MNXT complex were performed in mice bearing S 180 tumor.
The radiochemical purity of the ^99mTcO-MNXT complex was over 90%. It had good in vitro stability and its distribution coefficient indicated that it was a hydrophilic complex. When ^99mTc and Re complexes were coinjected in HPLC, both radioactivity (for ^99mTc complex) and UV detectors (for Re complex) showed nearly identical HPLC profiles, suggesting their structures are similar. The tumor cell experiment and the biodistribution in mice bearing S 180 tumor showed that the ^99mTcO-MNXT complex had a good hypoxic selectivity and accumulated in the tumor with high uptake and good retention. Single photon emission computed tomography (SPECT) image studies showed that the tumor detection was observable.
^99mTcO-MNXT is prepared from a kit without the need for purification and shows high tumor uptake, tumor/blood and tumor/muscle ratios, suggesting that it would be a promising candidate for imaging tumor hypoxia.
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Citation Excerpt :
The first F-18–labeled drug to be clinically tested was 1-(2-nitro-1-H-imidazol-1-yl)-3-fluoro-2-propan-2-ol (FMISO), and it remains the most extensively tested agent (for review see 37,44). Owing to some perceived problems with FMISO׳s stability in vivo45 and failure to achieve image intensities in humans comparable to what had been achieved in animal models, or for example the very high intensity contrast seen with FDG, many additional nitroimidazoles have been synthesized for the purpose of NII and several have progressed from preclinical development to therapeutic trials. These include 1-(2-nitro-1-H-imidazol-1-yl)-4-fluoro-butane-2,3-diol (FETNIM), 2-(2-nitro-1-H-imidazol-1-yl)-N-(2-fluoroethyl)-acetamide (FETA), 1-(6-deoxy-6-iodo-b-d-galactopyranosyl)-2-nitroimidazole (IAZGP), EF5, EF3, IAZA, 1-(5-fluoro-5-deoxy-a-d-arabinofuranosyl)-2-nitroimidazole (FAZA), HX4, and others—for review of structures and properties see Horsman et al.46
Clinical studies using Eppendorf needle sensors have invariably documented the resistance of hypoxic human tumors to therapy. These studies first documented the need for individual patient measurement of hypoxia, as hypoxia varied from tumor to tumor. Furthermore, hypoxia in sarcomas and cervical cancer leads to distant metastasis or local or regional spread, respectively. For various reasons, the field has moved away from direct needle sensor oxygen measurements to indirect assays (hypoxia-inducible factor–related changes and bioreductive metabolism) and the latter can be imaged noninvasively. Many of hypoxia׳s detrimental therapeutic effects are reversible in mice but little treatment improvement in hypoxic human tumors has been seen. The question is why? What factors cause human tumors to be refractory to antihypoxia strategies? We suggest the primary cause to be the complexity of hypoxia formation and its characteristics. Three basic types of hypoxia exist, encompassing various diffusional (distance from perfused vessel), temporal (on or off cycling), and perfusional (blood flow efficiency) limitations. Surprisingly, there is no current information on their relative prevalence in human tumors and even animal models. This is important because different hypoxia subtypes are predicted to require different diagnostic and therapeutic approaches, but the implications of this remain unknown. Even more challenging, no agreement exists for the best way to measure hypoxia. Some results even suggest that hypoxia is unlikely to be targetable therapeutically. In this review, the authors revisit various critical aspects of this field that are sometimes forgotten or misrepresented in the recent literature. As most current noninvasive imaging studies involve PET-isotope–labeled 2-nitroimidazoles, we emphasize key findings made in our studies using 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide (EF5) and F-18–labeled EF5. These show the importance of differentiating hypoxia subtypes, optimizing drug pharmacology, ensuring drug and isotope stability, identifying key biochemical and physiological variables in tumors, and suggesting therapeutic strategies that are most likely to succeed.
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