Imaging Tumor Burden in the Brain with 89Zr-Transferrin

The effective management of tumors in the brain imposes several unique clinical challenges. For example, the complete surgical resection of a primary brain tumor—a critical factor influencing prognosis—is often complicated by atypical tumor margins or proximity to essential neurologic tissue (1,2). Moreover, because the blood–brain barrier can obstruct the delivery of systemically administered therapeutics, the pharmacokinetic limitations of drugs designed to address primary or metastatic brain tumors can severely dampen clinical responses (3). With some success, noninvasive imaging modalities have been invoked to address these challenges. One of the most visible examples of progress has been the use of MR imaging to localize a tumor mass or to monitor tumor burden after therapy (4). However, the low sensitivity of this modality, and its inability to distinguish tumors from nonmalignant pathologies (infection), precludes its application to some common clinical issues (e.g., detection of residual or recurrent subclinical disease). Because of its comparatively lower detection limit, and its ability to intercalate tumor biology independent of morphologic changes, nuclear medicine technologies (e.g., PET) are regarded as an attractive complement to anatomic imaging. Indeed, several clinical studies have been conducted with common (18F-FDG) and investigational radiotracers (3′-deoxy-3′-18F-fluorothymidine, 11C-labeled amino acids), resulting in some degree of disease contrast and effectively establishing proof of concept (5). However, shortcomings have been documented and are generally attributed to obfuscating uptake in normal brain tissue, ongoing questions concerning mechanism of action, and the practical limitations of studying radiotracers with rapid decay kinetics. On the basis of these observations, we hypothesized that 89Zr-transferrin, a radiotracer we previously developed to target transferrin receptor (TFRC) in prostate cancer (6), could be a generally useful tool for the detection and monitoring of tumor burden in the brain. Indeed, there is a known tropism of transferrin for primary and metastatic brain tumors (7,8), leading several groups to exploit this property therapeutically by coupling transferrin to anticancer drugs to foster tumor-specific delivery (9–12). Moreover, our previous work with this radiotracer (and with 89Zr-labeled monoclonal antibodies) resulted in high-contrast images of tumors, with generally low uptake in normal tissues (13,14). Part of the success can be attributed to 89Zr itself—the radionuclide has highly attractive physical properties such as its long half-life (~78 h), which is well suited to the length of time required for large biomolecules such as transferrin to distribute in vivo (15). Collectively, these observations led us to profile the avidity of primary brain tumor models for 89Zr-transferrin.