99mTc-Diethylenetriaminepentaacetic-mannosyl-dextran (99mTc-DTPA-mannosyl-dextran) is a 99mTc-labeled molecular imaging agent designed for sentinel lymph node (SLN) detection and mapping with a gamma-detecting probe or gamma imaging (1-6). 99mTc-DTPA-Mannosyl-dextran binds specifically to the macrophage mannose (mannose-fucose) receptors (MRCs) or mannose binding protein (MBP). It is currently an investigational agent developed for intraoperative lymphatic mapping. 99mTc is a gamma radionuclide with a physical half-life (t½) of 6.01 h.
The primary function of the lymphatic system is to drain ~10% of the interstitial fluid from small capillaries to lymphatic vessels through lymph nodes and finally to the venous system (2, 7-10). Lymph nodes form a natural filter for the lymphatic drainage and prevent the possible migration of cancer cells from the lymphatic system into the body. As the first lymph node that receives lymph drainage from a tumor bed, the SLN is very likely to contain cancer cells if the primary tumor has spread via the lymphatics (1, 2). Because lymphatic drainage may be directed to more than one lymph node, accurate identification and mapping of SLN is critically important. This observation has formed the basis of the sentinel node concept and the clinical applications of SLN mapping that have been applied to staging, management, and treatment of cancer (3, 5). Successful applications of SLN mapping have been reported in patients with melanomas, breast cancers, and some other cancers (1-3). Injection of isosulfan blue dye and 99mTc-sulfur colloid (99mTc-SC) near the tumor have been the two primary methods of SLN mapping (8).
The lymphatic system is complex, and its detection and mapping remain challenging (7, 8, 11, 12). However, with advances of new imaging agents and techniques, imaging and mapping of both the lymphatic vessels and the lymph nodes are now possible with x-ray–computed tomography, ultrasound, nuclear medicine, and magnetic resonance imaging (12-14). Most conventional SLN imaging agents, such as filtered 99mTc-SC or 99mTc-albumin nanocolloids, are nonspecific particles or macromolecules, and they work by passive diffusion to follow the lymphatic drainage after injection around the tumor and accumulate within the lymph node by phagocytes (2, 15, 16). They generally lack the ideal imaging properties of rapid injection-site clearance and high SLN extraction (2, 16). Molecular imaging of the lymphovascular system is possible with the development of agents designed for specific molecular targets (1, 12). Vera et al. (2) first reported the synthesis of 99mTc-DTPA-mannosyl-dextran, which is designed to bind to MRCs within the lymphoid tissues for SN imaging. The MRC is a165-kD membrane glycoprotein, and MRC belongs to the C-type lectin superfamily (1, 6). They are involved in mediating phagocytosis of microbes and intracellular killing mechanisms (17). Lymphoid tissues contain macrophages, and lymph nodes become enlarged from the accumulation of macrophages. 99mTc-DTPA-Mannosyl-dextran consists of a clinical grade dextran, a polysaccharide backbone with an average molecular weight of 9,500 (2, 9, 18). The molecule contains 55 mannose glycosides for ultrahigh-affinity binding to MRCs, and 8 DTPA for 99mTc chelation. Vera et al. (2) suggested that the resulting linear molecule with a diameter of 7.1 nm would be an ideal size to promote injection site clearance.