title: Mannosylated dextran derivatives labeled with fac-[M(CO)₃]+ (M = (99m)Tc, Re) for specific targeting of sentinel lymph node.
abstract: Despite being widely used in the clinical setting for sentinel lymph node detection (SLND), (99m)Tc-based colloids (e.g., (99m)Tc-human serum albumin colloids) present a set of properties that are far from ideal. Aiming to design novel compounds with improved biological properties, we describe herein the first class of fully characterized (99m)Tc(CO)₃-mannosylated dextran derivatives with adequate features for SLND. Dextran derivatives, containing the same number of pendant mannose units (13) and a variable number (n) of tridentate chelators (9, n = 1; 10, n = 4, 11, n= 12), have been synthesized and fully characterized. Radiolabeled polymers of the type fac-[(99m)Tc(CO)₃(k³-L)] (12, L = 9, 13, L = 10, 14, L = 11) have been obtained quantitatively in high radiochemical purity (≥ 98%) upon reaction of the dextran derivatives with fac-[(99m)Tc(CO)₃(H₂O)₃]+. The highly stable compounds 13 and 14 were identified by comparing their HPLC chromatograms with the ones obtained for the corresponding rhenium surrogates fac-[Re(CO)₃(k³-10)] (13a) and fac-[Re(CO)₃(k³-11)] (14a), which have been characterized both at the chemical (NMR and IR spectroscopy, and HPLC) and physical level (DLS, AFM and LDV). Compounds 13a and 14a present a positive zeta potential (+ 7.1 mV, pH 7.4) and a hydrodynamic diameter in the range 8.4-8.7 nm. Scintigraphic imaging and biodistribution studies in Wistar rats have shown good accumulation in the sentinel node at 60 min postinjection (6.71 ± 2.35%, 13; and 7.53 ± 0.69%, 14), with significant retention up to 180 min. A clear delineation of the sentinel lymph node without significant washout to other regions was observed in the scintigraphic images. The popliteal extraction of 94.47 ± 2.45% for 14 at 1 h postinjection, as compared to 61.81 ± 2.4% for 13, indicated that 14 is a very promising compound to be further explored as SLN imaging agent.
authors.affiliation: Unidade de Ciências Químicas e Radiofarmacêuticas, ITN , Estrada Nacional 10, 2686-953 Sacavém, Portugal.
authors.forename: Maurício
authors.initials: M
authors.lastname: Morais
authors.forename: Suresh
authors.initials: S
authors.lastname: Subramanian
authors.forename: Usha
authors.initials: U
authors.lastname: Pandey
authors.forename: Grace
authors.initials: G
authors.lastname: Samuel
authors.forename: Meera
authors.initials: M
authors.lastname: Venkatesh
authors.forename: Manuel
authors.initials: M
authors.lastname: Martins
authors.forename: Sérgio
authors.initials: S
authors.lastname: Pereira
authors.forename: João D G
authors.initials: JD
authors.lastname: Correia
authors.forename: Isabel
authors.initials: I
authors.lastname: Santos
mesh_terms: D000818:Animals; D003911:Dextrans / Q000737:chemistry*; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000187:drug effects*; D008358:Mannose / Q000737:chemistry*; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D012211:Rhenium / Q000737:chemistry*; D021701:Sentinel Lymph Node Biopsy; D013667:Technetium / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D003911:Dextrans; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D012211:Rhenium; D013667:Technetium; D008358:Mannose