Development of ¹⁷⁷Lu-DOTA-Dendrimer and Determination of Its Effect on Metal and Ion Levels in Tumor Tissue

Abstract

Dendrimers are synthetic nanomolecules with well-defined chemical structures. Different strategies have been used for radiolabeling dendrimers with different radioisotopes. In this study, the aim was to conjugate dendrimers with (177)Lu, to observe the in vivo behavior of the labeled compound and to measure the elementary changes in tumor tissue that could be caused by ionizing radiation. PAMAM G4 dendrimers conjugated with DOTA were labeled with (177)Lu. The radiolabeled compound was characterized and its stability was evaluated by reverse phase high performance liquid chromatography. Radiolabeling yield was >98% and stable for 24 hours. Biodistribution studies of (177)Lu-DOTA-dendrimers in C57BL/6 melanoma-bearing mice showed blood clearance with hepatic and renal depuration and tumor uptake. The concentrations of Br, Ca, Cl, Fe, K, Mg, Na, Rb, S, and Zn were determined in tumor tissues of C57BL/6 mice treated with (177)Lu-DOTA-dendrimers and in untreated mice. The results showed decreased concentrations of Br (62%), Ca (24%), Cl (51%), K (12%) and Na (60%) and increased concentrations of Fe (8%), Mg (28%), Rb (100%), S (6%) and Zn (4%) in tumor tissues of mice treated with (177)Lu-DOTA-dendrimers. These data may be useful to evaluate changes in tumor tissues as indicators of damage that could be caused by ionizing radiation.

Radiolabelling of nanomaterials for medical imaging and therapy

“…435 Furthermore, PAMAM dendrimers have been radiolabelled with the radiotherapeutic isotope 177 Lu. [427][428][429][430][431] using the amine reactive BFCs DOTA-NHS, 428 and p-SCN-Bn-DOTA. 429,430 The radiolabelling of PAMAM dendrimers with 64 Cu has also been performed using the DOTA-NHS BFC system.…”

Current outlook on radionuclide delivery systems: from design consideration to translation into clinics

“…The 68 Ga-labeled dendrimers showed an effective tumor targeting in case of prostate, glioblastoma, colorectal and pancreatic cancers. The radionuclide-based theranostic dendrimers labeled with radionuclides emitting both β and γ rays simultaneously ( 177 Lu, 131 I, 188 Re) were investigated in References [151–154]. For instance, the theranostic 131 I-labeled PAMAM dendrimers modified with PEG and chlorotoxin (CTX) as the targeting agent were employed for targeted SPECT imaging and radiotherapy of a matrix metalloproteinase-2 (MMP-2) overexpressing xenografted glioma model in vivo [152].…”

Methods for Radiolabeling Nanoparticles (Part 3): Therapeutic Use

“…The size-exclusion radio-HPLC confirmed a level of radiochemical purity of more than 95% [ 73 ]. Two further examples were published by Mendoza-Nava et al [ 69 ] and by Kovacs et al [ 72 ]. Here, DOTA was bound to polyamidoamine (PAMAM) dendrimers, followed by an incubation of 1–1.5 h, and, subsequently, by the addition of 177 LuCl 3 , and incubated at 37–50 °C for 20–60 min.…”