177Lu-Labeled HEDP-Functionalized Manganese-Substituted Maghemite Nanocarriers for Localized Radionuclide Therapy

Background/Objectives: Effective intratumoral radionuclide therapy requires nanocarriers that enable stable radionuclide coordination and prolonged tumor retention. Integrating these properties with efficient magnetic heating within a single nanoplatform remains challenging because optimization of one property may compromise another. This study investigated whether manganese substitution could improve the magnetic heating performance of 1-hydroxyethylidene-1,1-diphosphonic acid (HEDP)-functionalized maghemite nanoparticles while preserving their suitability for radiopharmaceutical applications. Methods: Three MnxFe2−xO3 compositions (x = 0, 0.221, and 0.480) were evaluated in terms of their structural and physicochemical properties, colloidal stability, and magnetic heating performance. The most promising Mn-substituted formulation and the unsubstituted reference were evaluated by 177Lu radiolabeling, in vitro radiochemical stability testing, whole-body imaging, ex vivo biodistribution analysis, and therapeutic efficacy assessment in 4T1 tumor-bearing mice. Results: Moderate Mn substitution (x = 0.221) provided the most favorable combination of magnetic heating performance (SAR = 360 W g−1; ILP = 5.65 nH m2 kg−1) and colloidal stability. HEDP functionalization enabled direct radiolabeling with 177Lu, with labeling yields of 86–92% and radiochemical stability exceeding 94% after 96 h in saline and human serum. Following intratumoral administration, qualitative whole-body imaging showed persistent tumor-associated radioactivity for both nanoparticle formulations on days 5 and 14. On day 14, tumor-associated activity was 91.68 ± 0.73%ID and 84.53 ± 2.26%ID for [177Lu]Lu-NP1 and [177Lu]Lu-NP2, respectively, compared with 17.49 ± 8.06%ID for free [177Lu]LuCl3. Both nanoparticle formulations inhibited tumor growth compared with saline, with a more pronounced response and partial tumor regression in animals bearing smaller tumors at treatment initiation. Conclusions: Moderate Mn substitution improved magnetic heating performance and colloidal stability while preserving the radiochemical stability, intratumoral retention, and therapeutic efficacy of the 177Lu-labeled HEDP-functionalized nanocarriers. This nanoplatform warrants further investigation for intratumoral 177Lu therapy and its potential integration with magnetic hyperthermia.