Loco-regional radiopharmaceutical therapy in breast carcinoma using [177Lu]Lu-microseed implants: Development to proof-of-concept

Local recurrence following tumor resection and limited efficacy of existing therapies for residual or unresectable tumors remain major clinical challenges. To address this, we introduce two loco-regional therapeutic strategies: intraoperative radiopharmaceutical therapy (IORPT), involving direct placement of radioactive microseeds in the tumor bed during surgery, and intratumoral radiation ablation (IRA), involving direct intratumoral administration for tumor downstaging and localized ablation. Tin oxide microseeds were synthesized and radiolabeled with [ 177 Lu]LuCl 3 , followed by physicochemical characterization and quality control. The cellular uptake, apoptotic response, and cytotoxic effects were assessed in MCF-7 cells. Preliminary therapeutic efficacy was assessed in TNBC tumor-bearing Wistar rats using IORPT for residual disease post-resection and IRA for treatment of unresectable tumors. Tumor response, survival, and radiotracer retention were monitored using serial SPECT/CT and CT imaging. The synthesized microseeds were quasi-spherical (~ 1.95 µm) with a ζ-potential of –13.34 mV. [ 177 Lu]Lu-microseeds exhibited high radiochemical yield (> 99%), and was sterile, apyrogenic, and stable for > 25 days in human serum. FITC-microseeds showed maximal internalization at 6 h in MCF-7 cells with sustained retention up to 48 h. Significant cytotoxicity was observed (IC 50 : 126 µCi at 48 h; 80 µCi at 72 h), with a time- and dose-dependent shift from apoptosis to necrosis. In vivo, IORPT delayed tumor recurrence (10.5 ± 2.9 vs 4.0 ± 1.6 weeks in controls; p = 0.130). IRA resulted in marked tumor reduction (1.8 ± 1.8 cc) and significantly prolonged survival (> 40 weeks vs 16.2 ± 3.5 weeks; p = 0.001). Serial SPECT/CT confirmed sustained intratumoral retention with no detectable leaching upto 2 months post-therapy. [ 177 Lu]Lu-microseeds emerged as safe, well-tolerated and biocompatible permanent seed implants for both IORPT and IRA in tumor bearing animal models, enhancing local tumor control and OS with negligible adverse effects.