Development of [177Lu]lu-Lnc1010 for Peptide Receptor Radionuclide Therapy of Nasopharyngeal Carcinoma

Somatostatin Receptor 2 (SSTR2)-targeted radiopharmaceutical [68Ga]Ga-DOTATATE has potential advantages in the diagnosis of nasopharyngeal carcinoma (NPC). This study introduces a novel long-lasting SSTR2 analogue, LNC1010, based on DOTATATE, a truncated Evans blue-binding moiety, and a polyethylene-glycol linker. We hypothesised that peptide receptor radionuclide therapy (PRRT) is more effective with [177Lu]Lu-LNC1010 than with [177Lu]Lu-DOTATATE in treating metastatic NPC. We assessed binding characteristics of LNC1010 in vitro using C666-1 NPC cells and in-vivo pharmacokinetics of [68Ga]Ga/[177Lu]Lu-LNC1010 in C666-1 NPC xenografts via PET and SPECT imaging, biodistribution studies, and PRRT, and compared them with [68Ga]Ga/[177Lu] Lu-labelled DOTATATE. Furthermore, a proof-of-concept approach for imaging and therapy was conducted in a patient with metastatic NPC. LNC1010 exhibited strong uptake and specific affinity for SSTR2 in C666-1 NPC cells. PET and SPECT imaging demonstrated higher uptake and longer tumour retention of [68Ga]Ga/[177Lu]Lu-LNC1010 than [68Ga]Ga/[177Lu]Lu-DOTATATE in C666-1 NPC xenografts, indicating its suitability for PRRT applications in NPCs. Biodistribution studies confirmed the higher uptake and prolonged retention of [177Lu]Lu-LNC1010 than [177Lu]Lu-DOTATATE. In preclinical PRRT studies, [177Lu]Lu-LNC1010 showed greater inhibition of tumour growth in C666-1 NPC xenografts than [177Lu]Lu-DOTATATE. In a subsequent pilot clinical study, PRRT with [177Lu]Lu-LNC1010 achieved favourable therapeutic and negligible side effects in a patient with metastatic NPC. [177Lu]Lu-LNC1010 demonstrated increased tumour uptake and prolonged retention in SSTR2-positive NPCs, with superior anti-tumour efficacy to that of [177Lu]Lu-DOTATATE in preclinical studies. These findings suggest that PRRT with [177Lu]Lu-LNC1010 is a promising treatment for advanced NPC, extending the clinical scope of PRRT beyond neuroendocrine tumours.