Development of [¹⁷⁷Lu]Lu-LNC1010 for peptide receptor radionuclide therapy of nasopharyngeal carcinoma.

Abstract

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.