Preparation and evaluation of a novel albumin-binding heterodimer therapeutic radiopharmaceutical with remarkable tumor accumulation and retention

Abstract

The intricate heterogeneity exhibited across diverse tumor types and the inconsistent expression levels of a specific receptor within tumors make it difficult for single-targeting radiotracers to meet clinical needs. The combination of “dual-targeting” and “albumin-binding” strategies can overcome it and effectively improve tumor uptake and retention of radiopharmaceuticals, thereby enhancing the effect of tumor theranostics. In this study, an albumin binder-conjugated heterodimeric precursor L21 targeting integrin αvβ3 and CD13 was successfully developed and labeled with ⁶⁸Ga and ¹⁷⁷Lu to evaluate therapeutic potential in BxPC-3 xenograft mice. In vitro, [⁶⁸Ga]Ga-L21 and [¹⁷⁷Lu]Lu-L21 exhibited excellent radiochemical stability in phosphate buffered saline (PBS) or fetal bovine serum (FBS) at 37 °C for 5 h. Compared to [⁶⁸Ga]Ga-L00 without albumin binder, the introduction of albumin binder did not substantially alter the water solubility of [⁶⁸Ga]Ga-L21, but substantially increased its affinity for serum albumin in FBS. In vivo, [⁶⁸Ga]Ga-L21 showed significantly higher tumor uptake and longer tumor retention time than [⁶⁸Ga]Ga-L00 (0.70 ± 0.06 standardized uptake value [SUV] vs. 0.33 ± 0.02 SUV at 3 h, P = 0.0004). [¹⁷⁷Lu]Lu-L21 exhibited excellent tumor uptake, tumor-to-nontumor ratios and tumor retention, with tumor uptake keeping 2.79 ± 0.30 percentage of injected radioactive dose per gram of tissue (%ID/g) even at 96 h post-injection. Biodistribution results of [¹⁷⁷Lu]Lu-L21 were consistent with SPECT imaging, demonstrating that [¹⁷⁷Lu]Lu-L21 is a promising radiopharmaceutical for tumor radionuclide therapy.