Enhanced Radionuclide Therapy via the Conjugation of Pentadecanoic Acids With ²²⁵Ac- and ¹⁷⁷Lu-Labeled RGD Peptides

Improved peptide pharmacokinetics are needed to enhance the therapeutic effects of peptide-based radionuclide therapy. Conjugation of albumin binders, such as fatty acids, to tumor-targeting peptides slows blood clearance, resulting in higher tumor uptake. In this study, we synthesized PD-conjugated monomeric and dimeric RGD peptides, PD-K-(¹¹¹In-DOTA)-c(RGDfK) and PD-K(¹¹¹In-DOTA)-E[c(RGDfK)]₂, and evaluated their albumin binding. We compared pharmacokinetics with and without PD in tumor-bearing mice. The therapeutic effects of PD-K(¹⁷⁷Lu-DOTA)-c(RGDfK) (7.5, 15, and 30 MBq) and PD-K(²²⁵Ac-DOTA)-c(RGDfK) (20 and 40 kBq) were investigated in tumor-bearing mice. ¹⁷⁷Lu-DOTA-c(RGDfK) (30 MBq) was used as a control to evaluate the therapeutic effects of PD conjugation in comparison with PD-K(¹⁷⁷Lu-DOTA)-c(RGDfK). An in vitro binding study using HSA showed that the conjugation of PD significantly enhanced the albumin-binding ability. The albumin-binding percentages of ¹¹¹In-DOTA-c(RGDfK) and ¹¹¹In-DOTA-E[c(RGDfK)]₂ were less than 1%, while their PD conjugates were 50.93 ± 1.87 and 29.96 ± 1.60, respectively. A biodistribution study revealed that PD conjugates significantly prolonged blood clearance and increased tumor uptake. Unexpectedly, the tumor uptake of PD-K-(¹¹¹In-DOTA)-c(RGDfK) was more sustained than that of PD-K(¹¹¹In-DOTA)-E[c(RGDfK)]₂, corresponding to their albumin-binding ability. In the therapeutic experiments with PD-K(¹⁷⁷Lu-DOTA)-c(RGDfK), only 30 MBq suppressed tumor growth. PD-K(²²⁵Ac-DOTA)-c(RGDfK) significantly inhibited tumor growth; however, elevated ALT and AST levels were observed in mice treated with 40 kBq. Thus, PD conjugation successfully increased tumor uptake by prolonging blood clearance, leading to preferential therapeutic efficacy. This study demonstrated that PD-K(²²⁵Ac-DOTA)-c(RGDfK) enhanced the therapeutic effects of radionuclide therapy by sustaining high tumor uptake, which led to significant tumor growth inhibition and prolonged median survival time.