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

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ABSTRACT 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‐( 111 In‐DOTA)‐c(RGDfK) and PD‐K( 111 In‐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( 177 Lu‐DOTA)‐c(RGDfK) (7.5, 15, and 30 MBq) and PD‐K( 225 Ac‐DOTA)‐c(RGDfK) (20 and 40 kBq) were investigated in tumor‐bearing mice. 177 Lu‐DOTA‐c(RGDfK) (30 MBq) was used as a control to evaluate the therapeutic effects of PD conjugation in comparison with PD‐K( 177 Lu‐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 111 In‐DOTA‐c(RGDfK) and 111 In‐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‐( 111 In‐DOTA)‐c(RGDfK) was more sustained than that of PD‐K( 111 In‐DOTA)‐E[c(RGDfK)] 2 , corresponding to their albumin‐binding ability. In the therapeutic experiments with PD‐K( 177 Lu‐DOTA)‐c(RGDfK), only 30 MBq suppressed tumor growth. PD‐K( 225 Ac‐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( 225 Ac‐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.

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