Macropa-Based 225Ac-Labeled RGD Peptides for Targeted Alpha Therapy

Area of Science:

• Radiochemistry
• Nuclear Medicine
• Oncology

Background:

• DOTA is a common chelator for Actinium-225 (225Ac), but Macropa forms more stable complexes.
• Targeted Alpha Therapy (TAT) offers potential for cancer treatment by delivering high-energy alpha particles directly to tumor cells.

Purpose of the Study:

• To design and synthesize novel 225Ac-labeled RGD peptides using Macropa as a chelator.
• To evaluate the therapeutic potential of these peptides for glioblastoma.
• To investigate the efficacy of combination therapy with homoarginine (hArg).

Main Methods:

• Synthesis of two 225Ac-labeled Macropa-RGD peptide conjugates: [225Ac]Ac-Macropa-c(RGDyK) ([225Ac]1) and [225Ac]Ac-Macropa-[c(RGDyK)]2 ([225Ac]2).
• In vitro evaluation of cellular uptake and cytotoxicity in Colon-26 and GL261 cells.
• In vivo studies in Colon-26 tumor-bearing mice to assess tumor accumulation and therapeutic efficacy.
• Assessment of combination therapy with hArg in vitro and in vivo.

Main Results:

• The dimeric peptide [225Ac]2 showed significantly higher cellular uptake and cytotoxicity than the monomeric peptide [225Ac]1 in Colon-26 cells.
• [225Ac]2 demonstrated enhanced tumor accumulation and significant tumor growth inhibition in Colon-26 bearing mice.
• In GL261 glioblastoma models, [225Ac]2 showed comparable uptake, and combination with hArg improved in vitro cytotoxicity, but not in vivo therapeutic efficacy.

Conclusions:

• 225Ac-labeled RGD peptides utilizing Macropa as a chelator are promising candidates for TAT of glioblastoma.
• The dimeric construct ([225Ac]2) exhibits superior preclinical efficacy compared to the monomeric version.
• Further research is needed to optimize combination strategies and pharmacokinetic profiles for improved therapeutic outcomes.