²²⁵Ac-H₄py4pa for Targeted Alpha Therapy

Area of Science:

• Radiochemistry and Nuclear Medicine
• Bioconjugation Chemistry
• Cancer Therapeutics

Background:

• Targeted alpha therapy (TAT) offers a promising approach for cancer treatment.
• Development of novel chelators is crucial for stable radiometal complexation in TAT.
• Monoclonal antibodies like Trastuzumab are vital for targeted delivery to HER2+ cancers.

Purpose of the Study:

• To synthesize and characterize a new undecadendate chelator, H4py4pa, and its bifunctional analog.
• To evaluate the chelator's affinity and stability with Actinium-225 (225Ac) for TAT.
• To conjugate the bifunctional chelator to Trastuzumab and assess its in vivo performance for HER2+ cancer targeting.

Main Methods:

• Synthesis and characterization of H4py4pa and H4py4pa-phenyl-NCS.
• Radiolabeling studies with 225Ac under optimized conditions (ambient temperature, pH 7).
• Bioconjugation of H4py4pa-phenyl-NCS to Trastuzumab via a phenyl-NCS linker.
• In vitro serum stability assays and in vivo biodistribution studies in animal models.
• Comparison with DOTA-benzyl-Trastuzumab conjugate.

Main Results:

• H4py4pa demonstrated quantitative radiolabeling yield with 225Ac at ambient conditions.
• The 225Ac-H4py4pa complex exhibited high stability in mouse serum for at least 9 days.
• Density functional theory (DFT) calculations and lanthanum (La3+) complexation confirmed high symmetry and stability of the [La(py4pa)]- complex.
• The H4py4pa-Trastuzumab conjugate showed excellent in vivo stability and tumor specificity, comparable to DOTA-benzyl-Trastuzumab.
• The bifunctional py4pa precursor allows facile bioconjugation through nucleophilic substitution.

Conclusions:

• H4py4pa is a highly effective chelator for 225Ac, suitable for TAT.
• The H4py4pa-Trastuzumab conjugate exhibits promising characteristics for HER2+ cancer targeted therapy.
• The chelator's design offers versatility for developing novel radiopharmaceuticals.