Abstract P3-12-21: Development of peptide-based targeted α-therapy for triple negative breast cancer
Authors: Nedrow JR , Cortez A , Josefsson A , Sgouros G 
Published: May 2019

Abstract
Triple-negative breast cancer (TNBC) is associated with a poorer prognosis, including a higher potential to metastasize and a decrease in the 5-year survival rate as compared to other breast cancer subtypes (77% vs. 93%). The poor prognosis is partially due to the lack of targeted treatments for TNBC, highlighting the need to develop targeted therapies for TNBC. Alpha-emitting radionuclides, such as Actinium-225, provide high linear energy transfer (LET) radiation. Clinical and pre-clinical studies have shown that targeted alpha-therapy is a highly potent treatment for metastatic cancer. Peptides and peptidomimetics are minimally immunogenic and have rapid tissue and tumor penetration, and rapid clearance from non-target tissues, providing an attractive platform for targeted therapeutic agent. The RGD peptide has been shown to have a high affinity for αvβ3, which has been implicated in TNBC. The purpose of these studies is to investigate the potential of modified RGD peptide scaffolds to deliver 225Ac to triple negative breast cancer cells for targeted alpha therapy.
Methods
DOTA-cyclo-RGD(fK) and DOTA-cyclo-RGD(fK) dimer were labeled with Indium-111, a SPECT imaging surrogate for 225Ac, and Actinium-225. The resulting labeled agents were evaluated in vitro, including binding affinity assays (111In) and colony formation assays (225Ac) that are underway using the MDA-MB-231 cell line. Biodistribution experiments were performed in athymic nude mice bearing MDA-MB-231 tumors to compare the distribution and pharmacokinetics of the 111In-labeled RGD peptide scaffolds in vivo. Alpha camera imaging evaluated the microscale distribution of 225Ac-DOTA-cyclo-RGD(fK) in non-tumor bearing mice.
Results
The saturation binding assay of 111In-labeled DOTA-cyclo-RGD(fK) and DOTA-cyclo-RGD(fK) dimer demonstrated selective binding and nanomolar affinity for αvβ3. Selective targeting of αvβ3was further demonstrated in vivo for both 111In-labeled RGD agents. The 111In-labeled DOTA-cyclo-RGD(fK) demonstrated significantly higher tumor uptake at 30 minutes compared to the dimer (5.3 ± 2.9 vs. 3.0 ± 1.4 %ID/g). The 111In-DOTA-cyclo-RGD(fK) dimer was better retained in the tumor over 6 hours with significantly higher uptake at the 6-hour time point (1.2 ± 0.4 vs. 2.8 ± 1.1 %ID/g). Furthermore, the dimer had significantly higher uptake in the kidney and liver over a 6-hour window as compared to 111In-DOTA-cyclo-RGD(fK). However, both 111In-labeled RGD agents demonstrated rapid clearance from normal organs. Alpha camera images of the 225Ac-labeled dimer supported the rapid clearance from the normal tissues, with the majority of the agents being cleared within the first 90 minutes.
Conclusion
Modified RGD peptides were successfully labeled with Indium-111 and Actinium-225. The resulting agents were shown to successfully target αvβ3 selectively both in vitro and in vivo. These studies provide encouraging data to support the development and optimization of the RGD platform for αvβ3-targeted alpha therapy to treat triple negative breast cancer. Future works will investigate the therapeutic efficacy, macro- and microscale dosimetry, and toxicity of the developed 225Ac-labeled αvβ3-targeted agents as well as explore the optimization of the RGD scaffold for improved pharmacokinetics with 225Ac.
Citation Format: Nedrow JR, Cortez A, Josefsson A, Sgouros G. Development of peptide-based targeted α-therapy for triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-12-21.