(636f) Alpha-Particle Nanotherapeutics Against Metastatic Triple Negative Breast Cancer

Introduction Metastatic and/or recurrent chemoresistant Triple Negative Breast Cancer (TNBC) is currently incurable. TNBC accounts for 12-17% of breast carcinomas with the lowest 5-year survival rates among all breast cancer patients. For such cases, key to the progression of the disease is the choice of therapeutics which need to be both tumor selective and potent against cancer cells. Alpha-particle therapy has been shown to be impervious to most resistance mechanisms. However, the diffusion-limited penetration depths of radionuclide nanocarriers (<50-80μm) combined with the short range of α-particles (40-100μm) result in only partial tumor irradiation.

Utilizing the α-particle emitter Actinium-225 (²²⁵Ac), we studied how the therapeutic potential of a general delivery strategy using nanometer-sized engineered nanoparticles (NPs) was affected by two key transport-driven properties: (1) the release from NPs, when in the tumor interstitium, of the highly diffusing ²²⁵Ac-DOTA that improves the uniformity of tumor irradiation by α-particles, and (2) the adhesion of NPs on the tumors’ ECM that increases NPs’ time-integrated concentrations within tumors and, therefore, the tumor-delivered dose.

Materials and Methods On an orthotopic MDA-MB-231 TNBC murine model forming spontaneous metastases, we evaluated the MTD, biodistributions and control of tumor growth and/or spreading after administration of ²²⁵Ac-DOTA-encapsulating NPs, with different combinations of the two transport-driven properties.

Results At 83% of MTD, ²²⁵Ac-DOTA-encapsulating NPs with both properties (1) eliminated formation of spontaneous metastases (Figure 1) and (2) best inhibited the progression of orthotopic xenografts, compared to NPs lacking one or both properties. These findings were primarily affected by the extent of uniformity of the intratumoral microdistributions of ²²⁵Ac followed by the overall tumor uptake of radioactivity. At the MTD, long-term toxicities were not detected 9.5 months post-administration.

Conclusion Our findings demonstrate the potential of a general, transport-driven strategy enabling more uniform and prolonged solid tumor irradiation by α-particles without cell-specific targeting.

Acknowledgements This work was supported by a grant from the Elsa U. Pardee Foundation, the American Cancer Society Research Scholar Grant RSG-12-044-01, the National Science Foundation grant CBET1510015, and the Under Armour-Innovation Award.