(137a) Diffusion-Based Delivery of Alpha-Particle Radiotherapeutics Effectively Controls Recurrent, Chemoresistant Triple Negative Breast Cancer

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 due to high proliferation and reoccurrence outside the breast combined with lack of effective targeted therapeutic modalities. 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. Given the vast heterogeneity of the disease identified as TNBC, this choice could be a major challenge.

Alpha-particle radiotherapy could be a strong candidate for such cases of difficult-to-treat cancers. The highly efficient irradiation of α-particle emitters (1-10 MeV energy), renders α-particles with a 3- to 8-fold greater relative biological effectiveness compared to photon or β-particle radiation. Alpha particles typically cause double-strand DNA breaks and their high killing efficacy (4-5 tracks across the nucleus result in cell kill) is also mostly independent of the cell-oxygenation state unlike β-particles. However, historically, the short range of α-particles in tissue has hampered the use of α-particle emitters for the treatment of solid tumors; the diffusion-limited penetration depths of traditional radionuclide carriers combined with the short range of α-particles result in only partial tumor irradiation. This is quite unfortunate given the killing power of α-particles.

In the past we have had remarkably promising initial results in effectively controlling the growth of TNBC tumors in vivo and in prolonging survival using α-particle nanoradiotherapy (lipid nanoparticles loaded with α-particle emitters).¹The key design element of these nanoradiotherapeutics to enable uniform tumor irradiation, was to engineer nanoparticles ('releasing' NPs) that upon their uptake by tumors release highly-diffusive forms of the α-particle emitters within the tumor interstitium, resulting in uniform distribution of emitters within tumors, and uniform irradiation of tumors without - as we demonstrated - additional toxicities.

In this work, to maximize the fraction of emitted energy retained by tumors we designed NPs ('adhering' NPs) that, in addition to interstitial release, they adhere on the extracellular matrix and on cancer cells but DO NOT become internalized by cells; this has the potential to enable slower clearance of NPs from tumors increasing the time-integrated delivered doses.

We systematically varied the release and adhesion properties on NPs loaded with the α-particle emitter Actinium-225 and present the effect of these properties on the dose response of large MDA-MB-231 TNBC spheroids used as surrogates of solid tumors' avascular regions. Preliminary studies in mouse models demonstrate the translational potential of this approach on controlling the growth rate of orthotopic TNBC xenografts and on delaying the spreading of spontaneous metastases.

Our findings demonstrate the potential of this 'diffusion-based' approach to lead to a new class of α-particle nanoradiotherapy as a platform technology to control tumor growth and/or spreading for a variety of difficult-to-treat tumors.

References

1. Zhu, C.; Sempkowski, M.; Holleran, T.; Linz, T.; Bertalan, T.; Josefsson, A.; Bruchertseifer, F.; Morgenstern, A.; Sofou, S. Alpha-particle radiotherapy: For large solid tumors diffusion trumps targeting. Biomaterials 2017, 130, 67-75.