LAUSR

Brain metastases present an increasing challenge to long-term survival for HER2-amplified breast cancer patients. While HER2 targeted therapies effectively control systemic metastases, they are largely ineffective against brain metastases due to their inability to cross the blood-brain barrier. We have recently demonstrated that brain uptake of targeted nanoparticles can be increased by adding an acid-cleavable linkage between transferrin (Tf) and the nanoparticle core [1]. Our lab has also developed a method for assembling targeted nanoparticles by complexing diol-containing polymer-drug conjugates and boronic acid-containing targeting agents [2]. Here, we report the first efficacy results of targeted nanoparticles formed via this assembly strategy in a preclinical model of breast cancer brain metastasis. Female Rag2-/-;Il2rg-/- mice were intracranially injected with human HER2-amplified BT-474 breast cancer cells, and formation of brain tumors was monitored by MRI. Mice were randomized into four groups of six mice per group (targeted nanoparticle, non-targeted nanoparticle, free drug, and saline). Targeted and non-targeted nanoparticles were prepared by functionalizing nanoparticle cores consisting of a mucic acid polymer conjugate of camptothecin (CPT) with either Tf-PEG or methoxy-PEG, respectively, using boronic acid-diol chemistry. The different formulations were administered intravenously once per week for four weeks at a dose of 4 mg/kg (CPT basis), and tumor volume was measured weekly by MRI. Targeted nanoparticles significantly reduced tumor growth in mice bearing intracranially implanted tumors compared to saline, free drug, and non-targeted nanoparticle controls. However, free drug and non-targeted nanoparticles also reduced tumor growth compared to saline, albeit to a lesser extent. Taken together, the results are highly suggestive that there isn9t a completely intact blood-brain or blood-tumor barrier, and furthermore that artificial transport pathways may be introduced following intracranial implantation. To overcome limitations of the intracranial injection model, female Rag2-/-;Il2rg-/- mice were intracardiacly or intravenously (tail vein) injected with human HER2-amplified BT-474 breast cancer cells, and formation of metastatic brain tumors was monitored by MRI. Unlike brain tumors from intracranially injected cells, brain tumors formed from intravenous cell injections were not affected by systemic doses of either lapatinib or trastuzumab. Current investigations involve collection of efficacy data for the different formulations in the intracardiac and intravenous models that may provide further insight into the blood-brain barrier integrity and nanoparticle delivery. [1] Clark, AJ, Davis, ME, PNAS, 112 (2015) 12486-12491. [2] Han, H, Davis, ME, Mol. Pharmaceutics, 10 (2013) 2558-2567. Citation Format: Emily A. Wyatt, Mark E. Davis. Improved chemotherapeutic delivery to brain metastases with targeted nanoparticles in preclinical breast cancer brain metastasis models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4641.