Targeted Delivery of Secretory Promelittin via Novel Poly(lactone-co-β-amino ester) Nanoparticles for Treatment of Breast Cancer Brain Metastases

Abstract

Breast cancer brain metastases (BCBM) is a devastating disease with dismal prognosis. Although chemotherapy is widely used for clinical management of most tumors, it is often ineffective for BCBM. Therefore, alternative approaches for improved treatment of BCBM are in great demand. Here, an innovative gene therapy regimen is reported that is designed for effective treatment of BCBM. First, poly(lactone-co-β-amino ester) nanoparticles that are capable of efficient gene delivery are synthesized and are engineered for targeted delivery to BCBM through surface conjugation of AMD3100, which interacts with CXCR4 enriched in the tumor microenvironment. Next, an artificial gene, proMel, is designed for the expression of secretory promelittin protein, which has limited toxicity on its own but releases cytolytic melittin after activation by MMP-2 accumulated in tumors. It is demonstrated that delivery of the proMel via the AMD3100-conjugated nanoparticles effectively inhibits tumor progression in a BCBM mouse model. This study suggests a new direction to treat BCBM through targeted delivery of promelittin-mediated gene therapy.