Prodrug Delivery Using Dual-Targeting Nanoparticles To Treat Breast Cancer Brain Metastases

Brain metastases from breast cancer are the most frequent brain metastasis in women, which are often difficult to be surgically removed due to the multifocal and infiltrative intracranial growth patterns. Cytotoxic drugs have potent anti-breast cancer properties. However, owing to the toxic side effects and the blood-brain barrier (BBB), these drugs cannot be fully and aggressively exploited with systemic administration and hence have very limited application for brain metastases. In this study, hyaluronidase-activated prodrug hyaluronic-doxorubicin (hDOX) was assembled by the BBB and metastatic breast cancer dual-targeting nanoparticles (NPs), which were constructed based on transcytosis-targeting peptide and hyaluronic acid co-modified poly(lactic-co-glycolic acid)-poly(epsilon-carbobenzoxy-L-lysine). hDOX showed enzyme-recovered DNA insertion, selective cytotoxicity to metastatic breast cancer cells rather than astrocytes, and efficient loading into dual-targeting NPs. hDOX@NPs displayed the ability of dually targeting the BBB and metastatic breast cancer and significantly extended the median survival time of mice with intracranial metastatic breast cancer. Based on these improvements, this prodrug delivery tactic may serve as an important direction for drug therapy against brain metastases.