Two‐Step Targeted Hybrid Nanoconstructs Increase Brain Penetration and Efficacy of the Therapeutic Antibody Trastuzumab against Brain Metastasis of HER2‐Positive Breast Cancer

• Published in: Advanced functional materials 2018-02, Vol.28 (9), p.n/a
• Main Authors: He, Chunsheng, Li, Jason, Cai, Ping, Ahmed, Taksim, Henderson, Jeffrey T., Foltz, Warren D., Bendayan, Reina, Rauth, Andrew Michael, Wu, Xiao Yu
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Biocompatibility; blood‐brain barrier; Brain; Brain cancer; brain metastasis; Breast cancer; Cancer; Central nervous system; Encapsulation; hybrid nanoconstructs; Hybrid systems; Immunotherapy; Materials science; Metastasis; Monoclonal antibodies; Polymers; Polyoxyethylene sorbitan monooleate; Polystyrene resins; Targeted cancer therapy; Three dimensional models; Toxicity; trastuzumab delivery; two‐step targeting
• ISSN: 1616-301X; 1616-3028
• DOI: 10.1002/adfm.201705668

Therapeutic antibodies (e.g., trastuzumab, TRA) against human epidermal growth factor receptor 2 (HER2)‐positive breast cancers have shown benefits in controlling primary tumors, yet are ineffective against brain metastases due to their inability to cross the blood‐brain barrier (BBB). A novel hybrid nanoconstruct system is designed to deliver trastuzumab to brain metastasis of HER2‐positive breast cancer via a two‐step sequential targeting approach. Self‐assembly of a polysorbate 80 (PS 80)‐containing polymer, lipid, and polymer‐conjugated TRA forms hybrid nanoconstructs (TRA–terpolymer nanoparticles (TPN)) with high encapsulation efficiency and bioactivity. The PS 80 moiety enables the first‐step targeting and receptor‐mediated trancytosis across BBB is demonstrated in vitro with a 3D human BBB model in healthy and brain tumor‐bearing mice. The subsequent partial dissociation of the nanoconstructs exposes the encapsulated TRA for the second‐step targeting to HER2‐positive cancer cells in the brain. Intravenously injected TRA–TPN delivers 50‐fold TRA compared to free TRA to the brain metastasis of HER2‐positive breast cancer. Treatment with TRA–TPN increases tumor cell apoptosis by 4‐fold, inhibits tumor growth by 43‐fold, and prolongs median survival by >1.3‐fold compared to free TRA, without causing noticeable organ toxicity. These findings suggest the two‐step targeted nanoconstruct system is promising for shuttling therapeutic antibodies to treat central nervous system diseases. A novel two‐step targeted polymer‐lipid nanocarrier system is developed which is capable of delivering clinically relevant doses of therapeutic antibody across the blood‐brain barrier following intravenous administration. The therapeutic potential of trastuzumab‐loaded nanoparticles is demonstrated in a side‐by‐side comparison with free trastuzumab to inhibit brain‐tumor growth and prolong survival of mice with brain metastases of human epidermal growth factor receptor 2‐positive breast cancer.