Treatment of pediatric brain tumors involves surgery followed by radiation and chemotherapy, inevitably leading to serious side effects. In particular, the sonic-hedgehog subtype of medulloblastoma (SHH MB), which represents approximately 30% of medulloblastoma, is associated with treatment failure and poor outcome due to non-specific cytotoxicity. One promising strategy to develop targeted therapeutics for SHH MB is to suppress the biological signal cascade in the SHH pathway while minimizing adverse effects associated with current anticancer chemotherapeutics. However, clinical outcomes of SHH inhibitors for the treatment of SHH MB remain questionable mainly due to the fast mutation and subsequent development of resistance. This challenge signifies unmet needs for drug carriers that can cross the blood-brain barrier (BBB), deliver drugs to targeted sites with high loading efficiency and long-term stability, and exhibit synergistic effect in combination with drugs upon systemic administration. In the present study, we report a novel strategy that applies engineered high-density lipoprotein (HDL)-mimetic nanoparticles with apolipoprotein A1 (eHNP-A1) for targeted delivery of the SHH inhibitor, sonidegib (LDE-225), to the SHH MB cells. Our microfluidic mixing technology enables for a simple and facile single-step reconstitution of eHNP-A1 with high homogeneity and reproducibility, addressing the challenge in biomedical applications of highly heterogeneous natural HDL nanoparticles. We further decorate an antibody against target stage-specific embryonic antigen-1 (SSEA-1+) or CD15 on the surface of eHNP-A1 while incorporating LDE-225 into the nanoparticle core (eHNP-A1-CD15-LDE225). We demonstrate the capability of eHNP-A1-CD15-LDE225 for the targeted delivery across the BBB and inhibiting efficacy at the molecular, cellular, and tissue levels, and in a mouse model of SHH MB. Finally, we investigate how eHNP-A1 can synergize the therapeutic effects with SHH inhibitors by disrupting cholesterol transport and discuss the potential as nanomedicine for the treatment of SHH MB.

Engineered HDL-mimetic nanoparticles synergize therapeutic effects on the cancer stem-like cell population in sonic hedgehog medulloblastoma

2019 Fall National Meeting

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