Engineered biomimetic nanoparticle for dual targeting of the cancer stem-like cell population in sonic hedgehog medulloblastoma
Menée in vitro et à l'aide de modèles murins de médulloblastome avec activation de la voie de signalisation des protéines sonic hedgehog (SHH), cette étude met en évidence l'intérêt thérapeutique de nanoparticules chargées en inhibiteurs SHH et ciblant les récepteurs SR-B1 ainsi que les antigènes CD15 des cellules souches cancéreuses
This study shows that an engineered biomimetic nanoparticle decorated with a targeting ligand and loaded with a sonic hedgehog inhibitor maintains its stability in the circulation, crosses the blood–brain barrier (BBB), and delivers drug molecules to the cancer stem-like cell population in sonic hedgehog subtype of medulloblastoma. Leveraging the natural capabilities of high-density lipoprotein, our nanoparticle enables the facilitated and targeted cellular uptake of drugs and receptor-mediated intracellular cholesterol depletion in medulloblastoma cells. Our successful in vivo validation of the nanocarrier performance suggests a new viable strategy by which to deliver other drugs that are reportedly unable to cross the BBB, have low bioavailability, and/or off-target effects for the treatment of brain tumors, including medulloblastoma.The sonic hedgehog subtype of medulloblastoma (SHH MB) is associated with treatment failure and poor outcome. Current strategies utilizing whole brain radiation therapy result in deleterious off-target effects on the normal developing childhood brain. Most conventional chemotherapies remain limited by ineffective blood–brain barrier (BBB) penetrance. These challenges signify an unmet need for drug carriers that can cross the BBB and deliver drugs to targeted sites with high drug-loading efficiency and long-term stability. We herein leverage the enhanced stability and targeting ability of engineered high-density lipoprotein-mimetic nanoparticles (eHNPs) to cross the BBB and deliver a SHH inhibitor effectively to the cancer stem-like cell population in SHH MB. Our microfluidic technology enabled highly reproducible production of multicomponent eHNPs incorporated with apolipoprotein A1, anti-CD15, and a SHH inhibitor (LDE225). We demonstrate the dual-targeted delivery and enhanced therapeutic effect of eHNP-A1-CD15-LDE225 via scavenger receptor class B type 1 (SR-B1) and CD15 on brain SHH MB cells in vitro, ex vivo, and in vivo. Moreover, we show that eHNP-A1 not only serves as a stable drug carrier, but also has a therapeutic effect itself through SR-B1-mediated intracellular cholesterol depletion in SHH MB cells. Through the facilitated and targeted cellular uptake of drugs and direct therapeutic role of this engineered biomimetic nanocarrier in SHH MB, our multifunctional nanoparticle provides intriguing therapeutic promise as an effective and potent nanomedicine for the treatment of SHH MB.The authors confirm that the data supporting the findings of this study are available within the article and its supplemental materials.