Blood-Nanoparticle Interactions Create a Brain Delivery Superhighway for Doxorubicin.
Zhuoxuan Li, Tatyana Kovshova, Julia Malinovskaya, Julian Knoll, Saeed Shanehsazzadeh, Nadezhda Osipova, Anastasia Chernysheva, Pavel Melnikov, Svetlana Gelperina, Matthias G Wacker
Author Information
Zhuoxuan Li: National University of Singapore, Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, Singapore.
Tatyana Kovshova: Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia.
Julia Malinovskaya: Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia.
Julian Knoll: National University of Singapore, Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, Singapore.
Saeed Shanehsazzadeh: National University of Singapore, Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, Singapore.
Nadezhda Osipova: Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia.
Anastasia Chernysheva: V. Serbsky Federal Medical Research Centre of Psychiatry and Narcology of the Ministry of Health of the Russian Federation, Moscow, Russia.
Pavel Melnikov: Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia.
Svetlana Gelperina: Dmitry Mendeleev University of Chemical Technology of Russia, Moscow, Russia. ORCID
Matthias G Wacker: National University of Singapore, Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, Singapore. ORCID
Purpose: This study investigated the brain targeting mechanism of doxorubicin-loaded polybutyl cyanoacrylate (PBCA) nanoparticles, particularly their interactions with the blood-brain barrier (BBB). The BBB protects the brain from drugs in the bloodstream and represents a crucial obstacle in the treatment of brain cancer. Methods: An advanced computer model analyzed the brain delivery of two distinct formulations, Doxil and surfactant-coated PBCA nanoparticles. Computational learning was combined with in vitro release and cell interaction studies to comprehend the underlying brain delivery pathways. Results: Our analysis yielded a surprising discovery regarding the brain delivery mechanism of PBCA nanoparticles. While Doxil exhibited the expected behavior, accumulating in the brain through extravasation in tumor tissue, PBCA nanoparticles employed a unique and previously uncharacterized mechanism. They underwent cell hitchhiking, resulting in a remarkable more than 1000-fold increase in brain permeation rate compared to Doxil (2.59 × 10 vs 0.32 h). Conclusion: The nonspecific binding to blood cells facilitated and intensified interactions of surfactant-coated PBCA nanoparticles with the vascular endothelium, leading to enhanced transcytosis. Consequently, the significant increase in circulation time in the bloodstream, coupled with improved receptor interactions, contributes to this remarkable uptake of doxorubicin into the brain.
