SCIENTIFIC ORGANIZATION:
Serbsky National Research Center for Social and Forensic Psychiatry, Moscow, 119991, Russia;

Lomonosov Moscow State University, School of Chemistry, Moscow, 119991, Russia;

Russian National Research Medical University, Moscow, 117997, Russia;

Research Institute of Human Morphology of the Russian Academy of Medical Sciences, Moscow, 117418, Russia;

Center for Nanotechnology in Drug Delivery and Division of Molecular Therapeutics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7362, USA

REPORT FORM:
«Oral report»

AUTHOR(S)
OF THE REPORT:
Natalia Nukolova, Sergey Shein, Vladimir Baklaushev, Anna Korchagina, Alexander Khalansky, Iliya Kuznetsov, Tatiana Abakumova, Alexander Kabanov, Vladimir Chekhonin

TALKING POINTS:

Introduction: 

Targeted delivery of drugs using nanocontainers is becoming a main stream in the modern approaches in medicine. One of potent targets for antitumor drug delivery is vascular endothelial growth factor (VEGF), since its over-expression in various tumor types. The aim of this study was to design different nanocontainers conjugated with monoclonal antibodies to VEGF and evaluate their ability for targeted drug delivery to the brain tumor.

Methods:

 Two types of nanocontainers were prepared: stealth liposomes and nanogels. mAbVEGF were conjugated to both nanocontainers via PEG-linker with high retained activity (70% of initial affinity) and loaded with anticancer drug cisplatin (CDDP). Glioma C6 and U87 cells were used to evaluate the cellular uptake of cisplatin-loaded nanoparticles as well as their cytotoxicity. To evaluate the ability of mAbVEGF for targeted delivery of nanocontainers to the brain tumor, fluorescent-labeled nanoparticles were injected into the femoral veins of rats at 20-day after implantation of C6 glioma and analyzed using imaging system IVIS Spectrum-CT.

Results:

 VEGF-targeted liposomes (200±20 nm) and nanogels (130±10 nm) exhibited pH-depended sustained drug release. The fluorescent-labeled targeted nanocontainers showed enhanced internalization in comparison with untargeted nanocontainers or non-specific IgG-targeted nanocontainers in glioma cells. This led to a considerable increase of cytotoxicity of CDDP-loaded targeted container in VEGF-overexpressed cells. VEGF-targeted liposomes accumulated in the brain tumor after i.v. injection with elevated penetration into malignant cells in comparison with untargeted and IgG-targeted liposomes. Note, within the intact nervous tissues the accumulation of liposomes was not observed due to maintaining function of blood brain barrier (BBB). Nanogel accumulation in the brain had the similar pattern (nanogels < IgG-nanogels VEGF-nanogels), however at the less extent. Also, we evaluated the antitumor activity of CDDP-loaded nanogels and revealed that VEGF-targeting groups promote therapeutic efficiency of anticancer drug.
Conclusions:

 VEGF-targeted nanoparticles penetrated through abnormal blood vessels of disturbed BBB into the extracellular space of glioma, where antibodies selectively recognize expressed VEGF. This leads to efficient accumulation of targeted nanoparticles in the brain tissues and enhanced therapeutic performance of CDDP-loaded nanocontainers. Thus, VEGF-targeted nanocontainers could be are prominent candidates for delivery of drugs and diagnostic agents into brain tumors.
This work was supported by RFBR grants (12-04-31731, 13-04-01383), grant of Russian Federation Government (11G34.31.0004) and RSF grants (14-15-00698,14-13-00731).