TARGETING EXPERIMENTAL ORTHOTOPIC GLIOBLASTOMA WITH CHITOSAN-BASED SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES (CS-DX-SPIONS)
Maxim Shevtsov, Boris Nikolaev, Yaroslav Marchenko, Ludmila Yakovleva, Nikita Skvorzov, Anton Mazur, Peter Tolstoy, Vyacheslav Ryzhov, Gabriele Multhoff. (08-01-2018).Technische Universität München, Klinikum rechts der Isar, Germany, Munich, 2018
Research Area B
Glioblastoma is the most devastating primary brain tumor of the central nervous system in adults. Magnetic nanocarriers may help not only for a targeted delivery of chemotherapeutic agents into the tumor but also provide contrast enhancing properties for diagnostics using magnetic resonance imaging (MRI). Synthesized hybrid chitosan-dextran superparamagnetic nanoparticles (CS-DX-SPIONs) showed a uniform diameter of 55 nm under transmission electron microscopy and superparamagentic characteristics as determined by T1 and T2 proton relaxation times. Application of the chitosan increased the charge from +8.9 to +19.3 mV of the dextran-based SPIONs. The nonlinear magnetic response at second harmonic of CS-DX-SPIONs following the slow change of stationary magnetic fields with very low hysteresis evidenced superparamagnetic state of particles at ambient temperatures. Confocal microscopy and flow cytometry studies showed an enhanced internalization of the chitosan-based nanoparticles in U87, C6 glioma and HeLa cervix carcinoma cells as compared to dextran-coated particles. After internalization cytotoxicity increased in a dose-dependent manner. Acceptable toxicity profiles of the synthesized nanoparticles were observed up to a concentration of 10 μg/ml. Intraveneously administered CS-DX-SPIONs in orthotopic C6 gliomas in rats accumulated in the tumor as shown by high-resolution MR imaging (11.0 T). Retention of nanoparticles resulted in a significant contrast enhancement of the tumor image that was accompanied with a dramatic drop in T2 values (P<0.001). Subsequent histological studies proved an accumulation of the nanoparticles inside glioblastoma cells. Hybrid chitosan-dextran magnetic particles demonstrated high MR contrast enhancing properties for the delineation of the brain tumor. Due to a significant retention of the particles in the tumor an application of the CS-DX-SPIONs could not only improve the tumor imaging but also could allow a targeted delivery of chemotherapeutic agents.