Targeting experimental orthotopic glioblastoma with chitosan-based superparamagnetic iron oxide nanoparticles (CS-DX-SPIONs)

Abstract

BackgroundGlioblastoma 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 site but also provide contrast enhancing properties for diagnostics using magnetic resonance imaging (MRI).MethodsSynthesized hybrid chitosan-dextran superparamagnetic nanoparticles (CS-DX-SPIONs) were characterized using transmission electron microscopy (TEM) and relaxometry studies. Nonlinear magnetic response measurements were employed for confirming the superparamagnetic state of particles. Following in vitro analysis of nanoparticles cellular uptake tumor targeting was assessed in the model of the orthotopic glioma in rodents.ResultsCS-DX-SPIONs nanoparticles showed a uniform diameter of 55 nm under TEM and superparamagentic characteristics as determined by T1 (spin-lattice relaxation time) and T2 (spin-spin relaxation time) 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 cells as compared to dextran-coated particles. Cytotoxicity assay demonstrated acceptable toxicity profile of the synthesized nanoparticles up to a concentration of 10 μg/ml. Intravenously administered CS-DX-SPIONs in orthotopic C6 gliomas in rats accumulated in the tumor site as shown by high-resolution MRI (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 the accumulation of the nanoparticles inside glioblastoma cells.ConclusionHybrid 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.

Chitosan-Based Nanocarriers for Nose to Brain Delivery

“…The NPs toxicity profile up to a concentration of 10 µg/ml was acceptable and the magnetic properties of the NPs were retained after internalization into the cell. Intravenously administered NPs in orthotopic C6 gliomas in rats resulted in an accumulation of the NPs in the tumor site, suggesting that the NPs can be used to improve the tumor imaging and for targeted delivery of chemotherapeutic agents [77]. Coating the nanoparticles with chitosan increased the charge of the nanoparticles to +19.2 mV.…”

“…The cytotoxic effect of the NPs was influenced by the surface area and enhanced cellular uptake of the NPs. More modifications on the surface of the nanoparticles with targeting ligands have the potential to further increase the accumulation of the particles in the glioma tissue [77]. Docetaxel-loaded D-α-tocopherol polyethylene glycol 1000 succinate conjugated chitosan nanoparticles were prepared with the presence or absence of transferrin on the surface [78].…”

Nanoparticle-modified chitosan-agarose-gelatin scaffold for sustained release of SDF-1 and BMP-2

“…The use of chitosan and heparin for the delivery of bioactive molecules has many advantages, including being inexpensive, biodegradable, noncytotoxic, nonimmunogenic, 34,35 easy to process, absorbable, and having safe degradation end product. 36,37 Our previous study about CSO/H NPs showed that they are stable in physiological pH solution and exhibited improved biocompatibility of chitosan-based nanoparticles. 19 However, nanoparticles composed of CSO and heparin cannot easily meet the time stipulations of tissue engineering, which usually requires a period of a few weeks.…”

Comparison of ultrasmall IONPs and Fe salts biocompatibility and activity in multi-cellular in vitro models

“…The doses varying from 1 to 25 µg Fe/ml correspond to clinical doses of IONPs-based contrast agents (lower) and drugs used for the treatment of iron deficiency anemia (higher) 28 , 29 , 64 . According to the most of in vitro studies, for such IONPs doses the lack or low toxicity is observed 13 , 14 , 22 , 23 . However, this is not the rule, as sometimes the cytotoxic effect is observed even at very low doses and short exposition time 20 .…”

“…The span of studied IONPs doses in the literature is very wide. They range from single micrograms of Fe/ml 18 – 22 to even milligrams of Fe/ml 23 – 27 . So, the doses studied by us belong rather to the lower ones analyzed in the context of IONPs toxicity.…”