Functional Inorganic Nanoparticles for Stem Cell Tracking and Ischemic Stroke Treatment

Abstract

During the last decade, various functional nanostructured materials with interesting optical, magnetic, mechanical, and chemical properties have been extensively applied to biomedical areas including imaging, diagnosis, and therapy. In particular, interdisciplinary collaborative research between material science and biomedicine enabled nanomaterials to translate the medical issues and application to clinical trials. Cellular therapies by the administration of therapeutic cells such as stem cells or immune cells benefit greatly from the inclusion of nanomaterials to achieve high-resolution tracking of the cells. Another application of nanomaterials is as intrinsic chemotherapeutic agents. Long-term cell tracking can be realized by producing highly sensitive nanoparticles or by the control of particle-cell interactions. Engineering physical and chemical properties of nanoparticles - such as size, surface, and composition, enables to obtain optimized therapeutic potentials at target tissues with minimal toxicity. Firstly, hollow manganese oxide core and mesoporous silica coated (HMnO@mSiO2) nanoparticles were fabricated for highly efficient T1 magnetic resonance imaging (MRI) contrast agent for labeling and MRI tracking of stem cells. These nanoparticles have been designed to enable optimal access of water molecules to core Mn ions combined with the large surface area-to-volume ratio, exhibiting much higher r1 relaxivity over other existing MnO nanoparticle-based MRI contrast agents. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, and detected on T1-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO2-labeled MSCs enabled serial MR monitoring of cell transplants over a prolonged period of time. Secondly, computed tomograpy (CT) cell tracking methods with gold nanoparticles were developed. CT cell tracking has been known to be very difficult due to its low sensitivity. Herein, 40 nm citrate stabilized gold nanoparticles were readily complexed with poly-L-lysine (PLL), which were then successfully used to label human mesenchymal stem cells (hMSCs). More importantly, gold nanoparticles labeling did not impair cellular viability, proliferation, and differentiation. Labeled hMSCs were visualized in vitro and tracked in vivo using micro-CT and their detection limit revealed to be ~ 10,000 cells/μl in vivo. This study represents, to the best of our knowledge, one of the first attempts to develop CT cell tracking, and can be applied in CT image-guided interventions and fluoroscopic procedures commonly used for injection of molecular and cellular therapeutics. Finally, the protective effects of ceria nanoparticles against ischemic stroke were studied. Reactive oxygen species (ROS) are a major cause of ischemic brain injury, and ceria nanoparticles are known to exhibit potent free radical scavenging activity. Discrete and uniform 3 nm-sized ceria nanoparticles which were colloidally very stable and tissue permeable were synthesized. These nanoparticles were successfully demonstrated to protect against ischemic stroke in living animals which has been done for the first time. Targeting infarct site after intravenous injection, optimal dose of ceria nanoparticles (0.5 and 0.7 mg/kg) significantly reduced infarct volume and ischemic cell death in vivo. These protective effects of ceria nanoparticles in in vivo model were mediated by scavenging of ROS and a decrease in apoptosis.