Supramolecular Polymerization-Induced Nanoassemblies for Self-Augmented Cascade Chemotherapy and Chemodynamic Therapy of Tumor.

The clinical application of chemodynamic therapy is impeded by the insufficient intracellular H2 O2 level in tumor tissues. Herein, we developed a supramolecular nanoparticle via a simple one-step supramolecular polymerization-induced self-assembly process using platinum (IV) complex-modified ß-cyclodextrin-ferrocene conjugates as supramolecular monomers. The supramolecular nanoparticles could dissociate rapidly upon exposure to endogenous H2 O2 in the tumor and release hydroxyl radicals as well as platinum (IV) prodrugs in situ, which is reduced into cisplatin to significantly promote the generation of H2 O2 in the tumor tissue. Thus, the supramolecular nanomedicine overcomes the limitation of conventional chemodynamic therapy via the self-augmented cascade radical generation and drug release. In addition, dissociated supramolecular nanoparticles could be readily excreted from the body via renal clearance to effectively avoid systemic toxicity and ensure long term biocompatibility of the nanomedicine. This work may provide new insights on the design and development of novel supramolecular nanoassemblies for cascade chemo/chemodynamic therapy.

Significant glial alterations in response to iron loading in a novel organotypic hippocampal slice culture model.

Aberrant iron deposition in the brain is associated with neurodegenerative disorders including Multiple Sclerosis, Alzheimer's disease and Parkinson's disease. To study the collective response to iron loading, we have used hippocampal organotypic slices as a platform to develop a novel ex vivo model of iron accumulation. We demonstrated differential uptake and toxicity of iron after 12 h exposure to 10 µM ferrous ammonium sulphate, ferric citrate or ferrocene. Having established the supremacy of ferrocene in this model, the cultures were then loaded with 0.1-100 µM ferrocene for 12 h. One µM ferrocene exposure produced the maximal 1.6-fold increase in iron compared with vehicle. This was accompanied by a 1.4-fold increase in ferritin transcripts and mild toxicity. Using dual-immunohistochemistry, we detected ferritin in oligodendrocytes, microglia, but rarely in astrocytes and never in neurons in iron-loaded slice cultures. Moreover, iron loading led to a 15% loss of olig2-positive cells and a 16% increase in number and greater activation of microglia compared with vehicle. However, there was no appreciable effect of iron loading on astrocytes. In what we believe is a significant advance on traditional mono- or dual-cultures, our novel ex vivo slice-culture model allows characterization of the collective response of brain cells to iron-loading.