Ferritin carriers to deliver Ru(II)-photosensitizers into cancer cells for photodynamic therapy

Human heavy-chain (H) ferritin is a nanocage protein constituted by 24 identical subunits that self-assemble giving rise to a hollow globular structure. It is characterized by the presence of an internal cavity of 8 nm in diameter able to safely store thousands of iron ions and to host different kinds of molecules including anticancer drugs. The peculiarity of human H-ferritin is the possibility to be internalized by cells exposing Transferrin receptor 1 (TfR1) which mediates its endocytosis. Cancer cells commonly overexpress cellular receptors; this feature prospects kind of targeted drug delivery in the development of ferritin-based nanocarriers loaded with compounds interesting for cancer therapy. Here, human homopolymeric H-ferritin has been easily produced in E. coli and successfully loaded with Ru(II)-polypyridyl photosensitizers for photodynamic therapy (PDT) application in cancer cells.[1] The resulting Ru(II)-ferritin nanocomposites were highly luminescent, displayed great stability in physiological conditions and preserved the native shell–core structure of the protein. Importantly, the encapsulated metal complexes retained the capacity to sensitize the production of the cytotoxic singlet oxygen species upon illumination. Ru(II)-ferritin nanocomposites were exclusively internalized by cancer cells expressing TfR1 (i.e. HeLa and A2780 cell lines with respect to non-cancerous C2C12 myoblasts lacking TfR1 expression) as revealed by immunofluorescence analysis and ICP-OES ruthenium quantification. Finally, the photoactivation of the nanocomposites induced a marked dosedependent cytotoxicity uniquely against TfR1-positive cancer cells. This study underlined the potential of human H-ferritin as a valuable tool for the tumor-targeting delivery of photosensitizers for PDT.