Titanium (Ti) and its alloys are widely used in orthodontic and orthopedic implants by virtue to their high biocompatibility, mechanical strength, and high resistance to corrosion. Biointegration of the implants with the tissue requires strong interactions, which involve biological molecules, proteins in particular, with metal oxide surfaces. An exocellular high-affinity titanium dioxide (TiO )-binding protein (TiBP), purified from Rhodococcus ruber, has been previously studied in our lab. This protein was shown to be homologous with the orthologous cytoplasmic rhodococcal dihydrolipoamide dehydrogenase (rhDLDH). We have found that rhDLDH and its human homolog (hDLDH) share the TiO -binding capabilities with TiBP. Intrigued by the unique TiO -binding properties of hDLDH, we anticipated that it may serve as a molecular bridge between Ti-based medical structures and human tissues. The objective of the current study was to locate the region and the amino acids of the protein that mediate the protein-TiO surface interaction. We demonstrated the role of acidic amino acids in the nonelectrostatic enzyme/dioxide interactions at neutral pH. The observation that the interaction of DLDH with various metal oxides is independent of their isoelectric values strengthens this notion. DLDH does not lose its enzymatic activity upon binding to TiO , indicating that neither the enzyme undergoes major conformational changes nor the TiO binding site is blocked. Docking predictions suggest that both rhDLDH and hDLDH bind TiO through similar regions located far from the active site and the dimerization sites. The putative TiO -binding regions of both the bacterial and human enzymes were found to contain a CHED (Cys, His, Glu, Asp) motif, which has been shown to participate in metal-binding sites in proteins.

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This work presents a UVA switchable integrin-targeted photodynamic therapy in melanoma, composed of an RGD-modified DLDH conjugated to TiO2 nanoparticles, with high selectivity towards integrin-expressing cancer cells.

We assessed the effect of antitumoural therapy at intensive doses on the haemopoietic system using long-term marrow cultures (LTMC) established from 33 patients (25 with haematological diseases and eight with solid tumours) after autologous bone marrow transplantation (ABMT). When compared to 42 pre-graft patients, a decreased CFU-GM production and a defect in stromal layer (SL) confluence were found after ABMT on day 90 but also on day 365. However, these abnormalities were observed only in patients with haematological diseases and no differences between pre-graft and post-graft results were found in patients with solid tumours. Among the patients with haematological diseases, on day 90 those with acute lymphoid leukaemias showed lower CFU-GM production whereas patients with non-Hodgkin's lymphomas developed more frequently subconfluent or confluent SL. Other factors studied such as sex, patient age, disease status, marrow purging and post-graft administration of growth factors did not appear to influence post-graft LTMC results. Multivariate analysis including all the patients has shown (a) that solid tumours were associated with higher CFU-GM production, and (b) that conditioning regimens with total body irradiation (TBI) or busulfan led more frequently to non-confluent SL. In conclusion, high-dose therapy followed by ABMT can induce a persistent impairment of the stem cell and stromal cell compartments, particularly in patients with haematological diseases conditioned with TBI, despite the absence of any alloimmune reaction and post-graft immunosuppressive therapy.

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