Platinum anticancer drugs are particularly in need of controlled drug delivery because of their severe side effects. Platinum(IV) agents are designed as prodrugs to reduce the side effects of platinum(II) drugs; however, premature reduction could limit the effect as a prodrug. In this work, a highly biocompatible, pH and redox dual-responsive delivery system is prepared by using hybrid nanoparticles of human serum albumin (HSA) and calcium phosphate (CaP) for the Pt^IV prodrug of cisplatin. This conjugate is very stable under extracellular conditions, so that it protects the platinum(IV) prodrug in HSA. Upon reaching the acidic and hypoxic environment, the platinum drug is released in its active form and is able to bind to the target DNA. The Pt–HSA/CaP hybrid inhibits the proliferation of various cancer cells more efficiently than cisplatin. Different cell cycle arrests suggest different cellular responses of the Pt^IV prodrug in the CaP nanocarrier. Interestingly, this delivery system demonstrates enhanced cytotoxicity to tumor cells, but not to normal cells.

Platinum phenanthroline complexes inhibit amyloid-β (Aβ) aggregation and reduce Aβ-caused neurotoxicity [Proc. Natl. Acad. Sci., 2008, 105, 6813–6818]. In this study, we investigated the interactions of Aβ_1–16 with [PtCl₂(phen)] (phen=1,10-phenanthroline) using HPLC, ESI-MS, and NMR spectroscopy , and characterized the identity of products using tandem mass spectrometry. Results indicated that the phenanthroline ligand could induce noncovalent interactions between Aβ peptide and platinum complexes, leading to rapid Aβ platination. Multiple products were generated in the reaction, in which His6/His14 chelation was preferentially formed. Coordination of Asp7, His13, and Lys16 was also detected in other products. The majority of products were monoplatinated adducts with binding of the {Pt(phen)} scaffold, which impeded intermolecular interactions between Aβ peptides. Moreover, noncovalent interactions were confirmed by the interaction between Aβ peptide and [Pt(phen)₂]Cl₂. The synergistic roles of the phen ligand and platinum(II) atom in the inhibition of Aβ aggregation are discussed.

Protein splicing is a unique post-translational process in which an intein excises itself from a precursor with the concomitant ligation of flanking sequences. The binding of zinc to intein inhibits protein splicing reversibly and EDTA relieves the inhibition. Copper was found to inhibit protein trans splicing; however, the recovery of intein splicing required both EDTA and TCEP, suggesting a different inhibition mechanism for copper compared to zinc. In this work, we have investigated the binding properties and inhibition effects of copper ions on the RecA intein from Mycobacterium tuberculosis. Both Cu⁺ and Cu²⁺ exhibited high binding affinity to inteins, while different binding sites were identified. Cu²⁺ coordinates to Cys1, the key residue involved in the mechanism of protein splicing, however, Cu⁺ does not coordinate to cysteine. An in vitro inhibition assay indicated that monovalent Cu⁺ demonstrates reversible inhibition to protein splicing, and the inhibitory efficiency is comparable to Zn²⁺. Redox reaction between Cu²⁺ and cysteine in inteins were observed and the rate constants were determined. The results suggested a dual role for Cu²⁺ in the inhibition of intein splicing: strong coordination of Cu²⁺ to key residues (including Cys1) in the intein, and subsequent oxidation of Cys1, the residue required for the NS acyl shift step in protein splicing. A kinetic study suggested that the coordination could be the major cause of inhibition effect of Cu²⁺ initially, whereas the redox reaction could play an additional role in inhibition at a later stage.