作者: Gabbiani, Chiara ; Cirri, Damiano ; Messori, Luigi ; Tolbatov, Iogann ; Paciotti, Roberto ; Marrone, Alessandro ; Re, Nazzareno ; Marzo, Tiziano ; Coletti, Cecilia

Quite surprisingly, cisplatin and cis-[PtI₂(NH₃)₂] were found to manifest significant differences in their reactions with the model protein lysozyme. We decided to explore whether these differences recur when reacting these two Pt compounds with other proteins. Notably, ESI-MS measurements carried out on cytochrome c nicely confirmed the reaction pattern observed for lysozyme. This prompted us to exploit a computational DFT approach to disclose the molecular basis of such behavior. We analyzed comparatively the reactions of cis-[PtCl₂(NH₃)₂] and cis-[PtI₂(NH₃)₂] with appropriate molecular models (Ls) of the sidechains of relevant aminoacids. We found that when Pt(II) complexes are reacted with sulfur ligands both quickly lose their halide ligands and then the resulting cis-[Pt(L)₂(NH₃)₂] species loses ammonia upon reaction with a ligand excess. In the case of imidazole, again cis-[PtCl₂(NH₃)₂] and cis-[PtI₂(NH₃)₂] quickly lose their halide ligands but the resulting cis-[Pt(L)₂(NH₃)₂] species does not lose ammonia by reaction with excess imidazole. These results imply that the two platinum complexes manifest a significantly different behavior in their reaction with representative small molecules in agreement with what observed in the case of model proteins. It follows that the protein itself must play a crucial role in triggering the peculiar reactivity of cis-[PtI₂(NH₃)₂] and in governing the nature of the formed protein adducts. The probable reasons for the observed behavior are critically commented and discussed.

2015-12-07·Molecular Pharmaceutics2区 · 医学

Combinatorial-Designed Epidermal Growth Factor Receptor-Targeted Chitosan Nanoparticles for Encapsulation and Delivery of Lipid-Modified Platinum Derivatives in Wild-Type and Resistant Non-Small-Cell Lung Cancer Cells

2区 · 医学

Article

作者: Amiji, Mansoor M. ; Nascimento, Ana Vanessa ; Sarmento, Bruno ; Ferreira, Domingos ; Singh, Amit ; Bousbaa, Hassan

Development of efficient and versatile drug delivery platforms to overcome the physical and biological challenges in cancer therapeutics is an area of great interest, and novel materials are actively sought for such applications. Recent strides in polymer science have led to a combinatorial approach for generating a library of materials with different functional identities that can be "mixed and matched" to attain desired characteristics of a delivery vector. We have applied the combinatorial design to chitosan (CS), where the polymer backbone has been modified with polyethylene glycol, epidermal growth factor receptor-binding peptide, and lipid derivatives of varying chain length to encapsulate hydrophobic drugs. Cisplatin, cis-([PtCl2(NH3)2]), is one of the most potent chemotherapy drugs broadly administered for cancer treatment. Cisplatin is a hydrophilic drug, and in order for it to be encapsulated in the developed nanosystems, it was modified with lipids of varying chain length. The library of four CS derivatives and six platinum derivatives was self-assembled in aqueous medium and evaluated for physicochemical characteristics and cytotoxic effects in platinum-sensitive and -resistant lung cancer cells. The results show that the lipid-modified platinate encapsulation into CS nanoparticles significantly improved cellular cytotoxicity of the drug. In this work, we have also reinforced the idea that CS is a multifaceted system that can be as successful in delivering small molecules as it has been as a nucleic acids carrier.

2014-06-12·Journal of Medicinal Chemistry1区 · 医学

Luminescent Ruthenium Complexes for Theranostic Applications

1区 · 医学

Article

作者: Cardoso, Carolina R. ; Venâncio, Tiago ; Farrell, Nicholas P. ; Carlos, Rose M. ; Cheleski, Juliana ; Lima, Márcia V. S. ; Peterson, Erica J.

The water-soluble and visible luminescent complexes cis-[Ru(L-L)2(L)2](2+) where L-L = 2,2-bipyridine and 1,10-phenanthroline and L= imidazole, 1-methylimidazole, and histamine have been synthesized and characterized by spectroscopic techniques. Spectroscopic (circular dichroism, saturation transfer difference NMR, and diffusion ordered spectroscopy NMR) and isothermal titration calorimetry studies indicate binding of cis-[Ru(phen)2(ImH)2](2+) and human serum albumin occurs via noncovalent interactions with K(b) = 9.8 × 10(4) mol(-1) L, ΔH = -11.5 ± 0.1 kcal mol(-1), and TΔS = -4.46 ± 0.3 kcal mol(-1). High uptake of the complex into HCT116 cells was detected by luminescent confocal microscopy. Cytotoxicity of cis-[Ru(phen)2(ImH)2](2+) against proliferation of HCT116p53(+/+) and HCT116p53(-/-) shows IC50 values of 0.1 and 0.7 μmol L(-1). Flow cytometry and western blot indicate RuphenImH mediates cell cycle arrest in the G1 phase in both cells and is more prominent in p53(+/+). The complex activates proapoptotic PARP in p53(-/-), but not in p53(+/+). A cytostatic mechanism based on quantification of the number of cells during the time period of incubation is suggested.

100 项与 EDP-20 相关的药物交易

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