title: Transferrin serves as a mediator to deliver organometallic ruthenium(II) anticancer complexes into cells.
abstract: We report herein a systematic study on interactions of organometallic ruthenium(II) anticancer complex [(η(6)-arene)Ru(en)Cl](+) (arene = p-cymene (1) or biphenyl (2), en = ethylenediamine) with human transferrin (hTf) and the effects of the hTf-ligation on the bioavailability of these complexes with cisplatin as a reference. Incubated with a 5-fold excess of complex 1, 2, or cisplatin, 1 mol of diferric hTf (holo-hTf) attached 0.62 mol of 1, 1.01 mol of 2, or 2.14 mol of cisplatin. Mass spectrometry revealed that both ruthenium complexes coordinated to N-donors His242, His273, His578, and His606, whereas cisplatin bound to O donors Tyr136 and Tyr317 and S-donor Met256 in addition to His273 and His578 on the surface of both apo- and holo-hTf. Moreover, cisplatin could bind to Thr457 within the C-lobe iron binding cleft of apo-hTf. Neither ruthenium nor platinum binding interfered with the recognition of holo-hTf by the transferrin receptor (TfR). The ruthenated/platinated holo-hTf complexes could be internalized via TfR-mediated endocytosis at a similar rate to that of holo-hTf itself. Moreover, the binding to holo-hTf well preserved the bioavailability of the ruthenium complexes, and the hTf-bound 1 and 2 showed a similar cytotoxicity toward the human breast cancer cell line MCF-7 to those of the complexes themselves. However, the conjugation with holo-hTf significantly reduced the cellular uptake of cisplatin and the amount of platinated DNA adducts formed intracellularly, leading to dramatic reduction of cisplatin cytotoxicity toward MCF-7. These findings suggest that hTf can serve as a mediator for the targeting delivery of Ru(arene) anticancer complexes while deactivating cisplatin.
authors.affiliation: Beijing National Laboratory for Molecular Sciences, Beijing Centre for Mass Spectrometry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Qun
authors.initials: Q
authors.lastname: Luo
authors.forename: Xianchan
authors.initials: X
authors.lastname: Li
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Shaoxiang
authors.initials: S
authors.lastname: Xiong
authors.forename: Fuyi
authors.initials: F
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011485:Protein Binding; D011990:Receptors, Transferrin / Q000378:metabolism; D012428:Ruthenium / Q000737:chemistry / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D011990:Receptors, Transferrin; D014168:Transferrin; D012428:Ruthenium; D002945:Cisplatin