Design And Antitumor Mechanism Of Mitochondrial-targeting Pt^ⅣComplex

The accidental discovery of cisplatin by Professor Rosenberg in 1960s opened the stage of metal-based drugs.Currently,platinum-based drugs have made a great contribution to the treatment of cancer and remain the first choice of chemotherapeutics.However,its clinical application is limited by serious problems like severe side effects and drug resistance.A promising strategy to overcome these disadvantages is to synthesis platinum complexes with novel structure and new targeting spots,which can avoid the nucleotide excision repair(NER)machinery.Among these,mitochondria have been found to be a potential target to overcome the resistance,as they play an important role in the regulation of tumor development and apoptosis.Meanwhile,taking the advantage of solubility,low toxicity and easiness of modifying,PtⅣ complex offers a platform to connect mitochondrial targeting groups.Inspired by this,we designed a mitochondrial targeting PtⅣ prodrug c,c,t-[Pt(NH3)2Cl2(OCOCH2CH2CH2CH2PPh3)2](Pt-TPP),with cisplatin scaffold on its plane and bearing TPP as homing moiety for mitochondria on its axial.The complex,Pt-TPP was synthesized and characterized by 1H,13C,31P,195Pt NMR spectroscopy and ESI-MS.Its purity was ascertained to be 98%by HPLC.Then,the chemical property of Pt-TPP was tested in vitro.The reduction potential indicated it can be reduced in cells effectively according to the literature.While,it showed usual properties in other tests.For example,the reduction rate of Pt-TPP was very slow as shown in ESI-MS.1H-NMR and CD spectrometry further implied interaction between Pt-TPP and DNA was not obvious,even under the attendance of 10 times ascorbic acid.These unique properties may help to reduce the ratio of PtⅣ which got reducted before entering mitochondria and partially prevent PtⅣ reacting with nuclear DNA.In celluar experiment,Pt-TPP exhibited better mitochondrial targeting property and stronger ability of disruption of mitochondrial morphology,membrane potential and oxidative phosphorylation,compared with cisplatin.As a consequence,Cytochrome C was released from mitochondria and caused cellular apoptosis.As a prodrug,Pt-TPP needed to be reduced before it can show affect,which leaded to a mild cytotoxicity to cancer cells.And in normal cells,it showed a even weaker cytotoxicity.This result showed that it may have weaker side effects.Cell cycle arrest which is a distinguishing feature of cisplatin mechanism of action,is not observed for the mitochondrially-targeted compound.It indicated that the mechanism of anti-proliferative activity of this new compound is different from that of cisplatin.Above all,this study exhibited that delivering cisplatin into mitochondrial matrix by using a mitochondria targeted PtⅣ prodrug may be beneficial to overcome the resistance of conventional platinum based chemotherapeutics.