Functional Design And Mechanism Study Of Platinum-based Antitumor Drugs

Platinum-based antitumor drugs,such as cisplatin,have been widely used to treat various cancers for nearly 40 years.However,its application has been heavily conditioned by severe systemic toxicities like nephrotoxicity and neurotoxicity.In addition,the efficacy of cisplatin is limited because of inherent or acquired drug resistance.These defects mainly result from its indiscriminate body distribution and insufficient tumor accumulation,and also from its detoxification by sulfur-containing biomolecules.In recent years,functionalizing platinum complexes with bioactive molecules,targeting groups,or nanomaterials has been paid attention,in order to improve the tumor selectivity or minimize the systemic toxicity of the drugs,to enhance the cellular accumulation of the drugs,to overcome the tumor resistance to the drugs,to visualize the drug molecules in vitro or in vivo.In this thesis,different strategies were used to study platinum complexes,including conjugation with magnetic resonance imaging(MRI)contrast agents(CAs)into a bifunctional single theranostic agent;nanoparticles system for passively targeted drug delivery and MR imaging;functionalized with a delocalized lipophilic cation to target mitochondria.These designs are explained and justified at the molecular or cellular level,associating with the requirements for diagnosis,therapy,and visualization of biological processes.The behavior of Pt complexes,such as distribution,accumulation,and metabolism,in tumors is poorly understood.Thus,a reliable strategy for real-time monitoring of the drug location and therapeutic responses during treatment is highly desired.Multifunctional Pt complexes are likely to exhibit synergic actions against tumor cells.Commonly,they can enhance selectivity for cancer cells or modulate the drug distribution in the body to increase drug accumulation at tumor sites.MRI provides a powerful noninvasive diagnostic modality for cancers with high spatial resolution and precise 3D positioning.We herein report two Pt—Gd complexes,1 and 2,as cancer theranostic agents,which were formed by conjugating GdL1 and GdL2 to the cytotoxic cis-[Pt(NH3)2Cl]+complex,respectively.Thus,the Gd-DTPA and Pt complexes were integrated into a single molecule with both antitumor and imaging functionalities.These complexes can enter cancer cells and interact with DNA;more importantly,they show higher proton relaxivity than that of Gd-DTPA and similar cytotoxicity to that of cisplatin at imaging concentrations.Therefore,they are capable of simultaneous drug tracing and cancer restraint.Targeted prodrug systems have been proven effective in minimizing the systemic toxicity and in maximizing the tumor accumulation of Pt drugs.SPIONs could guide drugs preferentially to the biological target through an external magnet and provide a strong negative contrast effect in T2-weighted MRI;and polymer modified SPIONs possess some excellent properties,such as hydrophilicity,nontoxicity,and nonimmunogenicity,for drug delivery.However,Pt? moieties are capable of reacting with bionucleophiles during the delivery,and hence could be toxic to normal tissues.Octahedrally coordinated Pt? complexes are substantially more inert than Pt?complexes and thus can avoid the undesirable side reactions in the blood plasma.GSH is one of the intracellular reductants that activate Pt? complexes.In this study,we use SPIONs(Fe3O4)to design the targeted Pt prodrug system.HSPt is loaded onto the surface of the PEGylated SPIONs,forming HSPt-PEG-SPIONs.This nanocomposite exhibits some unique properties in vitro,HSPt-PEG-SPIONs can be dissociated and reduced into Pt? species by glutathione(GSH).Instead of forming DNA-Pt crosslinks,the reduced product induces direct DNA single-or double-strand breaks,which is uncommon for Pt drugs.The cytotoxicity of HSPt-PEG-SPIONs is positively correlated with the GSH level of tumor cells,which is opposite to the scenario of current Pt drugs.Moreover,it produces a significant negative contrast in MRI,and thus could be a potential theranostic agent for chemotherapy.Due to the decreasing drug accumulation inside cells and the increasing activation of cellular self-repair mechanism,has always been a huge barrier for improving the clinical efficiency of platinum-based anticancer drugs.Therefore,complexes designed for new antitumor mechanism may bring a breakthrough against the drug resistance of traditional platinum antitumor drugs.Mitochondria,as an important organelle in the cells,not only play a central role in energy metabolism and calcium homeostasis,but also are essential components of the apoptotic machinery.Targeting mitochondria as a cancer therapeutic strategy has gained momentum in the recent years,and inducing damage to mitochondrial should be a feasible and effective mechanism for tumor therapy.Delocalized lipophilic cations,such as triphenylphosphonium cation(TPP+),with highly hydrophobic structures and positive charge,seem to be able to accumulate in the tumor mitochondria of tumor.A series of mitochondrial-targeted Pt? complexes was prepared in which the pyridine(py)was systematically varied by delocalized lipophilic triphenylphosphonium cation(TPP+),to get the complexes,OPT=[Pt(ortho-PPh3CH2Py)(NH3)2Cl](NO3)2,MPT=[Pt(meta-PPh3CH2Py)(NH3)2Cl](NO3)2 and PPT=[Pt(para-PPh3CH2Py)(NH3)2Cl](NO3)2.The resulting compounds were fully characterized and evaluated for biological activity.Among them,OPT was identified to exhibit greater efficacy than cisplatin in established human cancer cell lines.The cellular uptake and mitochondria accumulation,mitochondrial dysfunction,nuclei DNA binding of OPT were investigated to provide insight into the high potency of mitochondrial target,and result in apoptosis in cancer cells.Mitochondrial-targeted Pt?complexes may have potential to overcome the drug resistance of traditional platinum antitumor drugs through new mechanism.