Overcoming Cancer Resistance to Platinum Drugs by Inhibiting Cholesterol Metabolism

Drug resistance is a serious challenge for platinum anticancer drugs. Platinum complexes may get over the drug resistance via a distinct mechanism of action. Cholesterol is a key factor contributing to the drug resistance. Inhibiting cellular cholesterol synthesis and uptake provides an alternative strategy for cancer treatment. Platinum(IV) complexes FP and DFP with fenofibric acid as axial ligand(s) were designed to combat the drug resistance through regulating cholesterol metabolism besides damaging DNA. In addition to producing reactive oxygen species and active platinum(II) species to damage DNA, FP and DFP inhibited cellular cholesterol accumulation, promoted cholesterol efflux, upregulated peroxisome proliferator-activated receptor alpha (PPARα), induced caspase-1 activation and gasdermin D (GSDMD) cleavage, thus leading to both apoptosis and pyroptosis in cancer cells. The reduction of cholesterol significantly relieved the drug resistance of cancer cells. The double-acting mechanism gave the complexes strong anticancer activity in vitro and in vivo, particularly against cisplatin-resistant cancer cells.     

Insertion of (Bioactive) Equatorial Ligands into Platinum(IV) Complexes

Platinum(IV) prodrugs are highly interesting alternatives to platinum(II) anticancer therapeutics due to their increased tumor selectivity and reduced side effects. In contrast to the established theory, we recently observed that the equatorial ligand(s) of e.g. oxaliplatin(IV) complexes can be hydrolyzed with formation of [(DACH)Pt(OH_eq)₂(OAc_ax)₂]. In the work presented here, we investigated the reactivity and synthetic usability of this complex to be exploited as a precursor for the development of novel platinum(IV) complexes, not able to be synthesized by conventional protocols. Indeed, we could substitute the equatorial hydroxido ligand(s) e.g. by one or two monodentate biotin ligands (which would be oxidized under standard methods). The formed complexes turned out to be very stable with slow ligand release after reduction, ideal for long-circulating tumor-targeting strategies. Therefore, two platinum(IV) complexes with equatorial maleimides, capable of exploiting serum albumin as a natural nanocarrier, were synthesized as well. The complexes showed massively prolonged plasma half-life and distinctly improved anticancer activity in vivo compared to oxaliplatin. Taken together, the newly developed synthetic platform allows the simple and specific insertion of equatorial ligands into platinum(IV) complexes. This will enable the attachment of three different (bioactive) moieties generating targeted triple-action platinum(IV) prodrugs within one single platinum complex.     

Human Serum Albumin Conjugated Nanoparticles for pH and Redox‐Responsive Delivery of a Prodrug of Cisplatin

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.     

非经典铂类抗肿瘤药物研究

本文综述了非经典铂类抗肿瘤药物的发展概况,介绍了具有口服活性的铂(Ⅳ)配合物,具有空间位阻的铂(Ⅱ)配合物,反式铂(Ⅱ、Ⅳ)配合物,多核铂(Ⅱ)配合物和含有铂-硫键的铂(Ⅱ)配合物,并总结了这几类新型铂配合物的抗肿瘤机理,克服顺铂的耐药性机理及其临床进展。     

Integrating of lipophilic platinum(IV) prodrug into liposomes for cancer therapy on patient-derived xenograft model

Platinum-based anticancer agents such as cisplatin and its analogues are widely used for treating multiple cancers. However, due to the inferior water-solubility, chemoresistance and consequent adverse side effects, their clinical applications are limited. Herein, cholesPt(IV), a lipophilic platinum(IV) prodrug was synthesized for manufacture of CholesPt(IV)-Liposomes aiming to resolve the predefined obstacles encountered by platinum drugs. Following systematic screening, CholesPt(IV)-Liposomes showed a small particle size (105.6 nm), the rapid release of platinum (Pt) ions, and notable apoptosis of cancer cells. In addition, according to the fluidity and safety results of animal experiments in mice, CholesPt(IV)-Liposomes also showed better therapeutic effect, which significantly inhibited the growth of patient-derived xenograft tumors of hepatocellular carcinoma with an inhibition ratio of 80.7%, and effectively alleviated the drug toxicity brought by traditional platinum drugs. Overall, this study provides a promising route to enhance the therapeutic efficiency of platinum drugs in cancer treatment.     

Front Cover: Synthesis,Characterization, and Cytotoxicity of a Reactive Platinum(IV) Monotrifluoromethyl Complex (Eur. J. Inorg. Chem. 3/2023)

Platinum-based complexes are among the most widely utilized cancer therapeutics. Current Pt(II) drugs face some challenges including toxicity and drug resistance. To solve these issues, great efforts have been devoted to developing nonclassical platinum complexes, such as Pt(IV) prodrugs, that act via mechanisms distinct from those of the approved drugs. Compared with active Pt(II) counterparts, Pt(IV) complexes are relatively inert. Although direct interactions between Pt(IV) complexes and nucleotides have been reported, the reaction is slow due to the kinetic inertness of Pt(IV) complexes. Herein, we design and synthesize a Pt(IV) monotrifluoromethyl complex, in which the chloride ligand that is trans to trifluoromethyl ligand is reactive. The Pt(IV) monotrifluoromethyl complex is very stable in water but displays high reactivity towards various substrates including buffer components and 5’-dGMP. The study of reaction mechanism reveals that this Pt(IV) complex reacts with phosphate via S_N2 nucleophilic substitution pathway, which is different from Pt(II) drugs. The Pt(IV) monotrifluoromethyl complex is cytotoxic in human ovarian cancer cells. Our work reports an example of a reactive organometallic Pt(IV) complex that can directly interact with nucleophiles and implies its potential as an anticancer agent.     

The Prodrug Platin‐A: Simultaneous Release of Cisplatin and Aspirin

Cancer‐associated inflammation induces tumor progression to the metastatic stage, thus indicating that a chemo‐anti‐inflammatory strategy is of interest for the management of aggressive cancers. The platinum(IV) prodrug Platin‐A was designed to release cisplatin and aspirin to ameliorate the nephrotoxicity and ototoxicity caused by cisplatin. Platin‐A exhibited anticancer and anti‐inflammatory properties which are better than a combination of cisplatin and aspirin. These findings highlight the advantages of combining anti‐inflammatory treatment with chemotherapy when both the drugs are delivered in the form of a single prodrug.     

钯(Ⅱ)类抗肿瘤药物研究进展

20世纪60年代,美国密执安州立大学Rosenberg发现了顺铂具有抗癌活性,开辟了金属类抗肿瘤药物研究的新领域.经过40余年的研究,已相继成功开发了卡铂、奈达铂、奥沙利铂、舒铂、洛铂和双环铂等铂类抗肿瘤药物.虽然对于铂类抗肿瘤药物研究取得了一定的成绩,但在临床使用过程中也存在一些问题,如其毒副作用和抗药性,限制了其在临床上的进一步广泛应用.为了解决这些问题,科研工作者开始寻找新的金属类抗肿瘤药物以弥补现有铂类抗肿瘤药物的不足.在金属元素中,唯有钯(II)与铂(II)配合物具有相似或相同的结构特征,进而表现出相近或相似的化学性质.因此,继铂类抗肿瘤配合物后,钯(II)配合物作为潜在抗肿瘤药物成为一个诱人的领域.本文综述了近年来钯(II)类抗肿瘤药物的研究进展,并探讨了其构效关系,这对于指导新型钯(II)类抗肿瘤药物的合成具有重要的参考价值.     

Facile Preparation of Mono‐, Di‐ and Mixed‐Carboxylato Platinum(IV) Complexes for Versatile Anticancer Prodrug Design

Facile strategies were developed for the versatile functionalization of platinum(IV) axial sites, allowing for easy accessibility to unsymmetric mono‐ and mixed‐carboxylato, as well as symmetric di‐substituted platinum(IV) complexes. The first method involves the direct oxidation and carboxylation of the platinum(II) center using an appropriate peroxide and the carboxylate of choice to firstly yield a monocarboxylato monohydroxido platinum(IV) complex. This platinum(IV) intermediate can undergo further carboxylation to give rise to a mixed‐carboxylato platinum(IV) complex. The second method involves the activation of the carboxylate of choice by a common carbodiimide coupling reagent, and its reaction with a dihydroxido platinum(IV) precursor to give the monocarboxylato platinum(IV) complex. Uronium salts can be employed to promote efficient dicarboxylation of the dihydroxido platinum(IV) precursor. Lastly, an axial azide pendant group was demonstrated to be suitable for orthogonal “click” conjugation reactions.     

Targeted single-wall carbon nanotube-mediated Pt(IV) prodrug delivery using folate as a homing device

Most low-molecular-weight platinum anticancer drugs have short blood circulation times that are reflected in their reduced tumor uptake and intracellular DNA binding. A platinum(IV) complex of the formula c, c, t-[Pt(NH 3) 2Cl 2(O 2CCH 2CH 2CO 2H)(O 2CCH 2CH 2CONH-PEG-FA)] ( 1), containing a folate derivative (FA) at an axial position, was prepared and characterized. Folic acid offers a means of targeting human cells that highly overexpress the folate receptor (FR). Compound 1 was attached to the surface of an amine-functionalized single-walled carbon nanotube (SWNT-PL-PEG-NH 2) through multiple amide linkages to use the SWNTs as a "longboat delivery system" for the platinum warhead, carrying it to the tumor cell and releasing cisplatin upon intracellular reduction of Pt(IV) to Pt(II). The ability of SWNT tethered 1 to destroy selectively FR(+) vs FR(-) cells demonstrated its ability to target tumor cells that overexpress the FR on their surface. That the SWNTs deliver the folate-bearing Pt(IV) cargos into FR(+) cancer cells by endocytosis was demonstrated by the localization of fluorophore-labeled SWNTs using fluorescence microscopy. Once inside the cell, cisplatin, formed upon reductive release from the longboat oars, enters the nucleus and reacts with its target nuclear DNA, as determined by platinum atomic absorption spectroscopy of cell extracts. Formation of the major cisplatin 1,2-intrastrand d(GpG) cross-links on the nuclear DNA was demonstrated by use of a monoclonal antibody specific for this adduct. The SWNT-tethered compound 1 is the first construct in which both the targeting and delivery moieties have been incorporated into the same molecule; it is also the first demonstration that intracellular reduction of a Pt(IV) prodrug leads to the cis-{Pt((NH 3) 2} 1,2-intrastrand d(GpG) cross-link in nuclear DNA.     

Advances in Platinum Chemotherapeutics

The approved platinum(II)‐based anticancer agents cisplatin, carboplatin and oxaliplatin are widely utilised in the clinic, although with numerous disadvantages. With the aim of circumventing unwanted side‐effects, a great deal of research is being conducted in the areas of cancer‐specific targeting, drug administration and drug delivery. The targeting of platinum complexes to cancerous tissues can be achieved by the attachment of small molecules with biological significance. In addition, the administration of platinum complexes in the form of platinum(IV) allows for intracellular reduction to release the active form of the drug, cisplatin. Drug delivery includes such technologies as liposomes, dendrimers, polymers and nanotubes, with all showing promise for the delivery of platinum compounds. In this paper we highlight some of the recent advances in the field of platinum chemotherapeutics, with a focus on the technologies that attempt to utilise the cytotoxic nature of cisplatin, whilst improving drug targeting to reduce side‐effects.     

Cationic intermediates in oxidative addition reactions of Cl2 to [PtCl2(cis-1,4-DACH)

Oxidative addition and reductive elimination are fundamental processes in transition-metal chemistry. New interest in this field has been generated by the exploitation of platinum(IV) complexes as antitumor drugs. The two extra ligands can be used to render these species more resistant to attack by biological nucleophiles compared to their platinum(II) counterparts, to anchor additional pharmacologically active moieties, or, finally, to target the drug to specific sites by conferring responsiveness to some type of chemotaxis. On the other hand, platinum(IV) species are considered to be prodrugs and to require reduction to Pt(II) to become active. Thus, reductive elimination promoted by biological reducing agents becomes an important issue and it too could be exploited for targeting purposes. In this paper, we investigated the oxidation step in more detail and shown that, independent of the solvent used, a solvent molecule assists the reaction by entering in a trans position with respect to the attacking oxidant. In the case of bifunctional solvent molecules, such as dimethylsulfoxide, both S- and O-coordinated species are formed, the latter being thermodynamically favored. The substitution of the axially coordinated solvent molecule by a free chloride ion is found to be quite slow in organic solvents, as well as in water. It is also shown that the intermediate solvato-species can be exploited for binding just one molecule of another substrate in the axial position.     

Formation of anionic σ-aryl complexes of platinum (IV) in the reaction of H2PtCl6 with aromatic compounds. The crystal and molecular structures of platinum (IV) complexes of naphthalene and ortho-nitrotoluene

The crystal and molecular structures of anionic platinum(IV) complexes of naphthalene (I) and ortho-nitrotoluene (II) have been determined by X-ray diffraction. The structures of both complexes are similar. The platinum atom is octahedrally coordinated with four chlorine atoms occupying the equatorial positions and σ-bonded aryl and neutral ammonia ligands situated in the axial positions.     

Light-activated destruction of cancer cell nuclei by platinum diazide complexes

A possible way to avoid dose-limiting side effects of platinum anticancer drugs is to employ light to cause photochemical changes in nontoxic platinum prodrugs that release active antitumor agents. This strategy could be used in the treatment of localized cancers accessible to irradiation (e.g., bladder, lung, esophagus, and skin). We report here that nontoxic photolabile diam(m)ino platinum(IV) diazido complexes inhibit the growth of human bladder cancer cells upon irradiation with light, and are non-crossresistant to cisplatin. Their rate of photolysis closely parallels that of DNA platination, indicating that the photolysis products interact directly, and rapidly, with DNA. Photoactivation results in a dramatic shrinking of the cancer cells, loss of adhesion, packing of nuclear material, and eventual disintegration of their nuclei, indicating a different mechanism of action from cisplatin.     

Insights into the acid-base properties of Pt(IV)-diazidodiam(m)inedihyroxido complexes from multinuclear NMR spectroscopy

Platinum(IV) am(m)ine complexes are of interest as potential anticancer pro-drugs, but there are few reports of their acid-base properties. We have studied the acid-base properties of three photoactivatable anticancer platinum(IV)-diazidodiam(m)ine complexes (cis,trans,cis-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)], trans,trans,trans-[Pt(IV)(N(3))(2)(OH)(2)(NH(3))(2)], and cis,trans-[Pt(IV)(N(3))(2)(OH)(2)(en)]) using multinuclear NMR methods and potentiometry. In particular, the combination of both direct and indirect techniques for the detection of (15)N signals has allowed changes of the chemical shifts to be followed over the pH range 1-11; complementary (14)N NMR studies have been also carried out. A distinct pK(a) value of approximately 3.4 was determined for all the investigated complexes, involving protonation/deprotonation reactions of one of the axial hydroxido groups, whereas a second pH-dependent change for the three complexes at approximately pH 7.5 appears not to be associated with a loss of an am(m)ine or hydroxido proton from the complex. Our findings are discussed in comparison with the limited data available in the literature on related complexes.     

Synthesis and Analysis of the Structure,Diffusion and Cytotoxicity of Heterocyclic Platinum(IV) Complexes

We have developed six dihydroxidoplatinum(IV) compounds with cytotoxic potential. Each derived from active platinum(II) species, these complexes consist of a heterocyclic ligand (H_L) and ancillary ligand (A_L) in the form [Pt(H_L)(A_L)(OH)₂]²⁺, where H_L is a methyl‐functionalised variant of 1,10‐phenanthroline and A_L is the S,S or R,R isomer of 1,2‐diaminocyclohexane. NMR characterisation and X‐ray diffraction studies clearly confirmed the coordination geometry of the octahedral platinum(IV) complexes. The self‐stacking of these complexes was determined using pulsed gradient stimulated echo nuclear magnetic resonance. The self‐association behaviour of square planar platinum(II) complexes is largely dependent on concentration, whereas platinum(IV) complexes do not aggregate under the same conditions, possibly due to the presence of axial ligands. The cytotoxicity of the most active complex, exhibited in several cell lines, has been retained in the platinum(IV) form.     

Studies on the Oral Anticancer Drug JM-216: Synthesis and Characterization of Isomers and Related Complexes

The complex cis,trans,cis-[PtCl(2)(OAc)(2)NH(3)(c-C(6)H(11)NH(2))] (JM-216) is currently undergoing clinical evaluation as an antitumor agent. In support of characterization and analysis of this complex a study of its isomers and other complexes [PtCl(m)()(OAc)((4)(-)(m)()())NH(3)(c-C(6)H(11)NH(2))] (m = 0-4) has been undertaken. The complexes have been obtained by a variety of synthetic routes which now extend the scope for the preparation of platinum(IV) antitumor complexes. As platinum(IV) complexes are very stable to substitution in the absence of catalysis, use has been made of both light and base catalysis to promote substitution. Oxidative addition to platinum(II) using hypervalent iodine reagents has also been used. The stereochemistry of the complexes has been confirmed by spectroscopic studies, primarily NMR including natural abundance (15)N NMR spectroscopy.     

Comparison of the photophysical properties of a planar, PtOEP, and a nonplanar, PtOETPP, porphyrin in solution and doped films

The absorption and emission spectroscopic properties of planar (2,3,7,8,12,13,17,18-octaethylporphyrinato)platinum(II) (PtOEP) and nonplanar (2,3,7,8,12,13,17,18-octaethyl-5,10,15,20-tetraphenylporphyrinato)platinum(II) (PtOETPP) complexes have been studied at room temperature. Liquid solutions and doped films, in polystyrene (PS) and epoxy (EPO) polymers, have been investigated. In dilute liquid solution, the photophysical properties of the nonplanar complex are substantially perturbed compared to the planar analogue. Strong ligating solvents further affect the photophysical behavior of both Pt(II) complexes via axial ligation to the central metal ion. At high concentrations, ground state aggregation and excimer formation is observed for PtOEP films in PS and EPO hosts. Incorporation of the nonplanar PtOETPP complex in PS results in enhanced coplanarity of the meso-phenyl groups, leading to a more extended conjugation between the meso-substituents and the π-conjugated system of the macrocycle. A more planar conformer for the nonplanar PtOETPP is present in the EPO host.     

Synthesis and biological evaluation of new mono naphthalimide platinum(IV) derivatives as antitumor agents with dual DNA damage mechanism

Naphthalimide has emerged as an interesting DNA intercalator and possessed attracting antitumor properties. In this context, naphthalimide group was linked to platinum(IV) core to construct a series of new mono naphthalimide platinum(IV) derivatives. The title compounds exert effective antitumor activities to the tested tumor cells lines in vitro, especially the one with propionyl chain displays comparable or even better bioactivities than platinum(II) reference drugs cisplatin and oxaliplatin. Moreover, the mono naphthalimide platinum(IV) derivative displays comparable tumor growth inhibitory competence against CT26 xenograft tumors in BALB/c mice in vivo without severe toxic effects in contrast to oxaliplatin. A dual DNA damage mechanism was proven for the title complex. Both naphthalimide ligand and the liberated platinum(II) moiety could generate DNA lesions to tumor cells synergistically and active the apoptotic pathway by up-regulating the expression of caspase 9 and caspase 3. Meanwhile, the conversion of platinum(II) drug into tetravalent form by incorporating naphthalimide moiety increases the uptake of platinum in whole cells and DNA remarkably. All these facts might be the factors for the title platinum(IV) complexes to overcome platinum(II) drug resistance. Additionally, the mono naphthalimide platinum(IV) complex could interact with human serum albumin by hydrogen bond and van der Waals force which would further influence their storage, transport and bioactivities.     

A template-directed synthetic approach to halogen-bridged mixed-valence platinum complexes on artificial peptides in solution

A template-directed synthetic approach to halogen-bridged mixed-valence platinum complexes has been performed in organic media using, for instance, a synthetic peptide bearing two bis(ethylenediamine)-based Pt(IV) complexes with two axial bromide anionic ligands, [(Pt(IV)Br2(en))2](RSO3)4, and a [Pt(II)(en)2](RSO3)2 complex (R = (C12H25OCH2)2CHO(CH2)3-).