Pt-based Anticancer Drugs Research Articles

Joint forces of mass spectrometric techniques (ICP-MS and MALDI-TOF-MS) and fluorescence spectrometry in the study of platinum-based cytostatic drugs interactions with metallothionein MT2 and MT3

Herby, the interaction of metallothioneins with commonly used Pt-based anticancer drugs – cisplatin, carboplatin, and oxaliplatin - was investigated using the combined power of elemental (i.e. LA-ICP-MS, CE-ICP-MS) and molecular (i.e. MALDI-TOF-MS) analytical techniques providing not only required information about the interaction, but also the benefit of low sample consumption. The amount of Cd and Pt incorporated within the protein was determined for protein monomers and dimer/oligomers formed by non-oxidative dimerization. Moreover, fluorescence spectrometry using Zn2+-selective fluorescent indicator – FluoZin3 - was employed to monitor the ability of Pt drugs to release natively occurring Zn from the protein molecule. The investigation was carried out using two protein isoforms (i.e. MT2, MT3), and significant differences in behaviour of these two isoforms were observed.The main attention was paid to elucidating whether the protein dimerization/oligomerization may be the reason for the potential failure of the anticancer therapy based on these drugs. Based on the results, it was demonstrated that the interaction of MT2 (both monomers and dimers) interacted with Pt drugs significantly less compared to MT3 (both monomers and dimers). Also, a significant difference between monomeric and dimeric forms (both MT2 and MT3) was not observed. This may suggest that dimer formation is not the key factor leading to the inactivation of Pt drugs.

Nuclear-Targeting Lipid PtIV Prodrug Amphiphile Cooperates with siRNA for Enhanced Cancer Immunochemotherapy by Amplifying Pt-DNA Adducts and Reducing Phosphatidylserine Exposure.

Patients treated with Pt-based anticancer drugs (PtII) often experience severe side effects and are susceptible to cancer recurrence due to the limited bioavailability of PtII and tumor-induced immunosuppression. The exposure of phosphatidylserine on the cell's outer surface induced by PtII results in profound immunosuppression through the binding of phosphatidylserine to its receptors on immune cells. Here, we report a novel approach for enhanced cancer chemoimmunotherapy, where a novel nuclear-targeting lipid PtIV prodrug amphiphile was used to deliver a small interfering RNA (siXkr8) to simultaneously amplify Pt-DNA adducts and reduce the level of exposure of phosphatidylserine. This drug delivery vehicle is engineered by integrating the PtIV prodrug with self-assembly performance and siXkr8 into a lipid nanoparticle, which shows tumor accumulation, cancer cell nucleus targeting, and activatable in a reduced microenvironment. It is demonstrated that nuclear-targeting lipid PtIV prodrug increases the DNA cross-linking, resulting in increased Pt-DNA adduct formation. The synergistic effects of the PtIV prodrug and siXkr8 contribute to the improvement of the tumor immune microenvironment. Consequently, the increased Pt-DNA adducts and immunogenicity effectively inhibit primary tumor growth and prevent tumor recurrence. These results underscore the potential of utilizing the nuclear-targeting lipid PtIV prodrug amphiphile to enhance Pt-DNA adduct formation and employing siXkr8 to alleviate immunosuppression during chemotherapy.

Platinum-based Cancer Chemotherapeutics: Recent Trends and Future Perspectives

Abstract: Platinum-based drugs have been proved as one of the prevalent successes in the field of inorganic medicinal chemistry. So far, three generations of platinum-based drugs are in the market and are recognized to play critical roles in the treatment of various types of tumors. The most commonly used anticancer chemotherapeutics worldwide are particularly cisplatin, oxaliplatin, and carboplatin. They are known to exhibit prominent and interesting chemo-therapeutic effects. Nevertheless, Pt chemotherapy can be limited in transformative clinical implementation owing to the severe side effects triggered by off-target activity and lowered efficacy because of acquired/intrinsic resistance in some cancer types. Incidentally, monofunctional Pt complexes, those bearing one labile ligand, initially studied in the late 1980s, are again enticing renewed attention. in comparison to the bifunctional anticancer complexes, bearing two labile ligands, viz., cisplatin which creates a distortion in the DNA strands by forming inter-and intrastrand crosslinks, monofunctional Pt(II) complexes were found to exclusively bind to DNA via a solo coordination site revealed by the one leaving chloride group. However, till date, no other non-platinum metal-based anticancer drug has been able to efficaciously pass all stages of clinical trials. Hence, the hunt for novel Pt-based anticancer drug is being pursued vigorously for the reason that they still play a principal role in the chemotherapeutic profiles of almost 50% of all cancer patients. Meanwhile, the major significant goals in the search for new Pt chemotherapeutic drugs is to focus- a) on exploiting their potential, b) averting the undesirable side effects, c) in curing resistant tumors, and d) in refining the cellular pharmacokinetic regimes. This mini review highlights the numerous continuing efforts to produce the next generation of Pt anticancer drugs.

Property evaluation of two anticancer candidate platinum complexes with N-isobutyl glycine ligand against human colon cancer.

Small molecules have potential usage in cancer therapy due to their remarkable potency of disarranging the natural structure of nucleic acids. In this study, two complexes [Pt(NH3)2(IBgly)]NO3 (1) and [Pt(bipy)(IBgly)]NO3 (2) based on Pt(II), N-isobutylglycine (IBgly), 2,2'-bipyridine, and ammonia were prepared and characterized by spectroscopic methods. Pharmacokinetic ADME data, absorption, distribution, metabolism, excretion, and bioavailability radar showed two complexes can be introduced for Pt-based anti-cancer drugs. Mechanism of tumor inhibition and DNA interaction of these compounds was studied by UV-Vis, fluorescence, and CD spectroscopies. Also, thermodynamic parameters and the binding constants were calculated through absorption measurements. The fluorescence data showed that a static quenching mechanism occurred for both complexes with a binding constant and binding affinity towards DNA (Kb ≈ 3500M-1 and kq ≈ 2.1 × 1011M-1s-1). The thermodynamic parameters indicated electrostatic approaching and groove binding were more feasible than intercalation mode between Pt(II) complexes and DNA. CD spectra indicated the increasing intensity of the positive band and the negative band decreasing. Density functional theory calculations confirmed the experimental data and determined the quantum chemical descriptors including total energy, hardness, chemical potential, electrophilicity, electronegativity, etc. According to this, the binding tendency of these compounds with DNA could be predicted. Further, molecular docking studies were also performed. Docking studies revealed that the desolvation, hydrogen, and electrostatic binding were effective for the interaction between complexes and DNA with binding energy (- 10.44 and - 9.57kcal/mol) for complexes 1 and 2, respectively, which is mainly of partially electrostatic and groove binding type. The cytotoxic activity of Pt complexes was examined against human colon cancer cell line which indicated good activity with IC50 values of (41.66 and 47.30μM) for both complexes after 72h, respectively. Also, they demonstrated more inhibitory effects compared to carboplatin.

A multifunctional platform with metallacycle-based star polymers and gold nanorods for combinational photochemotherapy

Although platinum-based anticancer drugs have prevailed in traditional chemotherapy, the severe side effects and drug resistance hampered their clinical applications. Combinational therapies have exhibited promises in antitumor treatments. However, the integration of different anticancer modalities is often challenging because of the conflicts between maximal synergy of therapeutic effects and reduction of side effects. Here, we report a multifunctional platform composed of metallacycle-based star polymer and gold nanorods for synergistic photochemotherapy. We applied the Pt-based metallacycle-cored star polymers as both a photodynamic photosensitizer and a Pt-based anticancer drug. The gold nanorods play the dual role of photothermal converter and energy acceptor of fluorescence resonance energy transfer effect from the star polymers. The photothermal effect enhanced tumor permeability of reactive oxygen species and Pt-based drug molecules and the photodynamic effect destructed heat shock proteins to prevent the mechanism of cellular self-protection response to heat. This mutually beneficial strategy results in high therapeutic efficacy and negligible side effects verified by both in vitro and in vivo studies. This study offers a new avenue in designing a multifunctional platform for the synergy of different antitumor modalities.

Platinum-based drugs for cancer therapy and anti-tumor strategies.

Platinum-based drugs cisplatin, carboplatin, and oxaliplatin are widely used for chemotherapeutic eradication of cancer. However, the side effects of platinum drugs, such as lack of selectivity, high systemic toxicity, and drug resistance, seriously limit their clinical application. With advancements in nanotechnology and chemical synthesis, Pt-based anti-cancer drugs have made great progress in cancer therapy in recent years. Many strategies relied on the anti-cancer mechanism similar to cisplatin and achieved some success by modifying existing platinum drugs. Pt-based nanodrugs, such as platinum nanoclusters, have novel anti-cancer mechanisms and great potential in tumor-targeted therapy and have shown promising results in clinical application. In this review, we systematically explored the development of first-line platinum chemotherapy drugs in the clinic and their anti-cancer mechanisms. We also summarize the progress of Pt-based anti-cancer drug application in cancer therapy, emphasizing their modification to enhance the anti-tumor effect. Finally, we address challenges faced by platinum chemotherapy drugs, especially Pt nanocluster-based nanodrugs, in cancer treatment. The new platinum drugs and their targeted modifications undoubtedly provide a promising prospect for improving the current anti-cancer treatments.

The endocytic pathway of Pt nanoclusters and their induced apoptosis of A549 and A549/Cis cells through c-Myc/p53 and Bcl-2/caspase-3 signaling pathways

In recent years, multifunctional platinum nanoclusters (Pt-NCs) as new Pt-based anti-cancer drugs exhibit a promising therapeutic efficiency for several cancer diseases, especially for human pulmonary carcinoma. However, the endocytosis behaviors (like uptake pathway, etc.) and induced apoptosis mechanism of Pt-NCs for drug-resistant non-small cell lung cancer (NSCLC), are still inconclusive. In this research, we explored the endocytic pathway of Pt-NCs in both typical NSCLC A549 cells and cisplatin-resistant A549/Cis cells through qualitative confocal laser scanning microscope (CLSM) measurement and quantitative flow cytometry (FCM) and inductive coupled plasma-optical emission spectroscopy (ICP-OES) analysis, by the means of introducing the specific inhibitors which impede the classical ways of endocytosis. It was found that Pt-NCs dominatingly entered A549 cells via caveolin-mediated endocytosis as well as A549/Cis cells through micropinocytosis approach. Pt-NCs possessed an excellent inhibitory effect on the cell proliferation, migration and invasion, which the cell activity of A549 cells reduced to 14% and that of A549/Cis cells went down about four fifths. Moreover, Pt-NCs treatment increased caspase-3 protein levels and downregulated the expression of c-Myc and Bcl-2, proving the Pt-NCs-induced apoptosis of NSCLC cells was related to c-Myc/p53 and Bcl-2/caspase-3 signal pathways. These results demonstrate the explicit uptake pathway and apoptotic signaling pathway of Pt-NCs for NSCLC, which provides an in-depth and reasonable theoretical basis for the development of new Pt-NCs-based chemotherapeutics in future clinical practice.

Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment.

Colorectal cancer (CRC) is one of the intimidating causes of death around the world. CRC originated from mutations of tumor suppressor genes, proto-oncogenes and DNA repair genes. Though platinum (Pt)-based anticancer drugs have been widely used in the treatment of cancer, their toxicity and CRC cells’ resistance to Pt drugs has piqued interest in the search for alternative metal-based drugs. Ruthenium (Ru)-based compounds displayed promising anticancer activity due to their unique chemical properties. Ru-complexes are reported to exert their anticancer activities in CRC cells by regulating different cell signaling pathways that are either directly or indirectly associated with cell growth, division, proliferation, and migration. Additionally, some Ru-based drug candidates showed higher potency compared to commercially available Pt-based anticancer drugs in CRC cell line models. Meanwhile Ru nanoparticles coupled with photosensitizers or anticancer agents have also shown theranostic potential towards CRC. Ru-nanoformulations improve drug efficacy, targeted drug delivery, immune activation, and biocompatibility, and therefore may be capable of overcoming some of the existing chemotherapeutic limitations. Among the potential Ru-based compounds, only Ru (III)-based drug NKP-1339 has undergone phase-Ib clinical trials in CRC treatment.

Synthesis, structures and anticancer potentials of five platinum(II) complexes with benzothiazole-benzopyran targeting mitochondria

Mitochondria were potential therapeutic targets for Pt-based anticancer drugs. Thus, five mitochondrion-targeted novel Pt(II) complexes, [Pt(FB1)Cl2] (FB1-Pt), [Pt(OHB)Cl2] (OHB-Pt), [Pt(FB2)Cl2] (FB2-Pt), [Pt(MB)Cl2]⋅CH3OH (MB-Pt) and [Pt(ClB)Cl2] (ClB-Pt) containing 3-(benzo[d]thiazol-2-yl)-8-fluoro-2H-chromen-2-imine (FB1), 3-(benzo[d]thiazol-2-yl)-2-imino-2H-chromen-8-ol (OHB), 3-(benzo[d]thiazol-2-yl)-7-fluoro-2H-chromen-2-imine (FB2), 3-(benzo[d]thiazol-2-yl)-N,N-diethyl-2-imino-2H-chromen-7-amine (MB) and 3-(benzo[d]thiazol-2-yl)-6-chloro-2H-chromen-2-imine (ClB), has been synthesized and characterized by single-crystal X-ray diffraction and elemental analysis. All of them benzothiazole-benzopyran Pt(II) derivatives were more cytotoxic to the cisplatin-resistant A549/DDP cells, with complex FB1-Pt displaying 525.5-fold higher activity than cisplatin, which should be certainly correlated with the key roles of different substituted groups in the benzothiazole-benzopyran derivatives. Strikingly, complex FB1-Pt, featuring 8-fluoro-benzothiazole-benzopyran, was the most efficacious, with nanomole IC50 concentrations. Interestingly, the benzothiazole-benzopyran Pt(II) derivatives displayed low toxicity against normal HL-7702 cells. Cellular distribution studies suggested that FB1-Pt accumulate more preferentially in mitochondria than in nuclei fraction. As a result, FB1-Pt causes a remarkable decrease in the membrane of mitochondria in the A549/DDP cancer cells, leading to more radical mitochondrial dysfunctions than that of OHB-Pt. The results indicated that mitochondrion-targeted benzothiazole-benzopyran Pt(II) derivatives may have potential to overcome the drug resistance of traditional cisplatin-based antitumor drugs.

DNA Structural Distortions Induced by a Monofunctional Trinuclear Platinum Complex with Various Cross-Links Using Molecular Dynamics Simulation.

The monofunctional trinuclear platinum complex (MTPC), as a promising antitumor agent, can form MTPC-DNA adducts via bifunctional and trifunctional cross-links. Molecular dynamics simulations were used to investigate DNA structural distortions of the MTPC-DNA adducts. MTPC coordinating to DNA results in the decrease of base-pair thermal stability and DNA structural distortions. It is found that there are more significant DNA structural distortions in the trifunctional cross-link than in the bifunctional cross-link, in the 1,4-GG than in the 1,3-GG cross-link, and in the intrastrand than in the interstrand cross-link with the same spans. The results provide a better understanding of DNA structural distortions induced by MTPC with various cross-links at the nucleotide level and are helpful for exploring novel Pt-based anticancer drugs.

A novel molecularly imprinted polymer decorated by CQDs@HBNNS nanocomposite and UiO-66-NH2 for ultra-selective electrochemical sensing of Oxaliplatin in biological samples

A platform equipped with a well-designed synthetic interface, as a universal sensor, is required to detect highly selective and sensitive anticancer drugs in complex matrices of different biological samples. In this study, we developed a novel electrochemical sensor based on the combination of molecularly imprinted method with the 3D-framework UiO-66-NH2 as excellent target molecule recognizer on the surface of a glassy carbon electrode modified with carbon quantum dots incorporated hexagonal boron nitride nanosheets (CQDs@HBNNS/UiO-66-NH2 /MIP/GCE) for ultraselective detection of trace levels of Oxaliplatin (OXA) as an anticancer drug. The increased efficiency and sensitivity of the proposed MIP sensor was obtained due to the use of UiO-66-NH2 with high porosity structure which effectively increased the number of binding sites and specific surface area as well as CQDs@HBNNS nanocomposite (CQDs@HBNNS-NCs) with ideal electric conductivity and synergistic effects to facilitate the electron transfer process. During MIP preparation, optimal conditions were achieved by using experimental design, based on a standard orthogonal array, and different electrodes were characterized by scanning electron microscopy and cyclic voltammetry. Electrochemical responses of imprinted sensor displayed two dynamic linear ranges from 1.0 to 20.0 nM and 20.0 to 250.0 nM with a detection limit of 0.37 nM. In addition, superior anti-interfering ability of the designed MIP sensor toward OXA detection in the presence of interferents at high concentration especially other Pt-based anticancer drugs as well as reproducibility and stability of it proved that the CQDs@HBNNS/UiO-66-NH2 /MIP/GCE could be extensively applied in the clinical therapeutic drug monitoring.

Mitochondrial dysfunction, autophagy stimulation and non-apoptotic cell death caused by nitric oxide-inducing Pt-coated Au nanoparticle in human lung carcinoma cells

BackgroundReactive oxygen species (ROS)-mediated cancer therapeutic has been at higher appreciation than those mediated by reactive nitrogen species. Cytotoxic mechanism of a novel nitric oxide (NO) inducing-Pt coated Au nanoparticle (NP) has been comparatively studied with the well-established ROS inducing Pt-based anticancer drug cisplatin in human lung A549 carcinoma cells. MethodsCytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, thiobarbituric acid substances (TBARS) and C11-Boron dipyrromethene (BODIPY). ROS (O2·− and H2O2) was measured with dihydroethidium (DHE) and H2O2-specific sensor. Nitric oxide (NO) and mitochondrial dysfunction were evaluated respectively by NO-specific probe DAR-1 and JC-1. Autophagy was determined by lysotracker (LTR) and monodansylcadaverine (MDC) applied tandemly whereas apoptosis/necrosis by Hoechst/PI and caspase 3 activity. ResultsIC50 (concentration that inhibited cell viability by 50%) of Pt coated Au NP came to be 0.413 μM whereas IC50 of cisplatin came out to 86.5 μM in A549 cells treated for 24 h meaning NPs toxicity was over 200 times higher than cisplatin. However, no significant stimulation of intracellular ROS was observed at the IC50 of Pt coated Au NPs in A549 cells. However, markers like LDH release, TBARS, BODIPY and ROS were significantly higher due to cisplatin in comparison to Pt coated Au NP. ConclusionsPt coated Au NP caused NO-dependent mitochondrial dysfunction and autophagy. Mode of cell death due to NP was much different from ROS-inducing cisplatin. General significancePt coated Au NP offer promising opportunity in cancer therapeutic and warrants advanced study in vivo models of cancer.

Effects of platinum-based anticancer drugs on the trace element profile of liver and kidney tissue from mice

BackgroundPlatinum-based anticancer drugs are relatively successful chemotherapeutic agents, which can cause significant elemental changes in key organs and are known for undesirable side effects, such as nephrotoxicity (damage to the kidneys). Objectives and methodsInductively coupled plasma mass spectrometry (ICP-MS) and traditional statistical tools such as two-sample Student’s t-test and Pearson’s correlation analysis are used to evaluate the effects of different investigational Pt-based anticancer drugs on the elemental constitution of kidneys and liver of mice. Principal component analysis is used to uncover relationships in element concentration and potential correlations between those and clinical effects. Random forest importance is used to identify elements most associated with the drug’s maximum tolerated doses (MTDs). ResultsStrong negative correlations between Pt and both Cu (−0.814) and Zn (−0.784) in kidneys were observed for one of the Pt-acridine anticancer agents evaluated (Drug C). Strong positive correlations were observed between Cu in both kidneys (0.834) and liver (0.756) with Zn in liver for the same compound. Cisplatin administration correlates to higher concentrations of Ca, Cu, Rb and Zn in liver. Calcium and Mo in kidneys and Pt and Zn in liver are the features most associated with MTDs. ConclusionsThe results indicate that the Pt-based agents investigated are major modulators of ion homeostasis in excretory organs, which most likely contributes to their systemic toxicity and limits their efficacy. A better understanding of subtle patterns and correlations among elements in key organs may provide deeper insights into the mechanisms of action and ultimately contribute for better, safer drugs. To achieve this goal, researchers involved in cancer drug development may leverage the high sensitivity and high sample throughput of ICP-MS, and the capabilities of modern statistical tools to extract relevant information from a large dataset.

Influence of DFT Functionals and Solvation Models on the Prediction of Far-Infrared Spectra of Pt-Based Anticancer Drugs: Why Do Different Complexes Require Different Levels of Theory?

Computational modeling was applied to far-infrared (FIR) spectra of Pt-based anticancer drugs to study the hydrolysis of these important molecules. Here, we present a study that investigates the influence of different factors—basis sets on non-Pt atoms, relativistic effective core potentials (RECPs) on the Pt atom, density functional theory (DFT) functionals, and solvation models—on the prediction of FIR spectra of two Pt-based anticancer drugs, cisplatin and carboplatin. Geometry optimizations and frequency calculations were performed with a range of functionals (PBE, PBE0, M06-L, and M06-2X), Dunning’s correlation-consisted basis sets (VDZ, VTZ, aVDZ, and aVTZ), RECPs (VDZ-pp, VTZ-pp, aVDZ-pp, and aVTZ-pp), and solvation models (IEFPCM, CPCM, and SMD). The best combination of the basis set/DFT functional/solvation model was identified for each anticancer drug by comparing with experimentally available FIR spectra. Different combinations were established for cisplatin and carboplatin, which was rationalized by means of the partial atomic charge scheme, ChelpG, that was utilized to study the charge transfer between the Pt ion and ligands in both cisplatin and carboplatin.

Two telomerase-targeting Pt(ii) complexes of jatrorrhizine and berberine derivatives induce apoptosis in human bladder tumor cells.

Two novel Pt(ii) complexes, [Pt(B-TFA)Cl]Cl (Pt1) and [Pt(J-TFA)Cl]Cl (Pt2) with jatrorrhizine and berberine derivatives (B-TFA and J-TFA) were first prepared as desirable luminescent agents for cellular applications and potent telomerase inhibitors, which can induce bladder T-24 tumor cell apoptosis by targeting telomerase, together with induction of mitochondrial dysfunction, telomere DNA damage and cell-cycle arrest. Importantly, T-24 tumor inhibition rate (TIR) was 50.4% for Pt2, which was higher than that of Pt1 (26.4%) and cisplatin (37.1%). Taken together, all the results indicated that jatrorrhizine and berberine derivatives Pt1 and Pt2 show low toxicity and could be novel Pt-based anti-cancer drug candidates.

Chlorido and bromido oxaliplatin analogues as potential agents for CRC treatment: Solution behavior, protein binding and cytotoxicity evaluation

Despite the widespread use of platinum drugs in the treatment of colorectal cancer (CRC), due to the heavy side effects and to intrinsic or acquired Pt resistance, new and more efficient drugs are urgently needed. Starting from the encouraging results obtained for the complex PtI2(DACH), we summarise here our recent advances, reporting data on the synthesis and the chemical and biological features of two oxaliplatin analogues i.e. PtBr2(DACH) and PtCl2(DACH). The comparative approach of these studies reveals how these analogues possess interesting and differential pharmacological properties as well as some peculiar features that may be conveniently exploited to shed light in the mechanistic aspects involved in the pharmacological action of the parent drug oxaliplatin. Furthermore, these findings may inspire the design of more effective Pt-based anticancer drugs to be used in CRC treatment.

Cisplatin, Oxaliplatin, and Kiteplatin Subcellular Effects Compared in a Plant Model.

The immediate visual comparison of platinum chemotherapeutics’ effects in eukaryotic cells using accessible plant models of transgenic Arabidopsis thaliana is reported. The leading anticancer drug cisplatin, a third generation drug used for colon cancer, oxaliplatin and kiteplatin, promising Pt-based anticancer drugs effective against resistant lines, were administered to transgenic A. thaliana plants monitoring their effects on cells from different tissues. The transgenic plants’ cell cytoskeletons were labelled by the green fluorescent protein (GFP)-tagged microtubule-protein TUA6 (TUA6-GFP), while the vacuolar organization was evidenced by two soluble chimerical GFPs (GFPChi and AleuGFP) and one transmembrane GFP-tagged tonoplast intrinsic protein 1-1 (TIP1.1-GFP). The three drugs showed easily recognizable effects on plant subcellular organization, thereby providing evidence for a differentiated drug targeting. Genetically modified A. thaliana are confirmed as a possible rapid and low-cost screening tool for better understanding the mechanism of action of human anticancer drugs.

Retraction Note to: Urinary parameters predictive and electrolyte disturbances of cisplatin-induced acute renal associated with cancer as a critical target of the chemotherapeutic agent in patients with solid tumors.

Cisplatin (CP) is a remarkably effective Pt-based anticancer drug, but it also exhibits severe toxic side effects, including nephrotoxicity and ototoxicity, and CP nephrotoxicity is a major constraint for the treatment of solid tumors. This study was designed to evaluate the electrolyte and biochemical changes in dogs with acute kidney injury (acute renal failure) following administration of CP as a chemotherapeutic agent to exhibit broad efficacy in solid tumors. A total of 10 adult male dogs were selected (treated dogs = 7 and control dogs = 3). Cisplatin-treated animals were received 0.75 mg/kg via intravenous for 5 consecutive days. Urine and blood samples on days 0 (pre-dosing), 1, 2, 3, 4, 7, 10, 14, and 28 (post-dosing) were collected. For tracking the signs of toxicity with cisplatin, clinical examination was performed for 2 times a day. Serum samples were assayed urea, creatinine, sodium, chloride, potassium, calcium, phosphorus, and urine samples were used to measure creatinine. Serum creatinine levels indicating renal function (glomerular filtration rate) was 0.66 and 0.94 mg/dL in day 0, respectively, in treatment and control animals. After day 2, a significant change in creatinine was observed in treatment animals. On the end day of the study control and treatments, creatinine was measured with mean of 1.35 and 1.00 mg/dL, respectively. Electrolyte disturbances were observed after several days of cisplatin administration including changes in levels of sodium, potassium, phosphorus, calcium, and chloride. Clinical observations also identified CP toxicity. This study for the first time showed that compensation electrolyte abnormalities in dogs following administration of cisplatin is essential to prevent deaths by daily monitoring and measurement of electrolytes in patients. This may be advantageous if repetitive cycles of chemotherapy or subsequent administration of high dose chemotherapy were planned.

Targeted Drug Delivery System for Platinum-based Anticancer Drugs.

Platinum-based (Pt-based) anticancer drugs have been recognised as one of the most effective drugs for clinical treatment of malignant tumors due to its unique mechanism of action and broad range of anticancer spectrum. But, there are still some limitations such as side effects, drug resistance/cross resistance, no-specific targeting, becoming obstacles to restrict its expanding of clinical application. Targeted drug delivery system (TDDS) is a promising strategy for the research of novel Pt-based anticancer drugs. A variety of TDDS have been explored to improve the antitumor activity of Pt-based drugs such as nanoparticle drug systems, polymer-drug systems, drugs-macrocyclic compounds systems, etc. The review concentrates on recent development of various targeted drug delivery techniques, which could provide more opportunities for the development of Pt-based drugs with better efficiency, lower toxicity and less resistance.

Optimized sample preparation strategy for the analysis of low molecular mass adducts of a fluorescent cisplatin analogue in cancer cell lines by CE-dual-LIF.

Pt-based anticancer drugs, such as cisplatin, are known to undergo several (bio-)chemical transformation steps after administration. Hydrolysis and adduct formation with small nucleophiles and larger proteins are their most relevant reactions on the way to the final reaction site (DNA), but there are still many open questions regarding the identity and pharmacological relevance of various proposed adducts and intermediates. Furthermore, the role of buffer components or additives, which are inevitably added to samples during any type of analytical measurement, has been frequently neglected in previous studies. Here, we report on adduct formation reactions of the fluorescent cisplatin analogue carboxyfluorescein diacetate platinum (CFDA-Pt) in commonly used buffers and cell culture medium. Our results indicate that chelation reactions with noninnocent buffers (e.g., Tris) and components of the cell culture/cell lysis medium must be taken into account when interpreting results. Adduct formation kinetics was followed up to 60h at nanomolar concentrations of CFDA-Pt by using CE-LIF. CE-MS enabled the online identification of such unexpected adducts down to the nanomolar concentration range. By using an optimized sample preparation strategy, unwanted adducts can be avoided and several fluorescent adducts of CFDA-Pt are detectable in sensitive and cisplatin-resistant cancer cell lines. By processing samples rapidly after incubation, we could even identify the initial, but transient, Pt species in the cells as deacetylated CFDA-Pt with unaltered complexing environment at Pt. Overall, the proposed procedure enables a very sensitive and accurate analysis of low molecular mass Pt species in cancer cells, involving a fast CE-LIF detection within 5min.