Antitumor potential of platinum(II) complexes of selenium donor ligands.

Platinum(II) coordination compounds are widely applied in clinics as anticancer drugs. In this review, we provide a summary of the reports on cytotoxic properties of platinum(II) complexes of selenium donor ligands along with a brief description of their structural features. It has been observed that the platinum(II) complexes of selenones and selenoethers display reasonable antitumor properties and in some cases their cytotoxic activity is greater than cisplatin. The complexes containing NH3 ligands along with selenones were found to exhibit better cytotoxicity compared to the binary Pt-selenone complexes. The mechanistic insights showed that these complexes exert antitumor activity through reactive oxygen species (ROS) generation and induction of apoptosis. The platinum-selenoether coordination compounds can self-assemble into spherical aggregates capable of self-delivery. The self-assembled Pt-selenium aggregates induce cell apoptosis via ROS, which leads to high selectivity between cancer cells and normal cells in cytotoxicity assays.

Nanoarchitectonics: Complexes and Conjugates of Platinum Drugs with Silicon Containing Nanocarriers. An Overview.

The development in the area of novel anticancer prodrugs (conjugates and complexes) has attracted growing attention from many research groups. The dangerous side effects of currently used anticancer drugs, including cisplatin and other platinum based drugs, as well their systemic toxicity is a driving force for intensive search and presents a safer way in delivery platform of active molecules. Silicon based nanocarriers play an important role in achieving the goal of synthesis of the more effective prodrugs. It is worth to underline that silicon based platform including silica and silsesquioxane nanocarriers offers higher stability, biocompatibility of such the materials and pro-longed release of active platinum drugs. Silicon nanomaterials themselves are well-known for improving drug delivery, being themselves non-toxic, and versatile, and tailored surface chemistry. This review summarizes the current state-of-the-art within constructs of silicon-containing nano-carriers conjugated and complexed with platinum based drugs. Contrary to a number of other reviews, it stresses the role of nano-chemistry as a primary tool in the development of novel prodrugs.

Pt(IV) Prodrugs with NSAIDs as Axial Ligands.

A chemo-anti-inflammatory strategy is of interest for the treatment of aggressive cancers. The platinum (IV) prodrug with non-steroidal anti-inflammatory drugs (NSAIDs) as axial ligands is designed to efficiently enter tumor cells due to high lipophilicity and release the cytotoxic metabolite and NSAID intracellularly, thereby reducing side effects and increasing the therapeutic efficacy of platinum chemotherapy. Over the last 7 years, a number of publications have been devoted to the design of such Pt(IV) prodrugs in combination with anti-inflammatory chemotherapy, with high therapeutic efficacy in vitro and In vivo. In this review, we summarize the studies devoted to the development of Pt(IV) prodrugs with NSAIDs as axial ligands, the study of the mechanism of their cytotoxic action and anti-inflammatory activity, the structure-activity ratio, and therapeutic efficacy.

Delivery of Platinum(IV) Prodrugs via Bi2Te3 Nanoparticles for Photothermal-Chemotherapy and Photothermal/Photoacoustic Imaging.

Combinational administration of photothermal therapy (PTT) and chemotherapy (CT) shows great potential in improving the efficiency of tumor treatment. Herein, we designed a novel nanocomposite Pt@Bi2Te3 composed of bismuth telluride (Bi2Te3) nanoparticles and platinum(IV) prodrugs (Pt) for PTT-CT combination therapy. The obtained Bi2Te3 was synthesized by a simple solvothermal method and modified by polyethylene glycol, which exhibited excellent photothermal (PT) efficiency and stability and could also serve as a bimodal bioimaging contrast agent in PT and photoacoustic (PA) imaging. In vitro experiment results showed that the nanocomposite Pt@Bi2Te3 could effectively increase the uptake of platinum in cancer cells, which could kill tumor cells through the combined effect of PTT and CT. Furthermore, combination therapy of cancer in vivo was achieved with obvious tumor-growth inhibition without inducing observed side effects. We revealed the great potential of Bi2Te3 nanocomposites in increasing therapeutic efficiency by PTT-CT therapy and PA-PT imaging.

Platinum(II) Drug-Loaded Gold Nanoshells for Chemo-Photothermal Therapy in Colorectal Cancer.

In the present study, we utilize a poly[2-(N,N-dimethylamino)ethyl methacrylate]-poly(ε-caprolactone) (PDMA-PCL) micellar template-based gold nanoshell as a nanocarrier of a platinum-based chemotherapeutic drug, dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt). The gold nanoshells not only function as a drug delivery platform but also provide a remarkable photothermal effect, resulting in synergistically combined chemo-photothermal therapy. With the positively charged outstretched hydrophilic PDMA segments, chloroauric anions are attracted to the PDMA-PCL micellar surface and reduced to gold atoms in situ, forming small seeds that nucleate the subsequent growth of gold nanoshells. The DACHPt-loaded gold nanoshells possess strong absorption in the near-infrared (NIR) region and outstanding photothermal conversion effect; thus, they can promote a temperature increase that is sufficient to ablate tumor cells under NIR laser irradiation at a moderate power density (1 W/cm2). Furthermore, by exploiting the synergistic effects of platinum-based chemotherapy and photothermal therapy, the DACHPt-loaded gold nanoshells exhibited a profound inhibition of tumor growth compared to chemotherapy or photothermal therapy alone. Therefore, the platinum(II)-loaded gold nanoshells that we proposed herein may be a potential alternative for efficient curative therapy for colorectal cancer.

Light-Triggered Biomimetic Nanoerythrocyte for Tumor-Targeted Lung Metastatic Combination Therapy of Malignant Melanoma.

Red blood cell (RBC) membrane-cloaked nanoparticles, reserving the intact cell membrane structure and membrane protein, can gain excellent cell-specific functions such as long blood circulation and immune escape, providing a promising therapy nanoplatform for drug delivery. Herein, a novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability is constructed by embedding bovine serum albumin (BSA) encapsulated with 1,2-diaminocyclohexane-platinum (II) (DACHPt) and indocyanine green (ICG) in the targeting peptide-modified erythrocyte membrane (R-RBC@BPtI) for enhancing tumor internalization and synergetic chemophototherapy. R-RBC@BPtI displays excellent stability and high encapsulation efficiency with multiple cores enveloped in the membrane. Benefited from the stealth functionality and targeting modification of erythrocyte membranes, R-RBC@BPtI can significantly promote tumor targeting and cellular uptake. Under the near-infrared laser stimuli, R-RBC@BPtI presents remarkable instability by singlet oxygen and heat-mediated cleavage so as to trigger effective drug release, thereby achieving deep penetration and accumulation of DACHPt and ROS in the tumor site. Consequently, R-RBC@BPtI with tumor-specific targeting ability accomplishes remarkable ablation of tumors and suppressed lung metastasis in vivo by photothermal and chemotherapy combined ablation under phototriggering. This research provides a novel strategy of targeted biomimetic nanoplatforms for combined cancer chemotherapy-phototherapy.

The side effects of platinum-based chemotherapy drugs: a review for chemists.

The platinum-based drugs cisplatin, carboplatin and oxaliplatin are regularly prescribed in the treatment of cancer and while they are effective, their use is limited by their severe, dose-limiting side effects (also referred to as adverse effects/events). In total, a cancer patient can experience any combination of around 40 specific side effects. The dose-limiting side effect for cisplatin is nephrotoxicity, for carboplatin it is myelosuppression, and for oxaliplatin it is neurotoxicity. Other common side effects include anaphylaxis, cytopenias (including leukopenia and neutropenia, thrombocytopenia, and anaemia), hepatotoxicity, ototoxicity, cardiotoxicity, nausea and vomiting, diarrhea, mucositis, stomatitis, pain, alopecia, anorexia, cachexia, and asthenia. The side effects may require patients to be prescribed dose reductions in their platinum drugs of between 25 and 100%. Furthermore, patients require extensive monitoring of their biochemistries, kidney and liver function, and depending on the drug, hearing tests. Finally, patients are commonly co-prescribed additional non-chemotherapy based drugs to treat the side effects which can include antiemetics, antibiotics and myeloid growth factors, mannitol, propafenone, saline hyperhydration, magnesium supplements, monoclonal antibody cytokine blockers, and antioxidants.

Effects of cytotoxic cis- and trans-diammine monochlorido platinum(II) complexes on selenium-dependent redox enzymes and DNA.

Here we present the preparation of 14 pairs of cis- and trans-diammine monochlorido platinum(II) complexes, coordinated to heterocycles (i.e., imidazole, 2-methylimidazole and pyrazole) and linked to various acylhydrazones, which were designed as potential inhibitors of the selenium-dependent enzymes glutathione peroxidase 1 (GPx-1) and thioredoxin reductase 1 (TrxR-1). However, no inhibition of bovine GPx-1 and only weak inhibition of murine TrxR-1 was observed in in vitro assays. Nonetheless, the cis configured diammine monochlorido Pt(II) complexes exhibited cytotoxic and apoptotic properties on various human cancer cell lines, whereas the trans configured complexes generally showed weaker potency with a few exceptions. On the other hand, the trans complexes were generally more likely to lack cross-resistance to cisplatin than the cis analogues. Platinum was found bound to the nuclear DNA of cancer cells treated with representative Pt complexes, suggesting that DNA might be a possible target. Thus, detailed in vitro binding experiments with DNA were conducted. Interactions of the compounds with calf thymus DNA were investigated, including Pt binding kinetics, circular dichroism (CD) spectral changes, changes in DNA melting temperatures, unwinding of supercoiled plasmids and ethidium bromide displacement in DNA. The CD results indicate that the most active cis configured pyrazole-derived complex causes unique structural changes in the DNA compared to the other complexes as well as to those caused by cisplatin, suggesting a denaturation of the DNA structure. This may be important for the antiproliferative activity of this compound in the cancer cells.

High Antimetastatic Activity of Platin Liposomal Form after Lyophilization and Storage.

Antimetastatic activity of Platin in lyophilized liposomes stored for 7 years after fabrication was evaluated. The main flaw of liposomes as vehicles for drug delivery to the tumors is their high affinity for the liver, which accumulates a great amount thereof. This property of liposomes can be used for adjuvant therapy of operable primary tumors metastasizing to the liver. It is shown on the model of mouse GA-1 tumor metastases in the liver that platinum(II) complex compound Platin in phosphatidylcholine-cholesterol liposomes, stored for 7 years after lyophilization, causes complete cure of 40% animals, while free Platin prolongs the lifespan of mice with tumors by only 31.7% vs. control (no treatment).

Multifunctional Liposomes for Image-Guided Intratumoral Chemo-Phototherapy.

Intratumoral (IT) drug injections reduce systemic toxicity, but delivered volumes and distribution can be inconsistent. To improve IT delivery paradigms, porphyrin-phospholipid (PoP) liposomes are passively loaded with three hydrophilic cargos: sulforhodamine B, a fluorophore; gadolinium-gadopentetic acid, a magnetic resonance (MR) agent; and oxaliplatin, a colorectal cancer chemotherapeutic. Liposome composition is optimized so that cargo is retained in serum and storage, but is released in less than 1 min with exposure to near infrared light. Light-triggered release occurs with PoP-induced photooxidation of unsaturated lipids and all cargos release concurrently. In subcutaneous murine colorectal tumors, drainage of released cargo is delayed when laser treatment occurs 24 h after IT injection, at doses orders of magnitude lower than systemic ones. Delayed light-triggering results in substantial tumor shrinkage relative to controls a week following treatment, although regrowth occurs subsequently. MR imaging reveals that over this time frame, pools of liposomes within the tumor migrate to adjacent regions, possibly leading to altered spatial distribution during triggered drug release. Although further characterization of cargo loading and release is required, this proof-of-principle study suggests that multimodal theranostic IT delivery approaches hold potential to both guide injections and interpret outcomes, in particular when combined with chemo-phototherapy.

Quantification and clinical application of carboplatin in plasma ultrafiltrate.

Carboplatin is a chemotherapy drug used in a variety of cancers with the primary toxicity being exposure-dependant myelosuppression. We present the development and validation of a simple, robust inductively coupled plasma mass spectrometry (ICP-MS) method to measure carboplatin in plasma ultrafiltrate. Plasma ultrafiltrates samples were prepared using Amicon Ultra 30,000da cut-off filters and then diluted with ammonia EDTA before ICP-MS analysis. The assay was validated in the range 0.19-47.5mg/L carboplatin in ultrafiltrate. The assay was linear (r2>0.9999), accurate (<6% bias, 12% bias at LLOQ) and precise (intra- and inter-day precision of <3% coefficient of variation). No matrix effects were observed between plasma ultrafiltrate and aqueous platinum calibrators and recovery was complete. The assay was applied to 10 clinical samples from patients receiving carboplatin. Incurred sample reanalysis showed reproducible values over 3 analysis days (<6% CV). As plasma stability prior to ultrafiltration has been a major concern in previous clinical studies this was studied extensively at room temperature (22°C) over 24h. Carboplatin was found to be stable in both spiked plasma (n=3) and real patient samples (n=10) at room temperature for up to 8h before ultrafiltration. This makes routine measurement of carboplatin concentrations in clinical settings feasible.

In vitro anticancer activity evaluation of new cationic platinum(II) complexes based on imidazole moiety.

The development and the synthesis of cationic platinum(II) complexes were realized and their cytotoxic activity was tested on triple negative breast cancer MDA-MB-231 cell line and in two cell lines poorly responsive to cisplatin (DLD-1 and MCF-7). The complex 2c resulted the most potent cytotoxic agent in MDA-MB-231 (IC50=61.9µM) and more effective than cisplatin on both DLD-1 (IC50=57.4µM) and MCF-7 (IC50=79.9µM) cell lines. 2c showed different cellular uptake and pharmacodynamic properties than cisplatin, interfering with the progression of the M phase of the cell cycle. Thus, 2c represents a lead compound of a new class of cytotoxic agents with promising antitumor activity.

Chemical Imaging of Platinum-Based Drugs and their Metabolites.

Platinum-based drugs (cisplatin, carboplatin, and oxaliplatin) are widely used therapeutic agents for cancer treatment. Even though the platinum (Pt)-drugs are routinely used clinically, a clear picture of their distribution within tumor tissues is lacking. The current methods to image the distribution of Pt drugs are limited and do not enable the discrimination of the drug from its metabolites. In this manuscript, we demonstrate a methodology that enables chemical imaging of a Pt drug and its metabolites simultaneously and specifically. Matrix-Assisted Laser Desorption/Ionization (MALDI) Mass Spectrometry Imaging (MSI) is combined with an on-tissue chemical derivatization using diethyldithiocarbamate (DDTC). DDTC abstracts the Pt atom to generate ionizable complexes that can be imaged by MALDI MSI. We demonstrate that Pt drugs and their metabolites can be specifically imaged. This approach was successfully applied to map the penetration and metabolism of oxaliplatin in hyperthermic intraperitoneal chemotherapy (HIPEC)-like treated 3D colorectal tumor mimics. The distribution of cisplatin and carboplatin was mapped in additional 3D tumor mimics. We demonstrate that the approach can also be used to image the distribution of copper ions in cells. This method has the potential to be used to evaluate the penetration and distribution of a wide range of compounds.

Porous Pt Nanoparticles with High Near-Infrared Photothermal Conversion Efficiencies for Photothermal Therapy.

Plasmonic nanostructures are of potential in acting as a type of optical agents for cancer photothermal therapy. To effectively function as photothermal therapy agents, plasmonic nanostructures are strongly desired to have good biocompatibility and high photothermal conversion efficiencies. In this study, poly(diallyldimethylammonium chloride)-coated porous Pt nanoparticles are synthesized for photothermal therapy. The Pt nanoparticles possess broadband near-infrared light absorption in the range from 650 to 1200 nm, therefore allowing for selecting different laser wavelengths for photothermal therapy. The as-prepared Pt nanoparticles exhibit remarkable photothermal conversion efficiencies under 809 and 980 nm laser irradiation. In vitro studies indicate that the Pt nanoparticles display good biocompatibility and high cellular uptake efficiencies through an endocytosis pathway. Photothermal heating using 808 nm laser irradiation (>7.0 W cm-2 , 3 min) leads to notable cytotoxic effect, and more than 70% of cells are photothermally ablated after 3 min irradiation at 8.4 W cm-2 . Furthermore, simultaneous application of photothermal therapy synergistically enhances the cytotoxicity of an anti-cancer drug doxorubicin. Therefore, the porous Pt nanoparticles have great potential as an attractive photothermal agent for cancer therapy.

Design, syntheses, characterization, and cytotoxicity studies of novel heterobinuclear oxindolimine copper(II)-platinum(II) complexes.

Herein, the design and syntheses of two new mononuclear oxindolimine-copper(II) (1 and 2) and corresponding heterobinuclear oxindolimine Cu(II)Pt(II) complexes (3 and 4), are described. All the isolated complexes were characterized by spectroscopic techniques (UV/Vis, IR, EPR), in addition to elemental analysis and mass spectrometry. Cyclic voltammetry (CV) measurements showed that in all cases, one-electron quasi-reversible waves were observed, and ascribed to the formation of corresponding copper(I) complexes. Additionally, waves related to oxindolimine ligand reduction was verified, and confirmed using analogous oxindolimine-Zn(II) complexes. The Pt(IV/II) reduction, and corresponding oxidation, for complexes 3 and 4 occurred at very close values to those observed for cisplatin. By complementary fluorescence studies, it was shown that glutathione (GSH) cannot reduce any of these complexes, under the experimental conditions (room temperature, phosphate buffer 50mM, pH7.4), using an excess of 20-fold [GSH]. All these complexes showed characteristic EPR spectral profile, with parameters values gǁ>g⊥ suggesting an axially distorted environment around the copper(II) center. Interactions with calf thymus-DNA, monitored by circular dichroism (CD), indicated different effects modulated by the ligands. Finally, the cytotoxicity of each complex was tested toward different tumor cells, in comparison to cisplatin, and low values of IC50 in the range 0.6 to 4.0µM were obtained, after 24 or 48h incubation at 37°C. The obtained results indicate that such complexes can be promising alternative antitumor agents.

Platinum(iv) anticancer prodrugs - hypotheses and facts.

In this manuscript we focus on Pt(iv) anticancer prodrugs. We explore the main working hypotheses for the design of effective Pt(iv) prodrugs and note the exceptions to the common assumptions that are prevalent in the field. Special attention was devoted to the emerging class of "dual action" Pt(iv) prodrugs, where bioactive ligands are conjugated to the axial positions of platinum in order to obtain orthogonal or complementary effects that will increase the efficacy of killing the cancer cells. We discuss the rationale behind the design of the "dual action" prodrugs and the results of the pharmacological studies obtained. Simultaneous release of two bioactive moieties inside the cancer cells often triggers several processes that together determine the fate of the cell. Pt(iv) complexes provide many opportunities for applying new concepts in targeting, synergistic cell killing and exploiting novel nanodelivery systems.

Probing the biological evaluations of a new designed Pt(II) complex using spectroscopic and theoretical approaches: human hemoglobin as a target.

In recent years, using heavy metal compounds such as platinum as anticancer agent is one of the common ways in chemical therapy. In this study, a new anticancer compound of glycine derivatives of Pt(II) complex (amyl-glycine1, 10-phenanthroline Platinum nitrate) was designed, and the biological effects of this novel compound on the alterations in the function and structure of human hemoglobin (Hb) at different temperatures of 25 and 37°C were assessed by applying various spectroscopic (fluorescence and circular dichroism (CD)) and theoretical methods. Fluorescence data indicated the strong ability of Pt(II) complex to quench the intrinsic fluorescence of Hb. The binding constant, number of binding sites, and thermodynamic parameters at two temperatures were calculated, and the results indicated the major possibility of occurring van der Waals force or hydrogen bond interactions in the Pt(II) complex-Hb interaction. For evaluating the alteration of secondary structure of Hb upon interaction with various concentrations of complex, far-UV CD spectra were used and it was observed that in high dose of complex, significant changes were occurred which is indicative of some side effects in overdosing of this complex. On the other hand, the molecular docking results illustrate that are well in agreement in obtaining data with spectroscopy. Above results suggested that using Pt(II) complex as an anticancer agent, model drug in high-dose usage might cause some disordering in structure and function of Hb as well as improve understanding of the side effects of newly designed metal anticancer drugs undergoing.

Ninjin'yoeito and ginseng extract prevent oxaliplatin-induced neurodegeneration in PC12 cells.

Ninjin'yoeito (NYT) is a formula of Japanese traditional kampo medicine composed of 12 crude drugs, and is designed to improve the decline in constitution after recovery from disease, fatigue, anemia, anorexia, perspiration during sleep, cold limbs, slight fever, chills, persistent cough, malaise, mental disequilibrium, insomnia, and constipation. Oxaliplatin (L-OHP) is a platinum-based anticancer drug used to treat colorectal, pancreatic, and stomach cancers. However, it often causes acute and chronic peripheral neuropathies including cold allodynia and mechanical hyperalgesia. In this study, we investigated the preventive effects of NYT on neuronal degeneration caused by L-OHP using PC12 cells, which are derived from the rat adrenal medulla and differentiate into nerve-like cells after exposure to nerve growth factor. L-OHP treatment decreased the elongation of neurite-like projection outgrowths in differentiated PC12 cells. When PC12 cells were treated with NYT hot water extract, neurodegeneration caused by L-OHP was significantly prevented in a concentration-dependent manner. Among the 12 crude drugs composing NYT, the extract of Ginseng (the root of Panax ginseng) exhibited the strongest preventive effects on neurodegeneration in differentiated PC12 cells. By activity-guided fractionation, we found that the fraction containing ginsenosides displayed preventive activity and, among several ginsenosides, ginsenoside F2 exhibited significant preventive effects on L-OHP-induced decreases in neurite-like outgrowths in differentiated PC12 cells. These results suggest that NYT and ginseng are promising agents for preventing L-OHP-induced neuropathies and present ginsenoside F2 as one of the active ingredients in ginseng.

An Iron Oxide Nanocarrier Loaded with a Pt(IV) Prodrug and Immunostimulatory dsRNA for Combining Complementary Cancer Killing Effects.

There is major current interest in harnessing the immune system against cancer and in developing drugs that provide complementary cancer killing mechanisms. Although the recent advent of nanoparticle-based drug delivery systems has improved the efficacy of platinum drugs for chemotherapy, one of the fundamental paradigms in their design and use is evading surveillance by the immune system to enhance anticancer efficacy. However, new studies are showing that chemotherapy can profit from actively targeting stimulation of the immune system and that suitably functionalized nanomaterials might be ideal for overcoming some key challenges in immunotherapy. Pt(IV) prodrug-modified PEGylated phospholipid micelles that encapsulate biocompatible iron oxide nanoparticles (IONPs) as a new delivery system for cisplatin are reported. The Pt(IV)-IONPs are functionalized with polyinosinic-polycytidylic acid (poly (I:C))--a double stranded RNA (dsRNA) analog widely used as an adjuvant in clinical trials of cancer immunotherapy. The Pt(IV)-IONPs and poly (I:C)--Pt(IV)-IONPs enhance by more than an order of magnitude the prodrug cytotoxicity in different tumor cells, while greatly increasing the ability of cisplatin and poly (I:C) to activate dendritic cells--the key cellular players in immunotherapy. The results suggest that these constructs hold promise for targeted chemoimmunotherapy.

Stability of oxaliplatin in chloride-containing carrier solutions used in hyperthermic intraperitoneal chemotherapy.

PURPOSE: Oxaliplatin is increasingly becoming the chemotherapeutic drug of choice for the treatment of peritoneal malignancies using cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). Oxaliplatin is unstable in chloride-containing media, resulting in the use of 5% dextrose as the carrier solution in these procedures. Exposure of the peritoneum to 5% dextrose during perfusion times varying from 30 min to 90 min is associated with serious hyperglycemias and electrolyte disturbances. This can result in significant postoperative morbidity and mortality. In order to find out whether safer, chloride-containing carrier solutions can be used, we report the results of in-vitro analysis of oxaliplatin stability in both chloride-containing and choride-deficient carrier solutions and discuss the implications for oxaliplatin-based CRS-HIPEC procedures. METHODS: 5 mg of oxaliplatin was added to 50 mL of various carrier solutions at 42 °C: 5% dextrose, 0.9% sodium chloride, Ringer lactate, Dianeal(®) PD4 glucose 1.36% solution for peritoneal dialysis and 0.14 M sterile phosphate buffer pH 7.4. Samples were collected at standardized intervals and oxaliplatin concentration was determined using a stability indicating high-performance liquid chromatographic method, coupled to an UV detector (HPLC-UV); oxaliplatin degradation products were identified using HPLC-mass spectometry. RESULTS: In 5% dextrose, oxaliplatin concentration remained stable over a 2-hour period. Increasing chloride concentrations were associated with increasing degradation rates; however, this degradation was limited to <10% degradation after 30 min (the standard peritoneal perfusion time in most clinical CRS-HIPEC protocols) and <20% degradation after 120 min at 42 °C. In addition, oxaliplatin degradation was associated with the formation of its active drug form [Pt(dach)Cl2]. CONCLUSIONS: The use of chloride-containing carrier solutions for oxaliplatin does not relevantly affect its concentrations under the tested in-vitro conditions. Chloride seems to promote formation of the active cytotoxic drug form of oxaliplatin and therefore could enhance its cytotoxic effect. These data show that more physiological, chloride-containing carrier solutions can be used safely and effectively as a medium for oxaliplatin in CRS-HIPEC procedures.