Lipophilic Platinum Research Articles

Preparation, cytotoxic activity and DNA interaction studies of new platinum(II) complexes with 1,10-phenanthroline and 5-alkyl-1,3,4-oxadiazol-2(3H)-thione derivatives

This work describes the synthesis, characterization and in vitro anticancer activity of two platinum(II) complexes of the type [Pt(L1)2(1,10-phen)] 1 and [Pt(L2)2(1,10-phen)] 2, where L1 = 5-heptyl-1,3,4-oxadiazole-2-(3H)-thione, L2 = 5-nonyl-1,3,4-oxadiazole-2-(3H)-thione and 1,10-phen = 1,10-phenanthroline. As to the structure of these complexes, the X-ray structural analysis of 1 indicates that the geometry around the platinum(II) ion is distorted square-planar, where two 5-alkyl-1,3,4-oxadiazol-2-thione derivatives coordinate a platinum(II) ion through the sulfur atom. A chelating bidentate phenanthroline molecule completes the coordination sphere. We tested these complexes in two breast cancer cell lines, namely, MCF-7 (a hormone responsive cancer cell) and MDA-MB-231 (triple negative breast cancer cell). In both cells, the most lipophilic platinum compound, complex 2, was more active than cisplatin, one of the most widely used anticancer drugs nowadays. DNA binding studies indicated that such complexes are able to bind to ct-DNA with Kb values of 104 M−1. According to data from dichroism circular and fluorescence spectroscopy, these complexes appear to bind to the DNA in a non-intercalative, probably via minor groove. Molecular docking followed by semiempirical simulations indicated that these complexes showed favorable interactions with the minor groove of the double helix of ct-DNA in an A-T rich region. Thereafter, flow cytometry analysis showed that complex 2 induced apoptosis and necrosis in MCF-7 cells.

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.

Chlorambucil-conjugated platinum(IV) prodrugs to treat triple-negative breast cancer in vitro and in vivo

Modification of platinum (II) into lipophilic platinum (IV) compounds by introducing biologically active molecules were widely employed to develop new platinum-based prodrugs in the past decade. In this paper, two chlorambucil platinum (IV) complexes, CLB-Pt and CLB-Pt-CLB, were synthesized and displayed very potent antiproliferative activity against all the tested cancer cell lines, such as A549, HeLa and MCF-7, especially to treat the well-known refractory triple-negative breast cancer. CLB-Pt-CLB significantly improved cell-killing effect in triple-negative subtype MDA-MB-231 cells, and showed much stronger cytotoxicity than either monotherapy or combination of cisplatin and chlorambucil. CLB-Pt-CLB prodrug entered cells in dramatically increased amount compared with cisplatin and enhanced DNA damage, inducing cancer cell apoptosis. It exhibited high anticancer activity and no observable toxicity in BALB/c nude mice bearing MDA-MB-231 tumors. The chlorambucil moiety not only greatly assisted the passive diffusion of CLB-Pt-CLB into cells, but also produced the synergism with cisplatin in targeting DNA.

Differences in Nanoparticle Uptake in Transplanted and Autochthonous Models of Pancreatic Cancer.

Human pancreatic ductal adenocarcinoma (PDAC) contains a distinctively dense stroma that limits the accessibility of anticancer drugs, contributing to its poor overall prognosis. Nanoparticles can enhance drug delivery and retention in pancreatic tumors and have been utilized clinically for their treatment. In preclinical studies, various mouse models differentially recapitulate the microenvironmental features of human PDAC. Here, we demonstrate that through utilization of different organic cosolvents and by doping of a homopolymer of poly(ε-caprolactone), a diblock copolymer composition of poly(ethylene oxide)- block-poly(ε-caprolactone) may be utilized to generate biodegradable and nanoscale micelles with different physical properties. Noninvasive optical imaging was employed to examine the pharmacology and biodistribution of these various nanoparticle formulations in both allografted and autochthonous mouse models of PDAC. In contrast to the results reported with transplanted tumors, spherical micelles as large as 300 nm in diameter were found to extravasate in the autochthonous model, reaching a distance of approximately 20 μm from the nearest tumor cell clusters. A lipophilic platinum(IV) prodrug of oxaliplatin was further able to achieve a ∼7-fold higher peak accumulation and a ∼50-fold increase in its retention half-life in pancreatic tumors when delivered with 100 nm long worm-like micelles as when compared to the free drug formulation of oxaliplatin. Through further engineering of nanoparticle properties, as well as by widespread adoption of the autochthonous tumor model for preclinical testing, future therapeutic formulations may further enhance the targeting and penetration of anticancer agents to improve survival outcomes in PDAC.

A Potential Bone-Targeting Hypotoxic Platinum(II) Complex with an Unusual Cytostatic Mechanism toward Osteosarcoma Cells.

Osteosarcoma (OS) is the most common primary pediatric bone tumor lethal to children and adolescents. Chemotherapeutic agents such as cisplatin are not effective for OS because of their poor accessibility to this cancer and severe systemic toxicity. In this study, a lipophilic platinum(II) complex bearing a bisphosphonate bone-targeting moiety, cis-[PtL(NH3)2Cl]NO3 {BPP; L = tetraethyl [2-(pyridin-2-yl)ethane-1,1-diyl]bisphosphonate}, was prepared and characterized by NMR, electrospray ionization mass spectrometry, and single-crystal X-ray crystallography. The cytotoxicity of BPP toward OS cell lines U2OS and MG-63 was tested by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. BPP exhibits moderate inhibition against U2OS cells through a mechanism involving both DNA binding and a mevalonate pathway. The acute toxicity of BPP to mice is 7-fold lower than that of cisplatin. The relative low systemic toxicity may result from the steric hindrance of the ligand, which blocks BPP approaching the bases of DNA. The results suggest that incorporating bisphosphonates into a platinum complex not only enhances its bone-targeting property but also minimizes its reactivity toward DNA and thereby lowers the systematic toxicity of the complex. The diminished cytotoxicity of BPP could be compensated for by increasing the therapeutic dose with marginal harm. This strategy provides a new possibility for overcoming the ineffectiveness and systemic toxicity of platinum drugs in the treatment of OS.

Effects of Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma Using a Combination of Platinum Agents (Cisplatin plus Miriplatin): A Retrospective Comparison with Cisplatin Monotherapy

Background: Miriplatin is a slow-release, lipophilic platinum complex, developed to produce a superior antitumor effect for hepatocellular carcinoma (HCC). However, the miriplatin suspension is highly viscous and can form an embolism in the hepatic artery, which can result in insufficient antitumor effect. Thus, reducing the viscosity of the suspension compound by combining it with the less-viscous cisplatin suspension might reduce or even prevent vessel embolism, while providing the quick-release effects of cisplatin. Purpose: To compare the outcomes of therapy using miriplatin plus cisplatin and cisplatin monotherapy in transcatheter arterial chemoembolization (TACE) for HCC. Methods: We retrospectively evaluated a total of 87 patients with Barcelona Clinic Liver Cancer (BCLC) stage A or B HCC who received conventional TACE using a combination of platinum agents (cisplatin and miriplatin) (n = 50) or cisplatin alone (n = 37) for the first time from September 2006 to December 2012. Short term therapeutic effect was measured by dynamic computed tomography 1 - 3 months after TACE, in reference to the modified Response Evaluation Criteria in Solid Tumors. Treatment-related adverse effects were graded by the National Cancer Institute Common Terminology Criteria (ver. 4.0). 1-, 3-, and 5-year survival rates were calculated. Subgroup analyses were performed by Child-Pugh classification and BCLC criteria. Results: Median duration of follow-up was 35 months (range 7 - 90). Median overall survival was 38 months. Patients who had combination therapy had better 1-, 3-, and 5-year survival rates: 100%, 56.7%, and 26.2%, respectively, compared to monotherapy: 100%, 42.1%, and 9.0%, respectively (p = 0.034). No serious complication or treatment-related mortality was observed in both groups. Conclusion: TACE using miriplatin plus cisplatin was related to a prolonged survival, with comparable adverse effects of TACE using cisplatin alone.

Tetracarboxylatoplatinum(IV) complexes featuring monodentate leaving groups — A rational approach toward exploiting the platinum(IV) prodrug strategy

A series of novel symmetrically and unsymmetrically coordinated platinum(IV) complexes with monodentate carboxylato ligands was synthesized. The compounds exhibit a general coordination sphere of [Pt(en)(OCOR)2(OCOR′)(OCOR″)], where the carboxylato ligands are represented by acetato and succinic acid monoester ligands. Dicarboxylatoplatinum(II) complexes were synthesized and oxidized symmetrically or unsymmetrically to obtain platinum(IV) complexes, which were subsequently carboxylated with noncyclic anhydrides. The compounds were investigated in detail by elemental analysis, mass spectrometry, infrared and multinuclear (1H, 13C, 15N, 195Pt) NMR spectroscopy as well as by X-ray diffraction in some cases. The reduction behavior was followed by NMR spectroscopy, while stability and lipophilicity were examined by analytical reversed phase HPLC measurements. Cytotoxic properties were studied in three human cancer cell lines derived from cisplatin sensitive ovarian teratocarcinoma (CH1/PA-1), cisplatin insensitive colon carcinoma (SW480) and non-small cell lung cancer (A549). Thereby, the most lipophilic (yet water soluble) platinum(IV) complexes showed promising IC50 values in the low micromolar and even nanomolar range, demonstrating the significant advantage of using equatorially coordinated monodentate carboxylato ligands.

Acetate platinum(II) compound with 5,7-ditertbutyl-1,2,4-triazolo[1,5-a]pyrimidine that overcomes cisplatin resistance: structural characterization, in vitro cytotoxicity, and kinetic studies

The reaction of silver acetate with cis-[PtI2(dbtp)2], where dbtp = 5,7-ditertbutyl-1,2,4-triazolo-[1,5-a]pyrimidine, yielded cis-[Pt(OOCCH3)2(dbtp)2]·dmf (1). The complex has been analyzed by multinuclear magnetic resonance (1H, 13C, 15N), IR, and Raman. The compound formed two rotamers in CDCl3 and its spatial structures have been optimized using computational calculation. It was found that head-to-tail rotamer (1a) is more stable than its head-to-head counterpart (1b). In vitro antiproliferative activity against four tumor cell lines (A549, T47D, FaDu, and A2780cis) revealed in all cases significant cytotoxicity (IC50 = 0.26–1.80 μM), possessing IC50 values at least fivefold lower than cisplatin, carboplatin, and oxaliplatin (except A2780cis). The remarkable in vitro activity against T47D and A2780cis suggested the ability to overcome cisplatin resistance in these types of tumor cells. In addition, in vitro toxicity was evaluated against BALB/3T3 and has shown that the lipophilic platinum(II) complex (1) inhibits cell proliferation weaker than cisplatin and oxaliplatin. Additionally, cis-[Pt(OOCCH3)2(dbtp)2]·dmf exhibited selective activity, in contrast to cisplatin or oxaliplatin.

Transcatheter arterial chemotherapy with miriplatin for hepatocellular carcinoma patients with chronic renal failure: report of three cases.

Miriplatin is a novel lipophilic platinum complex that was developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting chronic renal failure, little prospective data are available regarding the clinical toxicity of chemotherapeutic agents used to treat HCC patients with chronic renal failure. In a phase II study, the plasma concentration of total platinum in patients who received miriplatin was very low, and no severe renal toxicity caused by miriplatin injection was reported. Here, we present three cases of HCC with stage 4 chronic renal failure who received transcatheter arterial chemotherapy with miriplatin. All cases were male, ages 72, 84, and 83 years, and had serum creatinine levels of 2.3, 1.6, and 1.9 mg/dL, respectively. Their estimated glomerular filtration rates were 21.9, 20.3, and 22.2 mL/min, respectively. All cases were treated for unresectable HCC with transcatheter arterial chemotherapy with miriplatin. No serious adverse events were observed, and serum creatinine levels did not elevate, even in the patient who experienced renal failure caused by cisplatin administration. These results might suggest that transcatheter arterial chemotherapy with miriplatin can be safely used in HCC patients with chronic renal failure.

Selective accumulation of platinum and formation of platinum–DNA adducts in hepatocellular carcinoma after transarterial chemoembolization with miriplatin

Miriplatin, a lipophilic platinum complex, is a novel intra-arterial chemotherapeutic agent for hepatocellular carcinoma (HCC). Little is known about platinum-DNA adduct levels in human HCC after administration of platinum-based drugs. We investigated whether miriplatin selectively accumulates and forms platinum-DNA adducts in human HCC tumors. Using inductively coupled plasma mass spectrometry, we determined the platinum concentrations and platinum-DNA adduct levels in paired HCC tumors and non-tumor liver tissues of four patients who received transcatheter arterial chemoembolization with miriplatin and subsequently underwent hepatic resection. The mean (± standard deviation) platinum concentrations were 730 ± 350 μg/g (range, 400-1100) in HCC tumors and 16 ± 9.2 μg/g (range, 9.2-29) in non-tumor liver tissues. The concentrations were approximately 50-fold higher in HCC tumors than in non-tumor liver tissues. The mean platinum-DNA adduct levels were 54 ± 16 pg Pt/μg DNA (range, 37-69) in HCC tumors and 13 ± 13 pg Pt/μg DNA (range, 4.8-33) in non-tumor liver tissues. The adduct levels were roughly 7.6-fold higher in HCC tumors than in non-tumor liver tissues. There were no significant correlations between platinum concentrations and platinum-DNA adduct levels in HCC tumors. Our results quantitatively demonstrate that there is a selective accumulation of platinum and formation of platinum-DNA adducts in human HCC tumors after transarterial chemoembolization with miriplatin. No correlation was observed between platinum concentrations and platinum-DNA adduct levels.

A transcatheter arterial chemotherapy using a novel lipophilic platinum derivative (miriplatin) for patients with small and multiple hepatocellular carcinomas

Miriplatin is a platinum complex developed to treat hepatocellular carcinoma (HCC) through administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. A single-institute pilot study was conducted to investigate the antitumor efficacy of miriplatin infusion therapy for small and multiple HCCs. Small HCCs sized 2 cm or less, judged to be inadequate for curative treatment, were indicated for transcatheter arterial miriplatin infusion therapy. We prospectively investigated the course of patients treated with miriplatin between March 2010 and September 2010. Efficacy was evaluated by computed tomography at 4-8 weeks and the overall evaluation was carried out more than 3 months after treatment. The study included 14 patients, of whom 13 were evaluable for efficacy. Of the 13 patients, one (8%) showed a complete response and three (23%) showed a partial response, with an overall response rate of 31%. Grade 3/4 hematological toxicity including thrombocytopenia was not seen. Increases to grade 3/4 in aspartate aminotransferase and alanine aminotransferase were observed for nonhematological toxicity. Irreversible deleterious changes in hepatic function were not seen. Miriplatin infusion therapy showed safe and moderate effects on small HCCs. However, transarterial chemoembolization as a standard therapy cannot be replaced. We await the results of an ongoing study of transarterial chemoembolization with miriplatin.

Abstract No. 35: Comparative study of short-term therapeutic effects of miriplatin-lipiodol suspension and cisplatin-lipiodol suspension in transcatheter arterial chemo-embolization for hepatocellular carcinoma

Miriplatin hydrate (Miripla; Dainippon Sumitomo Pharma Co. Ltd. Osaka, Japan) was released in 2010 and has been developed in Japan. Miriplatin contains a lipophilic platinum complex with a higher affinity for iodized oil than the cisplatin powder. The purpose of this study was to investigate the short-term therapeutic effects and adverse effects associated with the use of Miriplatin-lipiodol suspension in TACE for HCC as a single-institution retrospective study, using a cisplatin-lipiodol suspension as a control.

Clinical and pharmacokinetic evaluation of satraplatin

Introduction: The toxicities of cisplatin, that is, nephrotoxicity, neurotoxicity and emesis, provided the impetus for the development of more tolerable platinum analogs. Satraplatin is an investigational third-generation orally available lipophilic platinum, which has demonstrated safety and antitumor activity in multiple settings.Areas covered: The clinical activity of satraplatin in metastatic castrate-resistant prostate cancer (mCRPC), breast, lung and other advanced solid tumors is discussed with a focus on its pharmacokinetic properties. The article was formulated using publications found through PubMed search in addition to presentations given at major conferences.Expert opinion: Satraplatin was associated with dose-limiting myelosuppression, but no significant ototoxicity, neurotoxicity or nephrotoxicity. Despite the activity of satraplatin in mCRPC, survival was not extended in an unselected population included in a Phase III trial. While further development of satraplatin in large Phase III trials is not planned at this time, efforts are ongoing to develop tailored therapy in mCRPC based on excision repair cross-complementing group 1 expression or BRCAness. Moreover, based on potentially better central nervous system penetration due to lipophilicity, evaluation in patients with brain tumors is ongoing. Given the favorable toxicity profile and convenient oral administration, satraplatin may warrant development in settings that preclude cisplatin, for example, underlying renal dysfunction, elderly age and poor performance status.

Enhancing lipophilicity as a strategy to overcome resistance against platinum complexes?

Decreased influx represents one of the major resistance mechanisms of platinum complexes. In order to address the question if this mechanism of resistance can be overcome by enhancing the lipophilicity of platinum complexes, we investigated the influence of lipophilicity on cellular accumulation and cytotoxicity in a panel of oxaliplatin analogues with different carrier ligands. Cellular accumulation, DNA platination and cytotoxicity were measured in a cisplatin-sensitive and -resistant ovarian carcinoma (A2780/A2780cis) and in an oxaliplatin-sensitive and -resistant ileocecal colorectal adenocarcinoma (HCT-8/HCT-8ox) cell line pair. Platinum concentrations were determined by flameless atomic absorption spectrometry or adsorptive stripping voltammetry. Passive diffusion represented the main influx mechanism of oxaliplatin analogues during the first minutes of incubation as indicated by a correlation between lipophilicity and early influx rate. Afterwards, the predominant influx mechanism was lipophilicity-independent. More lipophilic complexes showed a reduced cytotoxic activity, although the early influx rate was increased. The resistance profiles of the two cell line pairs were found to be different: HCT-8ox cells were less resistant against more lipophilic complexes, whereas A2780cis cells exhibited a comparable degree of resistance against all investigated compounds. However, the reduction in resistance factor of HCT-8ox cells cannot be explained by increased influx suggesting that other resistance mechanisms are circumvented upon exposure to more lipophilic compounds. Though resistance against more lipophilic platinum complexes analogues is lower we conclude that enhancing lipophilicity is not a successful strategy to overcome platinum resistance as higher lipophilicity is also associated with lower cytotoxic activity.

Acquired resistance to miriplatin in rat hepatoma AH109A/MP10 is associated with increased Bcl-2 expression, leading to defects in inducing apoptosis

Miriplatin, a novel lipophilic platinum complex approved to treat hepatocellular carcinoma, is administered into the hepatic artery after suspension in an oily contrast medium. Little is known concerning the mechanism of acquired resistance to miriplatin. In this study, we established and characterized a rat hepatoma cell subline, AH109A/MP10, which was about 10-fold more resistant to miriplatin than the parental cell line, AH109A. The established miriplatin-resistant cells showed clear cross-resistance to platinum complexes containing diaminocyclohexane as a carrier ligand, such as oxaliplatin and dichloro[(1R,2R)-1,2-cyclohexanediamine-N,N']platinum (DPC), while three human cancer cell lines selected for resistance to cisplatin (A2780cis, NCI-H69/CPR, MOR/CPR) did not show cross-resistance to miriplatin. There was no apparent difference in either intracellular platinum accumulation or platinum-DNA adducts in formation between resistant and parental cells after treatment with miriplatin or cisplatin, consisted with the unchanged expression of proteins involved in DNA repair, such as excision repair cross-complementing 1 (ERCC1) and mutL homolog 1 (MLH1). The increased expression of Bcl-2 was observed in AH109A/MP10 cells, in which apoptosis induced by miriplatin, but not cisplatin, was reduced. In addition, Bcl-2 inhibitor YC137 partially reversed the resistance of AH109A/MP10 cells to miriplatin. These findings suggested that the acquired resistance to miriplatin in AH109A/MP10 cells was associated in part with increased Bcl-2 expression, leading to defects in inducing apoptosis.

Child-Pugh B肝硬変合併肝細胞癌に対するミリプラチン動注化学療法の検討

Miriplatin is a novel lipophilic platinum complex developed to treat hepatocellular carcinoma (HCC). Although HCC patients frequently have coexisting severe liver cirrhosis, there is no prospective data regarding clinical toxicity of miriplatin in HCC patients with severe cirrhosis. We retrospectively evaluated the safety and efficacy of transcatheter arterial chemotherapy with miriplatin in 34 HCC patients with severe liver cirrhosis (Child-Pugh grade B). An anti-tumor effect of complete response was achieved in 8 of 34 patients and no serious adverse events were observed. These results suggested that transcatheter arterial chemotherapy with miriplatin can be used safety for HCC patients with Child-Pugh B liver cirrhosis.

A randomized phase II trial of intra-arterial chemotherapy using a novel lipophilic platinum derivative (SM-11355) in comparison with zinostatin stimalamer in patients with hepatocellular carcinoma

4583 Background: SM-11355 (Miriplatin Hydrate) is a platinum complex developed to treat HCC via administration into the hepatic artery as a sustained-release formulation suspended in lipiodol. We conducted a phase II trial in patients with HCC to evaluate the efficacy and safety of SM-11355 using zinostatin stimalamer as a control. Methods: Patients with unresectable HCC were randomized 2:1 to receive an injection of SM-11355 or zinostatin stimalamer suspended in lipiodol into the hepatic artery at doses of up to 6 mL (SM-11355: 120 mg; zinostatin stimalamer: 6 mg) according to the tumor size. A second injection was given 4–12 weeks after the first injection. Efficacy was evaluated by CT 3 months after treatment and categorized as therapeutic effect (TE) V to I. The primary endpoint was achievement of TE V, which was defined as disappearance or 100% necrosis of all treated tumors. Lipiodol accumulation in tumors was regarded as indicating necrosis. Results: The study included 126 patients, of whom 122 were evaluable for efficacy and toxicity (SM-11355, n=83; zinostatin stimalamer, n=39). Baseline characteristics were similar in the two groups. The TE V rates were 26.5% (22/83) and 17.9% (7/39) in the SM-11355 and zinostatin stimalamer groups, respectively. The most frequent drug-related adverse events (AEs) of ≥ grade 3 (shown as SM-11355 vs. zinostatin stimalamer) were elevated AST (26.5 vs. 33.3%), elevated ALT (22.9 vs. 20.5%), thrombocytopenia (12.0 vs. 7.7%), and hyperbilirubinemia (9.6 vs. 5.1%). Serious AEs occurred in 9 (10.8%) and 3 (7.7%) patients in the SM-11355 and zinostatin stimalamer groups, respectively. The AEs with the largest difference in frequency between the two groups (SM-11355 vs. zinostatin stimalamer) were hepatic vascular injury (0 vs. 48.4%) and eosinophilia (84.3 vs. 41.0%). The 2-year survival rates were 75.9 and 70.3% in the SM-11355 and zinostatin stimalamer groups, respectively, and the 3-year survival rates were 58.4 vs. 48.7%, respectively. Conclusions: Our results suggest that SM-11355 in lipiodol has similar efficacy to that of zinostatin stimalamer, and that repeated dosing is possible without hepatic vascular injury in cases of relapse. No significant financial relationships to disclose.

Intra‐hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of human hepatoma cells orthotopically implanted in nude rats

Miriplatin is a lipophilic platinum complex which contains myristates as leaving groups and diaminocyclohexane as a carrier ligand. In order to examine in vivo the antitumor activities of miriplatin suspended in an oily lymphographic agent (Lipiodol Ultra-Fluide, LPD) against human hepatocellular carcinoma (HCC) after the intra-hepatic arterial administration, we have developed a novel orthotopic model of HCC in which the human hepatoma cell line Li-7 was successively implanted and maintained in the liver of nude rats. Li-7 tumors established in nude rat livers displayed a trabecular structure similar to their original morphology, and were exclusively supplied by the hepatic artery, suggesting that they exhibited in part the conditions of human HCC. Miriplatin suspended in LPD (miriplatin/LPD) administered into the hepatic artery of this model dose-dependently inhibited the growth of Li-7 tumors without markedly enhancing body weight loss and caused a significant reduction in the growth rate at a dose of 400 microg/head compared to LPD alone. In addition, at the therapeutic dose, miriplatin/LPD as well as cisplatin suspended in LPD (400 microg/head) was shown to be more active than zinostatin stimalamer suspended in LPD (20 microg/head) against Li-7 tumors after a single intra-hepatic arterial administration. These results suggest miriplatin to be a suitable candidate for use in transarterial chemoembolization.

Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis

BackgroundMiriplatin (formerly SM-11355), a novel lipophilic platinum complex developed to treat hepatocellular carcinoma, is administered into the hepatic artery using an oily lymphographic agent (Lipiodol Ultra-Fluide®) as a carrier. We clarified the usefulness of miriplatin as an agent for transarterial chemoembolization.MethodsPlatinum compounds released from miriplatin into serum, medium and Earle’s balanced salt solution were examined. Then, miriplatin and cisplatin were administered to rats bearing hepatoma AH109A tumors in livers. Platinum concentrations in tissues and DNA were assessed.ResultsMiriplatin showed a more sustained release than cisplatin. Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N′]platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells. Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.ConclusionMiriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.

Novel Lipophilic Platinum(II) Compounds of Salicylate Derivatives

A series of novel lipophilic platinum(II) compounds containing salicylate derivatives as the leaving group have been designed, synthesised and characterised. Most of the platinum compounds exhibit high solubility and have a partition coefficient suited to liposomal encapsulation. Some of the compounds are more pharmacologically active and/or less toxic than carboplatin and oxaliplatin. The liposomal formulation of the most promising compound has been successfully prepared with long stability and high encapsulation rate, showing great potential to be developed as a new tumour-target drug.