In the presence of a catalytic amount of tetrakis(triphenylphosphine) palladium, phenyl and methyl or methoxyphenyl iodides and bromides were found to react with thiolate anions in alcoholic solvents, to give the corresponding aryl sulfides in excellent yield. The reaction is useful to prepare symmetrical or unsymmetrical diaryl sulfides and aryl alkyl sulfides. The reaction mechanism does not involve aryl halide radical anions, but is thought to involve oxidative addition of aryl halide to Pd(0), nucleophilic substitution on the adduct followed by reductive elimination.

Cisplatin (CDDP) has been a key drug for chemotherapy in patients with head and neck squamous cell carcinoma. Nephrotoxicity is one of its adverse reactions that are dose limiting. To increase its antitumor effects and reduce such toxicity problems, polymeric micelles carrying CDDP (NC-6004) have been developed. The present study was designed to evaluate the efficacy and safety of NC-6004 for oral squamous cell carcinoma. In vitro antitumor activity was assayed in four oral squamous cell carcinoma cell lines. To investigate the antitumor and nephrotoxic effects of NC-6004, nude mice bearing OSC-19 were administered NC-6004 or CDDP. The in vitro growth-inhibitory effect of NC-6004 was significantly less than that of CDDP. However, both NC-6004 and CDDP showed equivalent antitumor effects in vivo. Mice with CDDP developed renal cell apoptosis; however, those injected with NC-6004 were almost free of renal cell injury. Moreover, in an orthotopic tongue cancer model using OSC-19, NC-6004 reduced the rate of sentinel lymph node metastasis to lower than that with CDDP. In conclusion, considering the potential advantages in terms of noticeable antitumor activity, lymphatic drug delivery and reduced nephrotoxicity, NC-6004 represents a significant structural improvement in the development of a platinum complex. (Cancer Sci 2013; 104: 369-374) H ead and neck cancer remains a significant public health problem and ranks in the six leading cancers by incidence worldwide, with an estimated 600 000 new cases every year.(1) Cisplatin (cis-dichlorodiammineplatinum; CDDP) has been demonstrated to be one of the most effective cytotoxic agents (2) and the CDDP-based chemotherapy regimen has gained widespread use in patients with head and neck squamous cell carcinoma (HNSCC). However, its administration has been hindered by its adverse reactions, for example, nephrotoxicity, neurotoxicity, gastrointestinal toxicity, hematological toxicity and ototoxicity.(3) Among these, the significant risk of nephrotoxicity frequently hinders the use of high doses to maximize its antineoplastic effects, which might be the cause of treatment failure.To overcome these problems and improve the therapeutic effect of CDDP, we have been applying superselective supradose intra-arterial CDDP infusion for advanced HNSCC. However, since this technique is more complicated than that of i.v. infusion of antitumor drugs, it is not prevalent in the chemotherapy scene. Recently, several kinds of nanoparticle therapeutic platforms, including liposomes, nanoparticles and polymeric micelles, have been developed based on the idea that the drug delivery system (DDS) can accumulate in the tumor selectively, with reduced distribution in normal tissues and minimized undesirable side-effects.(5-7) NC-6004, which is a CDDP-incorporating polymeric micellar nanoparticle, enhanced antitumor activity and reduced the nephrotoxicity and neurotoxicity of CDDP in gastric cancer. (8)(9)(10) Poly(ethylene glycol)-poly(glutamic acid) block copolymers (PEG-P [Gu]) confer a stealth...

Anthracyclines have long been considered to be among the most active agents clinically available for the treatment of breast cancer despite their toxicity. To improve their pharmacological profiles, a new macromolecular prodrug, denoted NC-6300, was synthesized. NC-6300 comprises epirubicin covalently bound to polyethyleneglycol polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure spontaneously in aqueous media with a diameter of 60-70 nm. The block copolymers are partially substituted with hydrophobic benzyl groups to stabilize the micellar structure. The present study was designed to confirm that polymeric micelles incorporating epirubicin through an acid-labile linker improve the therapeutic index and achieve a broad range of therapeutic doses. Pharmacokinetic studies in rats showed highly enhanced plasma retention of NC-6300 compared with native epirubicin. The maximal tolerated doses in mice of NC-6300 and native epirubicin were 25 and 9 mg/kg, respectively, when administered three times with a 4-day interval between each dose. NC-6300 at 15 and 20 mg/kg with the same administration schedule regressed a Hep3B human hepatic tumor with slight and transient bodyweight loss. Remarkably, NC-6300 also inhibited growth of an MDA-MB-231 human breast tumor at the same dosage. In contrast, native epirubicin at 7 mg/kg administered three times with a 4-day interval was only able to slow tumor growth. Tissue distribution studies of NC-6300 showed efficient free epirubicin released in the tumor at 74% by area under the concentration-time curve (AUC) evaluation, supporting the effectiveness of NC-6300. In conclusion, NC-6300 improved the potency of epirubicin, demonstrating the advantage of NC-6300 attributable to the efficient drug release in the tumor. (Cancer Sci 2011; 102: 192-199) A nthracyclines were first introduced for the treatment of metastatic breast cancer in the 1970s and are still among the most active single agents for the treatment of this disease despite their cardiotoxicity.(1) The aim of increasing their efficacy was first addressed using liposomes.(2) Efforts to design liposomes that are pH-sensitive, temperature-sensitive or antibody-targeted have all been pursued with various degrees of success.(3) However, current clinically approved liposomal formulations have still resulted in only modest increased efficacy for the treatment of cancer.(4) Its actual advantage is reduced toxicity rather than increased therapeutic effect. To increase the efficacy, polymer-based anthracyclines have also been studied extensively. (8,9) Recent strategies have been developed and successfully applied to attain desirable tumor localization through polymeric micelles composed of polyethylene glycol (PEG)-poly (amino acid) block copolymers.(10) These types of strategies involve drug release inside endosomes and lysosomes after cellular internalization, where the slightly acidic pH leads to cleavage of the acid-sensitive linkage.

Use of short interfering RNA (siRNA) is a promising new approach thought to have a strong potential to lead to rapid development of gene-oriented therapies. Here, we describe a newly developed, systemically injectable siRNA vehicle, the

Epirubicin is widely used to treat various human tumors. However, it is difficult to achieve a sufficient antitumor effect because of dosage limitation to prevent cardiotoxicity. We hypothesized that epirubicin-incorporating micelle would reduce cardiotoxicity and improve the antitumor effect. NC-6300 comprises epirubicin covalently bound to PEG polyaspartate block copolymer through an acid-labile hydrazone bond. The conjugate forms a micellar structure of 40-80 nm in diameter in an aqueous milieu. NC-6300 (10, 15 mg ⁄ kg) and epirubicin (10 mg ⁄ kg) were given i.v. three times to mice bearing s.c. or liver xenograft of human hepatocellular carcinoma Hep3B cells. Cardiotoxicity was evaluated by echocardiography in C57BL ⁄ 6 mice that were given NC-6300 (10 mg ⁄ kg) or epirubicin (10 mg ⁄ kg) in nine doses over 12 weeks. NC-6300 showed a significantly potent antitumor effect against Hep3B s.c. tumors compared with epirubicin. Moreover, NC-6300 also produced a significantly longer survival rate than epirubicin against the liver orthotopic tumor of Hep3B. With respect to cardiotoxicity, epirubicin-treated mice showed significant deteriorations in fractional shortening and ejection fraction. In contrast, cardiac functions of NC-6300 treated mice were no less well maintained than in control mice. This study warrants a clinical evaluation of NC-6300 in patients with hepatocellular carcinoma or other cancers. (Cancer Sci 2013; 104: 920-925) H epatocellular carcinoma (HCC) is the fifth most common cancer and the third largest cause of cancer mortality worldwide.(1,2) The range of available oncological treatment for HCC is sometimes limited due to poor liver function caused by concomitant chronic liver disease, especially liver cirrhosis, which is mainly the result of hepatitis virus infection. Surgical resection is widely considered the mainstay for curative treatment and yields a certain survival rate. However, <20% of patients with HCC can undergo surgical resection. (3,4) With the exception of patients at an early stage and with adequate liver function, recurrence rates after surgical resection are unfortunately high. High recurrence rates are also seen in patients treated by other local treatment options, such as ablation, percutaneous ethanol injection, and trans-arterial chemoembolization.(5) For advanced HCC, the only available option is sorafenib, a tyrosine kinase inhibitor, which was recently approved; however, the survival rate associated with its use is far from satisfactory.

No abstract

Oxaliplatin, a third-generation platinum compound incorporating oxalate and 1,2-diaminocyclohexane platinum, has been widely used in chemotherapy regimens for the treatment of metastatic colorectal cancer. Because of its wide spectrum of antitumor activity, oxaliplatin has been applied for the treatment of other carcinomas. However, the antitumor activity of single-agent oxaliplatin is insufficient. To increase its antitumor effects, polymeric micellar nanoparticles incorporating 1,2-diaminocyclohexane platinum (NC-4016) have been developed. The present study was designed to evaluate the efficacy of NC-4016 and its association with peripheral neuropathy, which is a primary dose-limiting factor in oxaliplatin therapy. The in vitro antitumor activity of NC-4016 was investigated using human carcinoma cell lines. To investigate the antitumor effects of NC-4016 in vivo, nude mice bearing the human carcinoma cell line KB were administered NC-4016 or oxaliplatin. The in vitro growth-inhibiting effect of NC-4016 was significantly weaker than that of oxaliplatin. However, the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in vivo. Moreover, we compared the severity of peripheral neuropathy induced by oxaliplatin and NC-4016 in a rat model. Oxaliplatin, NC-4016, or 5% glucose (control) were administered by a single tail vein injection. In the oxaliplatin-treated rats, neither mechanical nor heat allodynia was observed during the experimental period, whereas cold hyperalgesia/allodynia was observed from day 1 to 7. Conversely, cold hyperalgesia/allodynia was not observed in the NC-4016-treated rats. The present study demonstrated that the antitumor efficacy of NC-4016 was superior to that of oxaliplatin in a mouse model of human carcinoma cell line KB. In addition, NC-4016-treated rats did not develop acute cold hypersensitivity, which is frequently experienced by patients after oxaliplatin administration.

We have developed a novel and potent chemical series of 5,5-diphenylpentadienamides for targeting TRPV1 in vitro and in vivo. In this investigation, we examined a variety of replacements for the 5-position of dienamides with the goal of addressing issues related to pharmacokinetics. Our data suggest that substitution with alkoxy groups on the phenyl ring at the 5-position increases their ability to penetrate the blood-brain barrier. This investigation culminated in the discovery of compound (R)-36b, which showed a good pharmacokinetic profile. In vivo, compound (R)-36b was found to be effective at reversing mechanical allodynia in rats in a dose-dependent manner, and it reversed thermal hyperalgesia in a model of neuropathic pain induced by sciatic nerve injury.