Tumor‐targeted chemotherapy with the nanopolymer‐based drug NC‐6004 for oral squamous cell carcinoma

Abstract

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...

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