Assessment of antitumor activity and acute peripheral neuropathy of 1,2-diaminocyclohexane platinum (II)-incorporating micelles (NC-4016)

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.

Clinical Translation of Nanomedicine

“…294 NC-4016 (NanoCarrier Co. LTD) is a polymeric NP formulation of oxaliplatin that has demonstrated promising preclinical data and is under further clinical development. 295 The investigators demonstrated that NP formulation improved in vivo tumor growth delay in xenograft models when compared to small molecule oxaliplatin. Further, free oxaliplatin induced significant peripheral neuropathy as measured by cold hyperalgesia and allodynia, whereas NP-formulated oxaliplatin did not.…”

Bone invasion‐targeted chemotherapy with a novel anionic platinum complex (3Pt) for oral squamous cell carcinoma

“…NC‐6004 has progressed to a phase I clinical trial in the UK, and phase I/II trials are currently underway in East Asia . In addition, we reported the safety, with regard to acute neuropathy, and antitumor efficacy of NC‐4016, which is oxaliplatin contained in micelles . Currently, various treatments, such as bisphosphonate preparations, are being used for bone‐infiltrating cancer.…”

“…NC-6004 has 13,16,17 In addition, we reported the safety, with regard to acute neuropathy, and antitumor efficacy of NC-4016, which is oxaliplatin contained in micelles. 18 Currently, various treatments, such as bisphosphonate preparations, are being used for bone-infiltrating cancer. Although these methods contribute to a reduction in bone pain and hypercalcemia, they do not contribute to good prognosis.…”

Self-assembling prodrugs

“…This observation was attributed to the absence of the oxalate ligand (known to bind Ca 2+ and Mg 2+ ) and the slow-release kinetics from the micelles. 46 …”