Effect of combined treatment with the epirubicin‐incorporating micelles (NC‐6300) and 1,2‐diaminocyclohexane platinum (II)‐incorporating micelles (NC‐4016) on a human gastric cancer model

Abstract

Anticancer agent-incorporating polymeric micelles accumulate effectively in tumors via the enhanced permeability and retention effect to exert potent antitumor effects. However, combined use of such micelles has not been elucidated. We compared the effect of combining the epirubicin-incorporating micelle NC-6300 and 1,2-diaminocyclohexane platinum (II) (oxaliplatin parent complex)-incorporating micelle NC-4016 (NCs) with that of epirubicin and oxaliplatin (E/O) in 44As3Luc cells using the combination index method. The in vivo antitumor activities of NCs and E/O were evaluated in mice bearing 44As3Luc xenografts. Pharmacokinetic analysis was performed by high-performance liquid chromatography and mass spectrometry. Cardiotoxicity of NC-6300 and epirubicin was assessed by echocardiography. Neurotoxicity of NC-4016 and oxaliplatin was evaluated by examining the paw withdrawal response to noxious mechanical stimuli. NCs showed a highly synergistic activity equivalent to E/O. In vivo, NCs exhibited higher antitumor activity in the subcutaneous tumor model and longer overall survival in the orthotopic tumor model than E/O (p < 0.001, p 5 0.015, respectively). The intratumor concentrations of epirubicin and platinum were significantly higher following NCs than following E/O administration. Moreover, the micelles showed lower cardiotoxicity and neurotoxicity than the corresponding conventional drugs. The combined use of the micelles was associated with remarkable efficacy and favorable toxicities in the human gastric cancer model, and warrants the conduct of clinical trials.The therapeutic window of cytotoxic anticancer agents (ACAs) is known to be narrow; at concentrations falling outside this window, these agents either fail to work or cause severe adverse events. To overcome this drawback, drug delivery systems have been developed. By utilizing the enhanced permeability and retention (EPR) effect, based on the leaky blood vessels and impaired lymphatic drainage in tumor tissues, drug delivery systems in nanoparticle-form enable ACAs to accumulate selectively in the tumors and exert prominent antitumor effect while decreasing the toxicity of the drug payload.1 Several preclinical studies have demonstrated the advantages of using ACA-incorporating polymeric micelles, and some are currently under clinical evaluation as single micelle agents alone 2-6 or single micelle agents in

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

“…In addition, the previous study showed that NC-4016 preferentially accumulates within the tumor tissue compared with other tissue. 20,21 Higher Pt concentrations in the tumor may indicate a stronger antitumor effect of NC-4016 compared with that of oxaliplatin in vivo.…”

The Drug Discovery by NanoMedicine and its Clinical Experience

“…In this regard, combined use of ACA-incorporating polymeric micelles may be a good alternative therapeutic modality, because micellar formulations are delivered selectively to tumor tissues via the EPR effect while their distribution to normal tissues is suppressed. Very recently we successfully demonstrated that combined use of NC-6300 and NC-4016, 1,2-diaminocyclohexane platinum (II)-incorporating micelles exerted a stronger antitumor effect and lower toxicity in a human gastric cancer model as compared with epirubicin and oxaliplatin (63). Several types of nanoparticles, in which multiple ACAs are loaded on to one particle, have been developed recently and been shown to exhibit potent anticancer activity (64 -66).…”

Application of the combination index integrated with confidence intervals to study the toxicological interactions of antibiotics and pesticides in Vibrio qinghaiensis sp.-Q67

“…The CI is based on the mass-action law and median-effect equation and allows quantitative determinations of toxicological interactions, where CI <1, =1 and >1 suggest synergism, additive action and antagonism, respectively. CI was widely used in assessing both beneficial (active) and adverse (toxic) interactions between pharmaceuticals (Gonzalez-Sanchez et al, 2012;Kostkova et al, 2013;Santillo et al, 2013;Tanamatayarat et al, 2012;Yamamoto et al, 2014). For examples, CI was used to quantitate chemopreventive synergism (Khafif et al, 1998), to demonstrate synergism between phytochemical indoles and isothiocyanates in HepG2-C8 cells (Saw et al, 2011), and to determine interactions between plant-derived phenolic acids on hepato toxicity endpoints .…”