Preclinical Toxicology (Subacute and Acute) and Efficacy of a New Squalenoyl Gemcitabine Anticancer Nanomedicine

Abstract

This study investigates 1) the anticancer efficacy of a new squalenoyl prodrug of gemcitabine (SQgem) in nanoassembly form compared with gemcitabine at equitoxic doses and 2) the subacute and acute preclinical toxicity of these compounds. The toxicity studies revealed that SQgem nanoassemblies, like gemcitabine, were toxic, and they led to dose-dependent mortality after daily i.v. injections for 1 week, irrespective of the route of administration. However, a 4-to 5-day spaced dosing schedule (injections on day 0, 4, 8, and 13) was proved to be safer in terms of weight loss and hematological and other toxicity. Using this spaced dosing schedule, SQgem nanoassemblies exhibited impressive anticancer activity in mice bearing L1210 leukemia because this treatment led to 75% long-term survivors. In contrast, at equitoxic doses, neither free gemcitabine nor cytarabine led to longterm survivors and all the mice of these groups died of the disease. Further toxicity studies performed at lethal doses by blood and serum analysis and organ weight determinations revealed that the hematological toxicity was the dose-limiting toxicity in both SQgem nanoassemblies and gemcitabine, whereas probable gastrointestinal toxicity was also associated with free gemcitabine. The SQgem nanoassemblies did not display hepatotoxicity, which is one of the clinically encountered toxicities of gemcitabine. To summarize, these preclinical studies demonstrated that the toxicological profile of new squalenoyl gemcitabine nanomedicine was not distinct from that of the parent gemcitabine, whereas it was much more potent than gemcitabine at equitoxic doses and cytarabine at clinically relevant doses. These data support the candidature of SQgem for clinical trials.Gemcitabine is an anticancer nucleoside analog indicated in the clinic for the treatment of various solid tumors. Although the anticancer activity of gemcitabine against leukemia has been demonstrated in preclinical models in which the leukemia cells were introduced intraperitoneally (Hertel et al., 1990), it is not indicated in the clinic for this purpose. Furthermore, these preclinical models do not mimic the real clinical situations. In addition, gemcitabine was recently shown to be insufficiently active against leukemia in phase II clinical trials (Angiolillo et al., 2006, Wagner-Bohn et al., 2006. We have recently developed a new prodrug of gemcitabine by conjugation with squalene (squalenoylation) (Couvreur et al., 2006a). The linkage of squalene was performed at the level of the 4-amino group of gemcitabine, rendering the molecule more amphiphilic, and resulting in their spontaneous aggregation as nanoassemblies of approximately 130 nm in diameter. These squalenoyl gemcitabine (SQgem) nanoassemblies were demonstrated to prevent the deamination of gemcitabine in vitro, thus overcoming one of the main drawbacks to its use, its short biological half-life (Couvreur et al., 2006b). In addition, in vitro, the SQgem nanoassemblies were demonstrated to be more cytotoxic than gemcitabin...

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