Abstract 5530: Chitosan amphiphile nanoparticles reduced the myelosuppressive effects of lomustine

Abstract

Abstract Myelosuppression is the most important dose-limiting toxic effect of many cytotoxic agents. In this study we show that a nano-enabled formulation of lomustine based on glycol-chitosan amphiphile nanoparticles reduce the myelosuppressive effects of lomustine. Previously, we have shown that the chitosan amphiphile nanoparticles enabled dose intensification in the form of a ten-fold increase in the dose administered resulting in significant improvement in tumoricidal activity in an intracranial model of glioblastoma, without significant detriment to the health of the bone marrow. The myelosuppressive effects of lomustine formulations were assessed in healthy CD-1 male mice. Mice were assigned to treatment groups to receive either a high dose (13 mg/kg) nano-enabled formulation, a low dose (1.2 mg/kg) ethanolic formulation, or no drug treatment. The mice received the appropriate formulation by tail vein injection once daily for 10 consecutive days, after which they were sacrificed at pre-determined time points for analysis of blood parameters. A portion of blood samples was analysed using a clinical hemocytometer and a further portion of the samples was analysed using a flow cytometer. We hypothesise that a low propensity of these systems for cell uptake may contribute to their effect. Flow cytometry studies suggest low uptake of the chitosan amphiphile nanoparticles in macrophage (J774 A.1) cells. Bone marrow macrophages have been shown to be involved in maintaining the hematopoietic stem cell niche and may have a role in hematopoiesis. Our data support the hypothesis that this may contribute to the relatively low myelosuppression observed for the nano-enabled formulation (Table 1). Table 1.Analysis of blood samplesBlood cell countsDay 1 Red blood cellsDay 1 PlateletsDay 7 Red blood cellsDay 7 PlateletsDay 21 Red blood cellsDay 21 PlateletsTreatment groupsHemocytometer / Flow cytometerHemocytometer / Flow cytometerHemocytometer / Flow cytometerHemocytometer / Flow cytometerHemocytometer / Flow cytometerHemocytometer / Flow cytometerNano-enabled lomustine (13 mg/kg) formulation83* / 8061* / 71*93 / 10956* / 7794 / 10897 / 108Ethanolic lomustine (1.2 mg/kg) formulation96 / 8999 / 9699 / 12779* / 8298 / 11992 / 108Both hemocytometer and flow cytometer analysis showed no effect of either formulation on the white blood cells of treated mice* = Significantly different from untreated mice;p < 0.05Statistical analysis by one way ANOVA with Tukey's post hoc test While the overall study shows that the chitosan amphiphile nanoparticles based lomustine (13 mg/kg) formulation produced relatively low myelosuppression, we also report that flow cytometry could provide a means to readily evaluate myelosuppression in preclinical animal models. Citation Format: Funmilola Adesodun Fisusi, Omotunde Okubanjo, Kar Wai Chooi, Andreas G. Schatzlein, Ijeoma F. Uchegbu. Chitosan amphiphile nanoparticles reduced the myelosuppressive effects of lomustine. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5530. doi:10.1158/1538-7445.AM2015-5530