Abstract:
Purpose: Asulacrine (ASL) is a topoisomerase II inhibitor and show anticancer activity against breast and lung cancer but severe phlebitis was a major dose-liming toxicity during clinical trials. Solid lipid nanoparticles (SLNs) are biocompatible and have good tolerability profile which give new insight to address this problem. The aim of this study was to formulate and characterise SLN formulation containing ASL and evaluate cytotoxicity of ASL loaded SLN in comparison to free ASL solutions with in vitro cell culture models. Methods: Glyceryl monostearate (GMS) SLNs coated with Poloxamer 188 were prepared using a high sheer homogenisation-ultrasonication (HSH-U) method. Physicochemical characteristics, physical stability and in vitro drug release profile of ASL loaded SLNs were analysed. In vitro cytotoxicity study was tested via MTS and LDH assays on primary human umbilical vein endothelial cells (HUVEC) culture model to evaluate and compare the irritancy potential of ASL loaded SLNs and free ASL solutions. Results: ASL loaded SLN produced particle size that were appropriate for intravenous infusion and passive targeting (size 387.6 ± 8.9 nm, PDI 0.471 ± 0.2). High entrapment efficiency (95.9 ± 2.4%) and sufficient drug loading (4.6% ± 0.1) were achieved. ASL loaded SLNs were stable up to 12 days and ASL was released in a controlled manner over 48 hours in in vitro release study. With MTS and LDH assays, level of cytotoxicity was in the following order: free drug solutions > ASL loaded SLNs ≥ unloaded SLNs. With LDH and MTS assays, cell viability was significantly higher with ASL loaded SLNs especially at higher concentrations in comparison to free ASL solutions which exhibited strong concentration dependent cytotoxicity (P <0.05). Cytotoxicity of unloaded SLNs in both assays were minimal and similar to ASL loaded SLNs where obtained data had no significant difference (P >0.05). Discussion: High entrapment efficiency was achievable due to high solubility of ASL in lipid matrix which was desirable for this study. Irritancy potential on HUVEC was remarkably reduced when ASL was incorporated into SLN, possibly due to avoiding interaction of ASL with endothelial cells by controlled release profile of SLN and incorporation of ASL into the biocompatible SLN system. Conclusions: ASL incorporated into GMS-SLN coated with Poloxamer 188 showed promising results with potential to reduce incidence of phlebitis by preventing contact and reducing interaction between irritant, ASL and endothelial cells. Further investigation of physical stability of SLNs is required.