Brain Targeting of Temozolomide via the Intranasal Route Using Lipid-Based Nanoparticles: Brain Pharmacokinetic and Scintigraphic Analyses

替莫唑胺 鼻腔给药 药代动力学 药理学 固体脂质纳米粒 医学 脑瘤 胶质母细胞瘤 化学 药品 癌症研究 病理
作者
Anam Khan,Syed Sarim Imam,Mohd. Aqil,Abdul Ahad,Yasmin Sultana,Asgar Ali,Khalid Mohammed Khan
出处
期刊:Molecular Pharmaceutics [American Chemical Society]
卷期号:13 (11): 3773-3782 被引量:124
标识
DOI:10.1021/acs.molpharmaceut.6b00586
摘要

The aim of the present work was to investigate the efficacy of temozolomide nanostructured lipid carriers (TMZ-NLCs) to enhance brain targeting via nasal route administration. The formulation was optimized by applying a four-factor, three-level Box-Behnken design. The developed formulations and the functional relationships between their independent and dependent variables were observed. The independent variables used in the formulation were gelucire (X1), liquid lipid/total lipid (X2), Tween 80 (X3), and sonication time (X4), and their effects were observed with regard to size (Y1), % drug release (Y2), and drug loading (Y3). The optimized TMZ-NLC was further evaluated for its surface morphology as well as ex vivo permeation and in vivo studies. All TMZ-NLC formulations showed sizes in the nanometer range, with high drug loading and prolonged drug release. The optimized formulation (TMZ-NLCopt) showed an entrapment efficiency of 81.64 ± 3.71%, zeta potential of 15.21 ± 3.11 mV, and polydispersity index of less than 0.2. The enhancement ratio was found to be 2.32-fold that of the control formulation (TMZ-disp). In vivo studies in mice showed that the brain/blood ratio of TMZ-NLCopt was found to be significantly higher compared to that of TMZ-disp (intranasal, intravenous). Scintigraphy images of mouse brain showed the presence of a high concentration of TMZ. The AUC ratio of TMZ-NLCopt to TMZ-disp in the brain was the highest among the organs. The findings of this study substantiate the existence of a direct nose-to-brain delivery route for NLCs.
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