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

Abstract

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 (X), liquid lipid/total lipid (X), Tween 80 (X), and sonication time (X), and their effects were observed with regard to size (Y), % drug release (Y), and drug loading (Y). 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.

HPLC–UV method for temozolomide determination in complex biological matrices: Application for in vitro, ex vivo and in vivo studies

“…The results showed that intranasal administration of TMZ‐NLCs in rats was efficient to maintain the effect of TMZ with higher brain concentrations owing to direct brain targeting and increased residence time of the drug in the brain as compared with intranasal TMZ dispersion. These results illustrate the potential of the nose‐to‐brain delivery route for nanoparticles for the treatment of brain tumors (Khan et al, ). Nevertheless, during pharmaceutical development, it is essential to use an adequate methodology for drug determination in analytical or bioanalytical assays, with an accurate quantification of the compounds of interest (Baptista, Oliveira, & Ferreira, ; Yazbi, Hassan, Khamis, Ragab, & Hamdy, ).…”

“…However, there are some drawbacks that compromise TMZ treatment efficacy, such as its short half‐life (Ostermann et al, ). This requires the administration of high systemic doses to achieve therapeutic levels in the brain, leading to side effects such as headaches, nausea, bone marrow depression, oral ulcerations and even aplastic anemia (Khan et al, ; Trinh et al, ). As an alternative to new therapies, the nasal route can be considered for TMZ delivery to the CNS, thereby avoiding the interference of first pass metabolism; additionally, this is an easy and non‐invasive route of administration, contributing to patient adherence and high‐efficiency treatment (Bahadur & Pathak, ; Fonseca et al, ).…”

Complexation and enhancement of temozolomide solubility with cyclodextrins

“…It is used as an oral cytotoxic agent for adjuvant chemotherapy in malignant primary brain tumors such as glioblastoma (Stupp et al, 2005) and malignant glioma (glioblastoma multiforme and anaplastic astrocytoma) (Brada et al, 1999;Marchesi et al, 2007). The drug contains an imidazole group connected to a tetrazole ring ( Figure 1) (Khan et al, 2016). Due to its relatively high cytotoxicity for cancer cells, TMZ is commonly preferred by clinicians (Payne, Pratap, Middleton, 2005).…”

Ziprasidone Hydrochloride Loaded Nanostructured Lipid Carriers (Nlcs) for Intranasal Delivery: Optimization and in Vivo Studies

“…The observed higher flux may be attributed to the presence of permeation enhancing surfactants in ZRS-NLC. Moreover, the relatively higher lipophilicity of ZRS allows significantly better permeation through the nasal mucosa [30].…”