Development and characterization of sorafenib-loaded lipid nanocapsules for the treatment of glioblastoma

Anne Clavreul,Emilie Roger,Milad Pourbaghi-Masouleh,Laurent Lemaire,Clément Tétaud,Philippe Menei

doi:10.1080/10717544.2018.1507061

Abstract

Anticancer agents that target both tumor cells and angiogenesis are of potential interest for glioblastoma (GB) therapy. One such agent is sorafenib (SFN), a tyrosine kinase inhibitor. However, poor aqueous solubility and undesirable side effects limit its clinical application, including local treatment. We encapsulated SFN in lipid nanocapsules (LNCs) to overcome these drawbacks. LNCs are nanocarriers formulated according to a solvent-free process, using only components that have received regulatory approval. SFN-LNCs had a diameter of 54 ± 1 nm, high encapsulation efficiency (>90%), and a drug payload of 2.11 ± 0.03 mg/g of LNC dispersion. They inhibited in vitro angiogenesis and decreased human U87MG GB cell viability similarly to free SFN. In vivo studies showed that the intratumoral administration of SFN-LNCs or free SFN in nude mice bearing an orthotopic U87MG human GB xenograft decreased the proportion of proliferating cells in the tumor relative to control groups. SFN-LNCs were more effective than free SFN for inducing early tumor vascular normalization, characterized by increases in tumor blood flow and decreases in tumor vessel area. These results highlight the potential of LNCs as delivery systems for SFN. The vascular normalization induced by SFN-LNCs could be used to improve the efficacy of chemotherapy or radiotherapy for treating GB.

Highlights

Glioblastoma (GB) is the most frequent, aggressive, and fatal type of brain tumor, with a mean 5-year survival rate of less than 5% (Stupp et al, 2005, 2009)
Signaling pathways initiated by activated receptor tyrosine kinases (RTKs), including those for epidermal growth factor (EGFR), platelet-derived growth factor (PDGFR), or vascular endothelial growth factor (VEGFR), play a key role in the growth, invasiveness, and angiogenesis of this tumor and are attractive therapeutic targets (Chen et al, 2016; Miller & Wen, 2016; Lin et al, 2017)
B-lipid nanocapsules (LNCs) had a mean diameter of 49 ± 1 nm and narrow size distribution (PDI 1⁄4 0.11) (Table 2)

Summary

Introduction

Glioblastoma (GB) is the most frequent, aggressive, and fatal type of brain tumor, with a mean 5-year survival rate of less than 5% (Stupp et al, 2005, 2009). SFN treatment has been shown to be of very limited efficacy in patients with progressive or recurrent GB, either as a monotherapy or in combination with temozolomide or other targeted drugs, such as erlotinib (Reardon et al, 2011; Lee et al, 2012; Den et al, 2013; Peereboom et al, 2013; Zustovich et al, 2013; Hassler et al, 2014; Hottinger et al, 2014) This may be due, in part, to the route of SFN administration. The poor solubility of SFN strongly limits its application for local treatment and this drug is orally administered in the form of SFN tosylate tablets This mode of administration may be effective for peripheral tumors, such as hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer, but less so for brain tumors, due to the low efficiency of SFN passage across the blood-brain barrier (BBB) (Agarwal et al, 2011). Systems for delivering SFN for local or systemic treatment are, Supplemental data for this article can be accessed on the publisher’s website

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Conclusion