mPEG-PLA micelles for nose-to-brain delivery of crizotinib-heptamethine cyanine dye conjugate for potential treatment of glioblastoma.

Glioblastoma (GBM) is one of the most challenging tumours to treat, with considerable intra- and inter-tumoral heterogeneity and limited treatment options, mainly because of the presence of the blood-brain barrier (BBB). Heptamethine cyanine dyes (HMCDs), such as IR786, have been recently utilised to improve tumour tissue specificity of drugs for treating brain cancers. Their conjugates with drugs such as tyrosine kinase inhibitors (TKIs), which can target multiple pathways aberrantly activated in GBM, provide new avenues for GBM treatment. To improve the therapeutic potential of such drug-dye conjugates and minimise the off-target effects, polymeric micelles prepared using methoxy polyethylene glycol-block-polylactic acid (mPEG-PLA), were developed for encapsulation of a conjugate consisting of ALK inhibitor crizotinib and HMCD IR786 for nose-to-brain (intranasal) delivery. Crizotinib-IR786 micelles were 99.6 ± 9.1 nm in diameter with a zeta potential of 12.8 ± 2.2 mV and average drug loading of 2.9%. On U87MG and KNS42 GBM cell models, crizotinib-IR786 micelles showed comparable cytotoxicity to that of free crizotinib-IR786, and both were significantly more potent than crizotinib alone or crizotinib-only micelles. In a preliminary proof-of-concept trial, the crizotinib-IR786 micelles when administered intranasally to orthotopic GBM mice, demonstrated uptake through the nasal epithelium and accumulated in the GBM tumour, confirming the nose-to-brain delivery pathway. In conclusion, this study demonstrated that the mPEG-PLA micelles can be potentially used as a suitable delivery vehicle for nose-to-brain delivery of crizotinib-IR786 for the treatment of GBM. The promising in vivo preliminary proof-of-concept warrants further detailed in vivo efficacy studies.