Docetaxel and quercetin-loaded lipid nanocarrier optimized by quality by design for glioblastoma therapy: a ligand-conjugated and therapeutic repurposing approach

This study aimed to develop transferrin (Tf)-conjugated nanostructured lipid carrier (NLC) co-loaded with docetaxel (DTX) and quercetin (QUR) for brain delivery via intranasal route as glioblastoma multiforme (GBM) therapy. Molecular docking showed strong binding affinities of DTX and QUR to β-tubulin and PI3K, with docking scores of −7.134/−6.055 kcal/mol and −11.787/−12.830 kcal/mol, respectively. Synergistic effects were confirmed through MTT assay on U87-MG cells. NLCs were prepared using modified emulsiosonication method and optimized via central composite rotatable design, followed by Tf conjugation using carbodiimide chemistry. Optimized NLCs exhibited globule size < 200 nm, a polydispersity index ≡ 0.2, zeta potential between −5 and −25 mV, and entrapment efficiency > 85%. Compared to non-conjugated NLC and (DTX-QUR) suspension (SUS), Tf-(DTX-QUR) NLC showed 3.6- and 5.8-fold decrease in IC50, respectively. Cellular uptake studies demonstrated significantly (***p < 0.001) high internalization of Tf-conjugated NLC to U87-MG cells. In vitro release and permeability studies showed 2.8–3.5-fold increase in the release and permeation of the drugs in comparison to (DTX-QUR) SUS. Notably, the nasal ciliotoxicity study indicated no toxicity to the nasal tissues. The results suggested that Tf-conjugated NLC provides a promising noninvasive method for enhancing the delivery of combination, which may improve the effectiveness of GBM treatment.