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Intranasal Delivery of Piceatannol-Loaded Liposomes for Glioblastoma Management: Formulation Optimization, In Vitro, Ex Vivo, In Ovo and LC-MS/MS- Based In Vivo Pharmacokinetic and Brain Distribution Assessment
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DOI：10.1007/s12668-026-02757-5.png)
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Abstract
En 中文
Passion fruit (Passiflora edulis) contains piceatannol (PIC), a bioactive stilbene with potential anticancer and antiangiogenic potential via vascular endothelial growth factor (VEGF) inhibition. Glioblastoma multiforme (GBM) is a highly aggressive and vascularized brain tumor with poor prognosis, where VEGF-mediated angiogenesis plays a critical role. Despite the therapeutic advantages of PIC, its clinical translation is restricted by poor solubility and suboptimal brain bioavailability. In this study, a pH-sensitive PIC-loaded liposomes for intranasal (IN) delivery was developed to enhance nose-to-brain (N2B) transport of PIC. The optimized PIC-loaded liposomes (PIC-LPO) depicted a size and PDI of 112 ± 0.80 nm and 0.15 ± 0.006 respectively, portraying uniformity and suitability for IN delivery. Cholesteryl hemisuccinate (CHEMS) imparted pH sensitivity, portraying a biphasic release pattern characterized by an initial rapid followed by controlled drug release. In vitro anticancer efficacy was assessed via 2D cell culture and 3D tumor spheroid models, which demonstrated improved cytotoxicity (1.31-fold), cellular uptake, and tumor spheroid reduction compared to free PIC. Ex vivo nasal toxicity studies confirmed good biocompatibility showing no structural damage to the epithelium. Antiangiogenic potential was validated through hen’s egg chorioallantoic membrane (HET-CAM) assay and VEGF immunofluorescence studies in C6 cells which revealed marked inhibition of neovascularization and VEGF expression. Pharmacokinetic (PK) analysis after IN administration showed a 2.88-fold increase in drug targeting efficiency (%DTE) and a 1.84-fold increase in direct transport percentage (%DTP) compared with free PIC. Overall, this research establishes PIC-LPO as a safe, non-invasive, and effective strategy to enhance brain delivery and antiangiogenic therapy, highlighting the translational potential of PIC for GBM management.
Keywords:
pH-sensitive liposomes
Glioblastoma
Nose-to-brain delivery
Piceatannol
Pharmacokinetic studies
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