Targeted Delivery of Tetrahydrocurcumin using VEGF-conjugated Polymeric Micelles for Glioblastoma Therapy

Introduction: Tetrahydrocurcumin (THC) is a potent curcuminoid with anticancer potential. However, its poor solubility and low bioavailability are limiting its therapeutic application as an anticancer molecule against glioblastoma multiforme (GBM). In this context, a vascular endothelial growth factor (VEGF)-conjugated polymeric diblock poly (ethylene glycol)-b-poly (L-glutamic acid) (PEG-PGA) micellar-loaded THC drug was developed to improve the anti-tumor efficacy of THC against glioblastoma. Methods: Methoxy-poly (ethylene glycol)-b-poly (γ-benzyl L-glutamate) (MeO-PEG-PBLG) block copolymers were used to synthesize THC-entrapped micelles. The THC-entrapped micelles were subsequently conjugated with VEGF ligands. Cytotoxicity and cellular uptake were evaluated in U87MG glioblastoma cells using MTT assay, confocal microscopy, and flow cytometry. In vivo pharmacokinetic, tumour accumulation, and antitumor efficacy studies were performed in U87MG xenografted Swiss albino mice. Results: The study demonstrates that the polymeric micelles developed have an average diameter of 100 ± 20 nm, with an encapsulation efficiency of THC of 76.5%. The cellular uptake studies demonstrated that micelles conjugated with VEGF have a 3.5-fold increase in internalisation compared to unconjugated micelles. Furthermore, the in vivo results exhibited prolonged plasma retention and significantly enhanced tumour accumulation of VEGF-conjugated micelles compared to native THC and non-targeted micelles. Tumour growth inhibition assay revealed that the ligand-conjugated micellar has higher antitumor efficacy. Discussion: The VEGF-conjugated micelles targeting strategy effectively enhanced tumour selectivity and intracellular uptake of THC by exploiting VEGFR1 overexpression in GBM cells. The ligand conjugation stimulated receptor-mediated transcytosis and improved THC distribution across the tumour vasculature. This approach demonstrated a promising method overcoming the blood-brain barrier limitations and enhancing the therapeutic value of hydrophobic phytochemicals in glioblastoma treatment. Conclusion: VEGF-conjugated polymeric micelles significantly improved the solubility, bioavailability, and tumour-targeted delivery of tetrahydrocurcumin (THC).