Gallic Acid Loaded Pluronic F127 Polymeric Micelles For Glioma Therapy: A Novel Approach For Brain Cancer Treatment

Abstract

 Glioblastoma multiforme (GBM) represents the most aggressive and prevalent form of primary malignant brain tumors in adults, accounting for approximately 45% of all brain malignancies with a dismal median survival of 15 months and 5-year survival rate below 5%. The complex pathophysiology of GBM, characterized by highly invasive tumor cells, extensive neovascularization, and resistance to conventional therapies, presents formidable therapeutic challenges. The blood-brain barrier (BBB), a highly selective semipermeable membrane barrier, significantly restricts the penetration of therapeutic agents into brain tissue, limiting the efficacy of systemic chemotherapy. Current treatment modalities, including surgical resection, radiotherapy, and temozolomide chemotherapy provide only marginal survival benefits, necessitating the urgent development of innovative therapeutic strategies.

Keywords: Glioblastoma multiforme, Pluronic F127, Gallic acid, Polymeric micelles, Blood-brain barrier, Nanomedicine, Drug delivery, Brain cancer, Nanocarriers, Targeted therapy

Background: Glioblastoma multiforme (GBM) represents the most aggressive and prevalent form of primary malignant brain tumors in adults, accounting for approximately 45% of all brain malignancies with a dismal median survival of 15 months and a 5-year survival rate below 5%. The complex pathophysiology of GBM, characterized by highly invasive tumor cells, extensive neovascularization, and resistance to conventional therapies, presents formidable therapeutic challenges. The blood-brain barrier (BBB), a highly selective semipermeable membrane barrier, significantly restricts the penetration of therapeutic agents into brain tissue, limiting the efficacy of systemic chemotherapy. Current treatment modalities including surgical resection, radiotherapy, and temozolomide chemotherapy provide only marginal survival benefits, necessitating the urgent development of innovative therapeutic strategies.

Rationale: Gallic acid (3,4,5-trihydroxybenzoic acid), a naturally occurring phenolic compound abundant in plants such as Terminalia chebula, green tea, and oak bark, has emerged as a promising anticancer agent with demonstrated efficacy against various malignancies. Its mechanisms of action include induction of apoptosis through mitochondrial dysfunction, cell cycle arrest at G2/M phase, inhibition of angiogenesis, and modulation of key signaling pathways including PI3K/Akt and NF-κB. However, the clinical translation of gallic acid is severely hampered by its poor aqueous solubility (1.2 mg/mL at 25°C), rapid systemic clearance (t½ = 1.7 hours), extensive first-pass metabolism, and minimal brain bioavailability (<2% of administered dose). These pharmacokinetic limitations underscore the critical need for advanced drug delivery systems to optimize gallic acid's therapeutic potential in glioma treatment.

Objective: This comprehensive study aimed to develop, optimize, and characterize gallic acid-loaded Pluronic F127 polymeric micelles as an innovative nanocarrier system for enhanced brain tumor targeting and improved glioma therapy. The specific objectives included: (1) formulation optimization, (2) comprehensive physicochemical characterization, (3) evaluation of drug release kinetics, (4) assessment of in vitro anticancer efficacy, (5) investigation of blood-brain barrier permeability enhancement, and (6) elucidation of cellular uptake mechanisms.

Methods: GA- loaded Pluronic F127 micelles were systematically developed using the cold dispersion method with formulation optimization based on varying drug-to-polymer ratios (1:9 to 1:4 w/w). The optimized formulation (1:4 ratio) was selected based on key physicochemical attributes including minimal particle size, uniform distribution, and enhanced colloidal stability. Comprehensive characterization was performed using dynamic light scattering (DLS) for particle size and zeta potential, which revealed a mean size of 65.4±2.3 nm, PDI of 0.164±0.0005, and zeta potential of -34.4±1.2 mV. Fourier-transform infrared spectroscopy (FTIR) confirmed successful drug incorporation and absence of chemical incompatibility. Drug loading and encapsulation were optimized, and in vitro drug release was assessed under physiological condition (pH 7.4, 37℃), demonstrating sustained release behavior. Cytotoxic potential was evaluated via MTT assay on U87-MG human glioblastoma cells, revealing a significant dose dependent anticancer effect with IC₅₀ 15.77±0.13 µg/mL. Enhanced therapeutics efficacy was attributed to improved solubility, cellular uptake, and protection of gallic acid from premature degradation. Morphological changes consistent with apoptosis were observed post-treatment. These finding underscore the potential of GA-loaded Pluronic F127 micelles as a promising nanocarriers platform for glioma therapy, warranting further investigation in in vivo and blood brain barrier models.