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<p>Glioblastoma is an aggressive brain tumor with limited treatment efficacy due to poor blood–brain barrier (BBB) penetration and intrinsic resistance. Temozolomide (TMZ), the frontline chemotherapeutic, undergoes rapid hydrolysis at physiological pH, with low systemic bioavailability and efflux-mediated clearance. To address this, we developed chitosan-coated pH-sensitive liposomes (SpH-TMZ-CS-LIPO) that were optimized via Box–Behnken design, achieving 223.48 ± 1.93 particle size, 35.72 ± 0.51 zeta potential, and 78.85 ± 2.62% entrapment. The formulation exhibited pH-sensitive release, with cumulative TMZ release of 92–94% at pH 4.5–5.5, following diffusion-controlled kinetics. <i>Ex vivo</i> permeation across goat nasal mucosa at pH 5.5 showed a 1.39-fold increase in TMZ flux compared to Free TMZ, while mucin adsorption studies demonstrated superior mucoadhesion. In U87MG cells, SpH-TMZ-CS-LIPO showed 4.6-fold higher uptake than Free TMZ and markedly enhanced cytotoxicity, reducing viability to 3.92 ± 1.56% (IC<sub>50</sub>: 0.396 ± 0.105&#xa0;µg/mL; &gt; 33-fold improvement), reflecting improved intracellular delivery and pH-responsive release. Following intranasal administration in rats, it reached a C<sub>max</sub> of 260.82 ± 9.21&#xa0;µg/mL in the brain and a brain AUC<sub>₀₋∞</sub> of 12,720.42 ± 252.44&#xa0;µg/mL* h, &gt; 22-fold higher than Free TMZ, with prolonged cerebral residence (MRT<sub>₀₋∞</sub>: 36.52&#xa0;h, t<sub>₁/₂</sub>: 24.80&#xa0;h) and high nose-to-brain targeting (DTI: 17.72; DTE: 177.2%; DTP: 94.3%). These effects reflect pH-sensitive CHEMS-mediated release and CS-induced mucoadhesion, ensuring optimized CNS accumulation with minimal systemic exposure. Overall, SpH-TMZ-CS-LIPO represents a rationally engineered, non-invasive nanocarrier that markedly enhances TMZ delivery, cytotoxicity, and brain-targeting efficiency, offering a promising strategy for glioblastoma therapy.</p> Graphical Abstract <p></p>

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DoE-Optimized Chitosan-Coated pH-Sensitive Liposomes for Targeted Nose-to-Brain Delivery of Temozolomide

  • 期刊论文

  • 发表日期：

    2026年4月14日

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  • Ashish Jain,
  • Harsh P. Nijhawan,
  • Khushwant S. Yadav

摘要

Glioblastoma is an aggressive brain tumor with limited treatment efficacy due to poor blood–brain barrier (BBB) penetration and intrinsic resistance. Temozolomide (TMZ), the frontline chemotherapeutic, undergoes rapid hydrolysis at physiological pH, with low systemic bioavailability and efflux-mediated clearance. To address this, we developed chitosan-coated pH-sensitive liposomes (SpH-TMZ-CS-LIPO) that were optimized via Box–Behnken design, achieving 223.48 ± 1.93 particle size, 35.72 ± 0.51 zeta potential, and 78.85 ± 2.62% entrapment. The formulation exhibited pH-sensitive release, with cumulative TMZ release of 92–94% at pH 4.5–5.5, following diffusion-controlled kinetics. Ex vivo permeation across goat nasal mucosa at pH 5.5 showed a 1.39-fold increase in TMZ flux compared to Free TMZ, while mucin adsorption studies demonstrated superior mucoadhesion. In U87MG cells, SpH-TMZ-CS-LIPO showed 4.6-fold higher uptake than Free TMZ and markedly enhanced cytotoxicity, reducing viability to 3.92 ± 1.56% (IC50: 0.396 ± 0.105 µg/mL; > 33-fold improvement), reflecting improved intracellular delivery and pH-responsive release. Following intranasal administration in rats, it reached a Cmax of 260.82 ± 9.21 µg/mL in the brain and a brain AUC₀₋∞ of 12,720.42 ± 252.44 µg/mL* h, > 22-fold higher than Free TMZ, with prolonged cerebral residence (MRT₀₋∞: 36.52 h, t₁/₂: 24.80 h) and high nose-to-brain targeting (DTI: 17.72; DTE: 177.2%; DTP: 94.3%). These effects reflect pH-sensitive CHEMS-mediated release and CS-induced mucoadhesion, ensuring optimized CNS accumulation with minimal systemic exposure. Overall, SpH-TMZ-CS-LIPO represents a rationally engineered, non-invasive nanocarrier that markedly enhances TMZ delivery, cytotoxicity, and brain-targeting efficiency, offering a promising strategy for glioblastoma therapy.

Graphical Abstract