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Background <p>Paclitaxel remains a cornerstone chemotherapeutic for solid tumors, yet its clinical utility is hampered by profound hydrophobicity, dose-limiting systemic toxicities, less target tissue accumulation, off-target toxicity, and the development of multidrug resistance.</p> Purpose <p>To address these challenges, we engineered a multifunctional, folate receptor (FRα)-targeted, pH-responsive hybrid polymeric-liposomal nanoplatform designed for enhanced tumor delivery and compared against its passive-targeted counterpart.</p> Method <p>This system integrates a poly(lactic-co-glycolic acid) core for drug encapsulation and sustained release, a lipid bilayer for biocompatibility, stability and better targeting, and a surface-conjugated folate-D-α-tocopheryl polyethylene glycol 1000 succinate ligand for active targeting. Employing a Quality-by-Design approach via Box-Behnken design, the formulation was optimized to achieve critical quality attributes.</p> Results <p>A nano-sized dimension of 284.7&#xa0;nm, high monodispersity 0.043), excellent drug encapsulation (87.6%), and substantial negative zeta potential (-34.5 mV) for colloidal stability. Comprehensive characterization of the formulations, including Particles Sizes, Polydispersity Index, Encapsulation Efficiency, Drug Loading, Zeta Potential, Tyndall Effect, ATFT-IR, ¹H-NMR, DSC, XRD, Contrast Microscopy, HR-TEM, aqueous dispersion test, <i>invitro</i> release study, physiological stability study, release kinetics studies, and <i>invitro</i> cell-line studies confirmed successful fabrication of the active-targeted hybrid nanoparticles which achieved pronounced reduction in IC<sub>50</sub> form 41.67&#xa0;µg/mL (free paclitaxel) to 19.96&#xa0;µg/mL (PTX-THNP), more than 5 folds of florecences intensity, and reduction of live cells to 65.93% over 4&#xa0;h. Comparative in vitro assessment against a passive-targeted counterpart revealed that folate functionalization significantly altered physicochemical properties that have impact on selective toxicity and tumor-targeted concentrations. The platform also demonstrated pronounced pH-responsive drug release, with accelerated kinetics at tumor microenvironment-simulating pH 5.8 compared to physiological pH 7.4, following Fickian diffusion mechanisms. Furthermore, the nanoformulation exhibited exceptional stability under simulated physiological conditions over 24&#xa0;h.</p> Conclusion <p>This study successfully establishes the design, optimization, and thorough in vitro physicochemical characterization of a novel triple-targeted nanoplatform. The promising in vitro performance, including targeted ligand presentation and microenvironment-responsive release, provides a robust foundation and a critical benchmark for subsequent biological evaluation to validate its therapeutic potential.</p> Graphical Abstract <p></p>

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Targeted Delivery of Paclitaxel to Solid Tumors using Folate-Functionalized pH-Sensitive, Hybrid Polymeric Liposomes: Engineering and Evaluating Stimuli-Responsive Nanoplatform for Precision Chemotherapy

  • 期刊论文

  • 发表日期：

    2026年4月29日

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  • Balisa Mosisa Ejeta,
  • Malay K. Das

摘要

Background

Paclitaxel remains a cornerstone chemotherapeutic for solid tumors, yet its clinical utility is hampered by profound hydrophobicity, dose-limiting systemic toxicities, less target tissue accumulation, off-target toxicity, and the development of multidrug resistance.

Purpose

To address these challenges, we engineered a multifunctional, folate receptor (FRα)-targeted, pH-responsive hybrid polymeric-liposomal nanoplatform designed for enhanced tumor delivery and compared against its passive-targeted counterpart.

Method

This system integrates a poly(lactic-co-glycolic acid) core for drug encapsulation and sustained release, a lipid bilayer for biocompatibility, stability and better targeting, and a surface-conjugated folate-D-α-tocopheryl polyethylene glycol 1000 succinate ligand for active targeting. Employing a Quality-by-Design approach via Box-Behnken design, the formulation was optimized to achieve critical quality attributes.

Results

A nano-sized dimension of 284.7 nm, high monodispersity 0.043), excellent drug encapsulation (87.6%), and substantial negative zeta potential (-34.5 mV) for colloidal stability. Comprehensive characterization of the formulations, including Particles Sizes, Polydispersity Index, Encapsulation Efficiency, Drug Loading, Zeta Potential, Tyndall Effect, ATFT-IR, ¹H-NMR, DSC, XRD, Contrast Microscopy, HR-TEM, aqueous dispersion test, invitro release study, physiological stability study, release kinetics studies, and invitro cell-line studies confirmed successful fabrication of the active-targeted hybrid nanoparticles which achieved pronounced reduction in IC50 form 41.67 µg/mL (free paclitaxel) to 19.96 µg/mL (PTX-THNP), more than 5 folds of florecences intensity, and reduction of live cells to 65.93% over 4 h. Comparative in vitro assessment against a passive-targeted counterpart revealed that folate functionalization significantly altered physicochemical properties that have impact on selective toxicity and tumor-targeted concentrations. The platform also demonstrated pronounced pH-responsive drug release, with accelerated kinetics at tumor microenvironment-simulating pH 5.8 compared to physiological pH 7.4, following Fickian diffusion mechanisms. Furthermore, the nanoformulation exhibited exceptional stability under simulated physiological conditions over 24 h.

Conclusion

This study successfully establishes the design, optimization, and thorough in vitro physicochemical characterization of a novel triple-targeted nanoplatform. The promising in vitro performance, including targeted ligand presentation and microenvironment-responsive release, provides a robust foundation and a critical benchmark for subsequent biological evaluation to validate its therapeutic potential.

Graphical Abstract