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Purpose <p>To develop and optimize a Quality-by-Design (QbD)-based, colon-directed oral delivery system of 5-fluorouracil (5-FU) using hyaluronic acid (HA)-decorated chitosan nanoparticles encapsulated in dual-coated hard gelatin capsules, with potential HA-CD44 receptor interaction.</p> Methods <p>5-FU-loaded HA–chitosan nanoparticles were prepared by inverse ionic gelation and optimized using a three-factor Box–Behnken design. Critical quality attributes included particle size, zeta potential, and entrapment efficiency. The optimized nanoparticles were characterized by DLS, FTIR, PXRD, SEM, and TEM. In vitro drug release was evaluated at pH 5.0 and 7.4, followed by ex vivo permeation across isolated rat colon. Freeze-dried nanoparticles were filled into size “0” capsules and sequentially coated with HPMC/Eudragit E100 (inner layer) and Eudragit S100 (outer layer). pH-change dissolution testing and accelerated stability studies (40&#xa0;°C/75% RH, 6 months) were performed.</p> Results <p>The optimized nanoparticles exhibited a mean size of 220.5&#xa0;nm, PDI 0.088 (<i>n</i> = 3), zeta potential − 13.46 mV, and entrapment efficiency 67.89%. Release was pH-dependent, with faster and nearly complete release at pH 5.0 and sustained release at pH 7.4. Ex vivo studies demonstrated controlled permeation across colonic tissue. Dual-coated capsules resisted gastric and intestinal media and released ~ 95–100% drug at pH 7.2–7.4. Stability studies showed minimal drug loss and similar dissolution profiles (f₂ = 82.37).</p> Conclusion <p>The engineered nanoparticle-in-capsule platform integrates HA-mediated surface functionalization with pH-triggered colonic release, offering a promising colon-directed oral delivery platform for 5-FU. However, further in vitro studies using colon cancer cell lines are required to confirm CD44-mediated uptake, cytotoxic efficacy, and tumor-selective performance.</p> Graphical Abstract <p></p>

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QbD-Optimized CD44-Targeted Hyaluronic Acid Chitosan Nanoparticles in Dual pH-Responsive Capsules for Colon-Directed Oral Delivery of 5-Fluorouracil

  • 期刊论文

  • 发表日期：

    2026年7月6日

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  • Yash D. Dudhwala,
  • Dhiren P. Shah,
  • Riya K. Mehta,
  • Devesh U. Kapoor

摘要

Purpose

To develop and optimize a Quality-by-Design (QbD)-based, colon-directed oral delivery system of 5-fluorouracil (5-FU) using hyaluronic acid (HA)-decorated chitosan nanoparticles encapsulated in dual-coated hard gelatin capsules, with potential HA-CD44 receptor interaction.

Methods

5-FU-loaded HA–chitosan nanoparticles were prepared by inverse ionic gelation and optimized using a three-factor Box–Behnken design. Critical quality attributes included particle size, zeta potential, and entrapment efficiency. The optimized nanoparticles were characterized by DLS, FTIR, PXRD, SEM, and TEM. In vitro drug release was evaluated at pH 5.0 and 7.4, followed by ex vivo permeation across isolated rat colon. Freeze-dried nanoparticles were filled into size “0” capsules and sequentially coated with HPMC/Eudragit E100 (inner layer) and Eudragit S100 (outer layer). pH-change dissolution testing and accelerated stability studies (40 °C/75% RH, 6 months) were performed.

Results

The optimized nanoparticles exhibited a mean size of 220.5 nm, PDI 0.088 (n = 3), zeta potential − 13.46 mV, and entrapment efficiency 67.89%. Release was pH-dependent, with faster and nearly complete release at pH 5.0 and sustained release at pH 7.4. Ex vivo studies demonstrated controlled permeation across colonic tissue. Dual-coated capsules resisted gastric and intestinal media and released ~ 95–100% drug at pH 7.2–7.4. Stability studies showed minimal drug loss and similar dissolution profiles (f₂ = 82.37).

Conclusion

The engineered nanoparticle-in-capsule platform integrates HA-mediated surface functionalization with pH-triggered colonic release, offering a promising colon-directed oral delivery platform for 5-FU. However, further in vitro studies using colon cancer cell lines are required to confirm CD44-mediated uptake, cytotoxic efficacy, and tumor-selective performance.

Graphical Abstract