QBD-DRIVEN DEVELOPMENT OF HYALURONIC ACID-CHITOSAN SURFACE-FUNCTIONALIZED NANOSTRUCTURED LIPID CARRIERS FOR TARGETED DELIVERY OF RESVERATROL IN NON-SMALL CELL LUNG CANCER

Abstract

Background: Resveratrol (RSV) has a high anticancer potential in non-small cell lung cancer (NSCLC); however, its poor aqueous solubility, high first-pass metabolism and insufficient tumour targeting limit its clinical application.The purpose of this work was to design surface-functionalized nanostructured lipid carriers (NLCs) as a targeted pulmonary delivery system to increase intracellular delivery and therapy effect of resveratrol.

Method: A sequential hybrid Quality-by-Design (QbD) involving Plackett-Burman screening and Box-Behnken optimization, was adopted to determine important formulation variables affecting particle size, polydispersity index, encapsulation efficiency, and drug loading. The optimized NLCs were surface-functionalized by electrostatic deposition of chitosan (CS) and hyaluronic acid (HA), to facilitate active targeting to CD44 receptors that are overexpressed on NSCLC cells.MTT assay and cell uptake studies  using fluorescence microscopy were used to evaluate the antiproliferative activity and cellular internalization of drug loaded NLCs into A549 cells respectively.

Results: Optimized NLCs had the following characteristics: particle size of 76.23 nm, encapsulation efficiency of > 90%, and drug loading of 16.30%. In vitro release experiments showed a biphasic, diffusion-controlled profile at pH 4.5. IC₅₀ decreased progressively from 38.916 µM (free RSV) to 20.67 µM (RSV-NLCs) and 15.22 µM (HA-CS/RSV-NLC). Fluorescence experiments proved an increased internalization of HA-CS/RSV-NLC compared to non-functionalized ones.

Conclusion: Surface-functionalized NLCs showed better intracellular delivery and therapeutic efficacy, thus providing a promising platform of targeted pulmonary delivery of resveratrol to treat CD44-overexpressing NSCLC.