Development of CD44-Targeted Hyaluronic Acid-Coated Lipid Nanoparticles for the Delivery of Triptolide Against Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by rapid progression, therapeutic resistance, dense stromal barriers, and poor drug delivery. Triptolide possesses potent anticancer activity but its therapeutic application is limited by poor aqueous solubility, restricted bioavailability, nonspecific distribution, and systemic toxicity. The present study aimed to develop CD44-targeted hyaluronic acid (HA)-coated lipid nanoparticles for improving the delivery and anticancer efficacy of triptolide against PDAC. Triptolide-loaded lipid nanoparticles were prepared and optimized using formulation and process variables, followed by HA surface coating for CD44-mediated targeting. The optimized formulation was characterized for particle size, polydispersity index, zeta potential, encapsulation efficiency, morphology, stability, and in vitro drug release. Cellular uptake, cytotoxicity, apoptosis, cell-cycle progression, migration, invasion, and molecular signaling were subsequently evaluated in PDAC cells. In vivo antitumor efficacy, biodistribution, pharmacokinetic behavior, and systemic safety were also investigated. The optimized nanoparticles demonstrated favorable nanoscale characteristics, high drug encapsulation, sustained release, and satisfactory stability. HA-coated nanoparticles exhibited enhanced cellular uptake, while CD44-targeted nanoparticles produced the greatest uptake and cytotoxicity. Targeted treatment promoted ROS generation, mitochondrial dysfunction, apoptosis, and cell-cycle arrest while suppressing EMT, MMP-2/MMP-9, PI3K/AKT/mTOR, NF-κB, and STAT3 signaling. In vivo, targeted nanoparticles enhanced tumor accumulation and tumor growth inhibition with limited systemic toxicity. Collectively, CD44-targeted HA-coated lipid nanoparticles represent a promising strategy for enhancing triptolide delivery and therapeutic efficacy against PDAC.