Quercetin liposomes conjugated with hyaluronidase: An efficient drug delivery system to block pancreatic cancer
Ge Sun, Ying Wu, Jiekai Li, Mingjie Yang, Hang Xu, Yi‐Ping Li, Peilin Tong, Rong Shao, Yingbin Liu, Xianming Kong
Abstract
Pancreatic cancer characterized with intense hydraulic tissue in tumor extracellular matrix (ECM) resists most of chemotherapeutic drugs. Increased levels of hyaluronic acid (HA) represent the primary component of the hydraulic tissue, rendering tumors protective from drug targeting. Quercetin (Que), a natural flavonoid, has the ability to inhibit tumor cell growth in a number of cancers; however, its poor water solubility and low bioavailability largely limit its application in cancer therapy. Hence, we developed an efficient drug delivery system by encapsulation of Que. into liposomes and conjugation with hyaluronidase (HAase) at liposome surface, termed as HQL. In the presence of HAase, HQL were predominantly accumulated at tumor with enhanced permeability and retention effect. Treatment of xenografted tumor mice with HQL gave rise to suppressed tumor growth, while no toxic effects were observed in mice. HQL demonstrated the strong ability to inhibit cell proliferation, promote cell apoptosis, and induce arrest at G2/M cell cycle in pancreatic cancer lines, three-dimensional cultured cell spheroids and pancreatic ductal adenocarcinoma (PDAC)-derived organoids. Mechanistically, HQL downregulated expression of cell cycle-associated protein (CCNB1, CDK1 and PLK1) and cell apoptosis-associated factors PI3K/AKT and Bcl-2. In summary, HQL degraded HA in the tumor microenvironment to enhance nano-particle penetration and inhibited tumor cell growth, eliciting efficacy of anti-tumor therapy. Thereof, HQL may provide a novel efficient drug delivery approach for the adjuvant treatment of pancreatic cancer. • Develop an efficient drug delivery system by encapsulation of Que. into liposomes and conjugation with hyaluronidase (HAase) at liposome surface. • HQL has good encapsulation efficiency and sustained release ability. • Determine effects of the drug carrying materials on cultured cells and two models with 3D cell spheres and organoids in vitro. • Demonstrate that HQL are mainly accumulated at the tumor site and exhibit enhanced permeability and retention with no evident side effects. • HQL display a strong inhibition of cell proliferation, promotion of apoptosis and G2/M cell cycle arrest.