Redox-responsive engineered hybrid nanomedicine for gallbladder cancer therapy via hyaluronic acid depletion

Abstract

Gallbladder cancer (GBC) is a highly fatal and most common biliary tract cancer for which there is no uniform chemotherapy regimen at present. Although several chemotherapy regimens are currently being examined in clinical trials, they are limited by the high systemic toxicity and low drug delivery efficiency. Based on the characteristics of the tumor microenvironment of GBC tumors that it is rich in hyaluronic acid (HA), herein, we design a paclitaxel (PTX)-loaded organosilica hybrid nanocarrier (named as PTX@PDHNs-HAase) modified with hyaluronidase (HAase), aiming to enhance the delivery and therapeutic efficiency of PTX in GBC tumors. Once the nanocarrier reaches the tumor site through the enhanced permeability and retention effect, HAase loaded onto the nanocarrier will degrade the excess HA presented at the GBC tumor site to cause its depletion, thereby softening the hard extracellular matrix (ECM) and facilitating further penetration of nanomedicine into the GBC tumor cells and releasing PTX under glutathione (GSH) stimulation to accomplish the chemotherapeutic effect. More importantly, PTX@PDHNs-HAase not only presents excellent therapeutic effect in vivo (tumor inhibition rate: 88.6%), but also reduces the systemic toxicity of PTX. To the best of our knowledge, this is the first exploration of the strategy to enhance the efficacy of chemotherapeutic agent for GBC tumor therapy by degrading HA to dismantle ECM for enhanced nanomedicine delivery, thus providing a promising paradigm for GBC treatment.