Cisplatin-Cross-Linked and Oxygen-Resupply Hyaluronic Acid-Based Nanocarriers for Chemo-photodynamic Therapy

Tumor microenvironment (TME) is known to play a critical role in cancer progression and contributes to treatment failure or success. Herein, a versatile nanoplatform [HAFOE-Ce6/Pt-NPs(O2)] with cisplatin (Pt) cross-linking, chlorin e6 (Ce6) loading, pH sensitivity, active targeting, and oxygen resupply was developed to address this problem. This nanosystem presents as a spherical shape with a small size of 175.4 ± 2.16 nm and a negative charge of −25.32 ± 3.04 mV. Hyaluronic acid (HA) as the starting material not only improved the biocompatibility of the nanosystem but also enhanced cellular uptake by targeting the CD44 receptor. Interestingly, cisplatin could serve as both a cross-linker and anticarcinogen to increase the blood stability and therapeutic performance. Additionally, the micelles disintegration and drug release could be accelerated by the cleavage of ortho ester at low pH. More importantly, the fluorocarbon inside the particles has the ability to load oxygen and in situ release oxygen at tumor regions, which greatly reduced tumor hypoxia. In vitro and in vivo results demonstrated that HAFOE-Ce6/Pt-NPs(O2) could efficiently inhibit tumor growth by combined chemo-photodynamic therapy under 660 nm laser irradiation by way of oxygen sensitization, leading to a high mice survival rate (83.33%). Overall, this combined nanosystem could take advantage of TME while overcoming its disadvantages and was an efficient nanoplaform for cancer treatment.