Hyaluronic Acid-Decorated Glycol Chitosan Nanoparticles for pH-Sensitive Controlled Release of Doxorubicin and Celecoxib in Nonsmall Cell Lung Cancer.

ABSTRACT

Nonsmall cell lung cancer (NSCLC) is a leading cause of global cancer mortality. Recently, combinatorial treatment approaches have shown promise as they better address tumor heterogeneity. However, drug pharmacokinetics and tissue distribution differences remain problematic. To overcome these issues and improve therapeutic efficacies, the use of nanomedicines has been suggested. We devised a CD44 receptor target hyaluronic acid (HA)-decorated glycol chitosan (GC) nanoparticle which is conjugated to doxorubicin (DOX) by a pH-sensitive linker and coloaded celecoxib (CXB; HA-GC-DOX/CXB). Successful chemical conjugation of GC to DOX was confirmed and HA-GC-DOX/CXB showed ∼150 nm of uniform spherical shape. HA-GC-DOX/CXB were stable at pH 7.4 but steadily increased in size and released drugs at pH 6.0 and 4.0. In vitro NSCLC cells showed that DOX and CXB combination therapy has synergism in both free drug and nanoparticle formulation. In vivo NSCLC xenograft mice showed DOX and CXB exhibited a synergistic tumor suppressive effect in HA-GC-DOX/CXB. Furthermore, HA-GC-DOX/CXB dramatically inhibited tumor growth compared to other treatments as well as suppressed inflammation and metastasis-related gene/protein in the tumor tissues. Our findings demonstrate HA-GC-DOX/CXB is a potential anticancer therapy that controlled release under acidic tumor microenvironments and enhanced CD44 overexpressed tumor target efficacy.