β-cyclodextrin-modified carboxymethyl chitosan/hyaluronic acid-based crosslinked composite nanogels as a dual responsive carrier for targeting anti-tumor therapy

Advanced nanosized drug delivery systems can significantly improve efficacy and safety of first-line chemotherapeutics by enhancing tumor targeting. Herein, one-pot covalent crosslinking approach was developed to generate biodegradable tumor-targeted composite Nanogels from carboxymethyl chitosan, hyaluronic acid, cystamine and 6-ethylene-diamine-6-deoxy-β-cyclodextrin loaded with doxorubicin (DOX) for controlled intracellular DOX release. The optimized synthetic procedures generated Nanogels of about 190 nm in size and 28.3 % drug loading capability. DOX-loaded Nanogels was effectively internalized into tumor cells mainly by CD44 receptor-mediated endocytosis and rapidly released DOX in response to the high level of GSH in cytoplasm and acidic intracellular environments. DOX-loaded Nanogels significantly inhibited the tumor growth especially without appreciable side toxicities in 4 T1 tumor-bearing mice model owing to CD44 receptor-mediated active targeting and the passive targeting of Nanogels by enhanced permeation and retention effect. Overall, our newly developed composite Nanogels might be employed as a potentially effective therapeutic strategy for tumor therapy.