Acid-sensitive and L61-crosslinked hyaluronic acid nanogels for overcoming tumor drug-resistance

Low intracellular drugs concentration is one of the main representations of multidrug resistance (MDR), which often results in a weak or failed chemotherapy on cancer treatment. Herein, an acid-sensitive and pluronic L61-linked hyaluronic acid nanogels (HA-L61OE/NGs) were developed for solving this problem. The nanogels could well hold more drugs under neutral condition, while triggering efficiently drugs release (61.42% within 24 h) in acidic environment. In vitro cells experiments demonstrated that the nanogels greatly increased intracellular drugs concentration by CD44-mediated endocytosis and L61-mediated anti-MDR effect, resulting in the enhanced cell-killing in MDR cells. In vivo studies verified HA-L61OE/NGs could avoid drugs leakage in blood and reduce systemic toxicity. Subsequently, the specific accumulation and penetration of nanogels at tumor regions lead to the highest tumor growth inhibition (TGI, 77.42%). Overall, HA-L61OE/NGs were effective on MDR tumor therapy and expected to be further used in clinical trials.