Combined Effects of Core Rigidity and Surface Charge of Polymeric Nanomicelles on the Cellular Uptake Efficiency

To minimize macrophage recognition and rapid clearance, polymeric nanodrug carriers (e.g., nanomicelles) are typically engineered to be negatively charged and PEGylated. However, the physicochemical properties required for extended blood circulation often pose a challenge to the cellular uptake of polymeric nanomicelles, resulting in an ineffective drug delivery. Herein, we report that tuning the core rigidity of negatively charged polymeric nanomicelles could improve their cellular uptake efficiency, thereby enhancing the therapeutic effectiveness of polymeric nanomicelles-based nanodrugs. As a proof-of-concept, negatively charged polymeric nanomicelles composited with poly(lactic-co-glycolic acid) (PLGA), polycaprolactone (PCL), and polystyrene (PSt) with different levels of core rigidity were fabricated. It was found that cancer cells exhibited a higher uptake efficiency for soft-core PLGA nanoparticles (PLGA-NPs) and PCL-NPs compared with the stiff-core PSt-NPs. In particular, the top-performing PLGA1-NPs were able to internalize immediately into cells even within 5 min and penetrate deeply into tumor spheroids. Further studies revealed that the enhanced uptake and penetration capabilities of PLGA1-NPs are attributed to the combined effects of the soft core and the negative surface charge. As a result, paclitaxel (PTX)-loaded PLGA1-NPs have demonstrated enhanced efficacy in inhibiting tumor cell growth. Overall, this study discovered the combined effects of core rigidity and surface charge of polymeric nanomicelles in modulating cancer cell uptake. These findings have important implications for the development of more efficient nanocarriers for drug delivery.