Zwitterionic Sulfadiazine-Based Micelle Achieves Effective Drug Delivery to Glioblastoma by Overcoming Multiple Biological Barriers

-acetyl sulfadiazine) benzoyl oligo(ethylene glycol) methacrylate) (PCL-PSDMA) micelle is synthesized via atom transfer radical polymerization (ATRP), capable of overcoming multiple biological barriers with minimalistic structure. First, the PCL-PSDMA micelle shows a zwitterionic state in a physiological environment, exhibiting long blood circulation without triggering accelerated blood clearance. Second, the PCL-PSDMA micelle traverses the blood-brain barrier effectively owing to the pathway mediated by the l-type amino acid transporter on cerebrovascular endothelial cells. Third, the PCL-PSDMA micelle converts from zwitterionic state to positively charged state in tumor extracellular environment, facilitating deep tumor penetration and enhanced tumor cellular uptake. Lastly, the zeta potential of the PCL-PSDMA micelle transforms to a stronger positive value in the lysosomal microenvironment, resulting in effective lysosomal escape. The outstanding performance of overcoming five sequential biological barriers endows the PCL-PSDMA micelle with high drug delivery efficiency to glioblastoma, leading to pronounced antitumor effect in two types of glioblastoma-bearing mice model. Overall, this work not only adds a new member to the zwitterionic family but also broadens the horizon of developing powerful NPs for antiglioblastoma drug delivery.