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

Abstract

Multiple biological barriers in vivo severely restrict the delivery efficiency of nanoparticles (NPs) to tumors. To overcome biological barriers, traditional NPs usually require a complex design, which increases the difficulty of clinical translation. Therefore, there appears to be a dilemma between the complex biological barriers in vivo and clinical requirement for a simple molecular structure of NPs. Herein, an unprecedented zwitterionic polycaprolactone-poly(4-(N,N-dimethylamino-N-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.