Vigilancia Tecnológica

Modulation of the N?alkyl chain length in polysulfobetaine?based zwitterionic micelles enables precise tuning of nanocarrier interactions with proteins and cell membranes. The optimized micelles comprising poly(sulfobetaine methacrylate)?block?poly(??caprolactone) with N?butyl substituent (PSB4?PCL), which are protein?resistant yet cell membrane?philic, achieve a unique balance between prolonged circulation and efficient tumor transcytosis, leading to enhanced intratumoral accumulation, deep penetration, and potent antitumor efficacy.Long blood circulation and fast cellular uptake are essential yet paradoxical requirements for efficient tumor?targeted drug delivery carriers. For instance, polyzwitterions, generally nonfouling to proteins and cells, have been extensively explored as long?circulating drug delivery carriers but suffer ultraslow cell internalization, making them inefficient in delivering drugs to cells. Protein?resistant yet cell membrane?binding polymers will simultaneously achieve long blood circulation and fast cellular internalization, but their designs are generally complicated, such as introducing cell?membrane binding groups. Here, it is shown that the N?alkyl chain length of zwitterionic poly(sulfobetaine) can be used to tune its affinity toward proteins and cell membranes. A poly(sulfobetaine) with a moderately long N?alkyl chain became cell membrane?philic while retaining protein resistance, leading to long blood circulation and fast cellular uptake, which further triggered efficient tumor cell transcytosis and intratumor penetration. Thus, its paclitaxel (PTX)?loaded micelles demonstrated potent antitumor efficacy in triple?negative breast cancer models. This study showcases a paradigm of designing polyzwitterions harmonizing long blood circulation and fast cellular uptake properties as tumor?active drug delivery carriers.