Development of a Negative-Biased Zwitterionic Polypeptide-Based Nanodrug Vehicle for pH-Triggered Cellular Uptake and...

Albumin mimics could be an attractive platform for nanodrug carriers through systematic administration because of high safety and plentiful properties to be adjusted for a high drug efficacy, such as pH-triggered targeting cellular uptake and drug release. In this work, negative-biased zwitterionic nanodrug carriers based on zwitterionic polypeptide chains that mimic albumin were prepared, which have an outermost layer of zwitterionic glutamic acid (E) and lysine (K) pairs with a small amount of aspartic acid (D) to adjust the overall ζ potential. On the other hand, doxorubicin (Dox) was encapsulated in a hydrophobic core by 11-maleimidoundecanoic acid covalently linked with additional cysteine (C) residues on the polypeptide. The results show that the negative-biased zwitterionic nanodrug carriers can sensitively enhance the cellular uptake in responding to a pH change from 7.4 to 6.7 without reversing the ζ potential to a positive charge, leading to accelerating the Dox release rate in a slightly acidic environment through the polypeptide secondary structure change. Moreover, the anionic nanodrug carrier can also be easily enzymatically digested by trypsin for quick drug release. In short, this negative-biased zwitterionic nanodrug delivery vector could be an ideal candidate for a safer tumor inhibition with a high efficacy than conventional synthetic polymer-based ones.