Generation of protease-sensitive zwitterionic peptide coatings for gene delivery nanosystems to glioblastoma

Author

Arruga Torres, Yolanda

Abstract

Gene delivery is a promising treatment for many diseases, including brain cancers. However, the biological obstacles and barriers to overcome in gene delivery are numerous, so efficient and selective carriers must be developed. While an important goal is to deliver the genetic material with highly efficiency, selectivity is crucial to avoid off-target effects. poly-β-amino esters (pBAEs) is a state-of-the-art carrier family of biodegradable cationic polymer for gene delivery. However, pBAEs are notoriously promiscuous when it comes to cell transfection. Moreover, formation of protein corona may prevent efficient targeting. Here we propose a zwitterionic sheddable peptide coating that aims to decrease the transfection capacity of pBAE polyplexes and enable efficient retargeting. This coating is peptidic in nature and incorporates sequences cleavable by proteases with high expression levels in the tumor.
In this work, we have first synthesized the zwitterionic peptides and a transferrin-receptor targeting peptide and functionalized them with biorthogonally reactive handles. We have then derivatized pBAEs with the complementary handles. The zwitterionic-peptide-pBAE conjugates can generate polyplexes with DNA, which display 80-fold decreased internalization capacity. Finally, we have shown the peptides can be cleaved in the presence of the tumor target protease.

Director

Borrós Gómez, Salvador
Oller Salvia, Benjamí

Degree

IQS SE - Master’s Degree in Pharmaceutical Chemistry

Date

2022-07-08