Enhanced ASO-Mediated Gene Silencing with Lipophilic pH-Responsive Micelles.
Bioconjug Chem
; 34(7): 1244-1257, 2023 07 19.
Article
em En
| MEDLINE
| ID: mdl-37384839
ABSTRACT
Herein, we examine the ASO-mediated gene silencing efficiency of pH-responsive micelles, by incorporating 2-(diisopropylamino)ethyl methacrylate (DIP) into the micelle core and comparing physical and biological properties with non-pH-responsive micelles. Additionally, the lipophilic effect of the micelle cores was examined in both types of micelles. Varying lipophilicity was achieved by varying alkyl monomer chain lengthsâbutyl (4), lauryl (12), and stearyl (18) methacrylate. Each of the micelles formed within our family offered the added benefit of well-defined and uniform templates for loading antisense oligonucleotide (ASO) payloads. Overall, the micelles followed previously established trends of outperforming their linear polymer (nonmicelle) analogs and ASO only control. More specifically, the highest performing micelles were the pH-responsive micelles with longer alkyl chains or higher lipophilicityâD-DIP+LMA and D-DIP+SMA (â¼90% silencing). These two micelles demonstrated silencing efficiencies similar to Jet-PEI and Lipofectamine 2000 and caused lower toxicity than Lipofectamine 2000. The shortest alkyl chain pH-responsive micelle, D-DIP+BMA (64%), displayed strong gene silencing similar to that about that of its non-pH-responsive micelle, D-BMA (68%), and the pH-responsive micelle without an alkyl chain incorporated, D-DIP (59%). This work illuminates a minimum alkyl chain length dependence to allow gene silencing within our micelle family. However, including only longer alkyl chains into the micelle core without the pH-responsive unit DIP had a hindering effect, thus demonstrating the requirement of the DIP unit when including longer alkyl chain lengths. This work demonstrates the exemplary gene silencing efficiencies of polymeric micelles and uncovers the relationship between pH responsiveness and performance with lipophilic polymer micelles for enhancing ASO-mediated gene silencing.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Oligonucleotídeos Antissenso
/
Micelas
Idioma:
En
Revista:
Bioconjug Chem
Ano de publicação:
2023
Tipo de documento:
Article