Construction of Degradable and Amphiphilic Triblock Polymer Carriers for Effective Delivery of siRNA

The development of effective and safe delivery carriers is one of the prerequisites for the clinical translation of siRNA-based therapeutics. In this study, a library of 144 functional triblock polymers using ring-opening polymerization (ROP) and thiol-ene click reaction is constructed. These triblock polymers are composed of hydrophilic poly (ethylene oxide) (PEO), hydrophobic poly (epsilon-caprolactone) (PCL), and cationic amine blocks. Three effective carriers are discovered by high-throughput screening of these polymers for siRNA delivery to HeLa-Luc cells. In vitro evaluation shows that siLuc-loaded nanoparticles (NPs) fabricated with leading polymer carriers exhibit sufficient knockdown of luciferase genes and relatively low cytotoxicity. The chemical structure of polymers significantly affects the physicochemical properties of the resulting siRNA-loaded NPs, which leads to different cellular uptake of NPs and endosomal escape of loaded siRNA and thus the overall in vitro siRNA delivery efficacy. After systemic administration to mice with xenograft tumors, siRNA NPs based on P2-4.5A8 are substantially accumulated at tumor sites, suggesting that PEO and PCL blocks are beneficial for improving blood circulation and biodistribution of siRNA NPs. This functional triblock polymer platform may have great potential in the development of siRNA-based therapies for the treatment of cancers.

Automated summary

This study constructed a library of 144 functional triblock polymers and discovered three effective carriers for siRNA delivery through high-throughput screening. In vitro evaluation showed that the siRNA-loaded nanoparticles fabricated with these polymers effectively silenced luciferase genes with low cytotoxicity. The chemical structure of the polymers significantly affected the physicochemical properties and in vitro delivery efficacy of the siRNA-loaded nanoparticles. In vivo experiments demonstrated that siRNA nanoparticles based on a specific polymer accumulated at tumor sites, suggesting the potential of this polymer in improving blood circulation and biodistribution of siRNA nanoparticles. This functional triblock polymer platform holds great potential in siRNA-based cancer therapies.