Reversible Covalent-Crosslinked Polycations with Enhanced Stability and ATP-Responsive Behavior for Improved siRNA Delivery.

In this study, we proposed a new strategy of reversible-covalent crosslinking to enhance stability in circulation and enable stimuli-disassembly of polyplexes in tumor cells. Here, 25k polyethyleneimine (PEI) was chosen as model polycations for verifying the hypothesis. HA-PEI conjugation was formed by the crosslinking of adenosine triphosphate grafted HA (HA-ATP) with phenylboronic acid grafted PEI (PEI-PBA), via the chemical reaction between PBA and ATP. Compared with non-covalent polyplex by electrostatic interaction (HA/PEI), HA-PEI exhibited much better colloidal stability and serum stability. The covered HA-ATP layer on PEI-PBA could maintain stable in the absence of physiological anions, while HA layer on PEI in HA/PEI group showed obvious detachment after anion's competition. More importantly, the covalent crosslinking polyplex could selectively release siRNA in the ATP rich environment of cytosol and significantly improve siRNA silence. Besides, the covalent crosslinking with HA-ATP could effectively reduce the cytotoxicity of cationic polyplex, improve the uptake by B61F10 cells and promote the endosomal escape. Consequently, this strategy of HA-PEI conjugation significantly enhanced the siRNA transfection in the absence or presence of FBS (fetal bovine serum) on B16F10 cells and CHO cells. Taken together, the reversible covalent crosslinking approach shows obvious superiority compared with the non-covalent absorption strategy. It held great potential to be develope...
Source: Biomacromolecules - Category: Biochemistry Authors: Tags: Biomacromolecules Source Type: research