Crosslinked Peg-Nanoparticles Prepared through Inverse Flash Nanoprecipitation and Thiol-Michael Reaction and Its Potential to Delivery Hydrophilic Biologics

A hydrophilic nanoparticle composed of multi-armed PEG-acrylate and a multi-armed PEG-thiol was fabricated through multi-inlet vortex mixer (MIVM), using Pluronic copolymer as stabilizer and DMF/diethyl ether as solvent/anti-solvent system. Subsequent thiol-michael addition created a crosslinked PEG-nanoparticle (PEG-NP). Using different hydrophilic molecules as drug models, influences of formulation composition on PEG-NPs properties and performance were studied (e.g., ratio of solvent/anti-solvent on NP size, NP stability; percentage of co-solvent on NP stability and crosslinking; selection of PEG reactants on retention and release profile of model drugs; PEG network on bioavailability of drug, etc.) Due to the step-growth character of thiol-michael addition, thiol- or acrylate-bearing PEG-NP could be prepared by off-stoichiometric feeding of the multi-armed PEG reactants, which can facilitate further modification of the crosslinked PEG-NPs, such as hydrophobic surfacing and conjugation of targeting ligand. Based on the biocompatibility of PEG segments, the NP stability from the PEG-network, the scalable and mild fabricating condition, we anticipate that the crosslinked PEG-NP could be a promising candidate for delivery of hydrophilic biologics, such as protein and gene.