Study Based On Disulfide Cross-linked Biomimetic Micelles With Bio-responsiveness

Polymeric micelles with particular shell-core structure showed great potential for bimedical applications as drug delivery system. Ideal nanocarriers usually have high stability during the circulation process and effective drug release behavior after reaching the targeting sites. To solve problems exist in the development of polymeric micelles as nanocarriers, a kind of biomimetic and bio-responsive polymeric micelles based on disulfide cross-linking was investigated in this study.Firstly, functional monomer glycidyl methacrylate (GMA) was introduced into the amphiphilic random copolymers with 2-methacryloyloxyethylphosphorylcholine (MPC) as hydrophilic segment, stearyl methacrylate (SMA) as hydrophobic segment and GMA as reactive segment. Transmission electron microscope (TEM) and dynamic light scattering (DLS) tests indicated that these reactive phosphorylcholine-based copolymers could self assembled into stable polymeric micelles.Epoxy groups from the monomer GMA afforded the probability of post-modification of the micelles. Consequently, the reactive polymeric micelles were cross-linked with di-functional reagent, cystamine, via reaction between the amine groups and the epoxy groups from the micelles. After cross-linking process, the stability of the polymeric micelles was highly improved. Besides, the disulfide bond introduced from the cross-linking process endowed the cross-linked micelles with thiol-responsiveness as indicated by DLS measurement, which was carried in the simulated intracellular reducing environment. DLS results showed that the micellar size changed from 110.6 nm to 201.2 nm in 24 h after adding 10 mM reduced dithiothreitol (DTT), which indicated that the micelles were destabilzed after cleavage of the cross-linking bond. Besides, these polymeric micelles were also used as nanocarriers to encapsulate anticancer drugs and realized faster drug release through the thiol-responsiveness.Cell cytotoxicity tests indicated that, compared with the commercially drug-delivering vehicle polyoxyethylated castor oil (Cremophor EL), the bioinspired phosphorylcholine-based micelles showed excellent biocompatibility, i.e., the cell viability still kept 90% even the sample concentration reached to 250 mg·L-1. Cell experiments also indicated that the drug-loaded micelles especially the cross-linked drug-loaded micelles exhibited faster endocytosis behavior in short time(<2 h), while long time cell viability test showed that these drug-loaded micelles had obvious cell inhibition effects.Finally, fluorescein isothiocyanate(FITC)-labeled micelles were obtained through the reactive epoxy groups and the endocytosis behavior was preliminarily studied for further research of tracking the drug-loaded micelles.These disulfide bond contained biomimetic micelles with improved stability and bio-responsiveness showed great potential for applications in the field of nanocarrier systems.