Viral Capsids Mimicking Based On PH-Sensitive Biodegradable Polymeric Micelles For Efficient Anticancer Drug Delivery

In recent years,a series of novel nanoassemblies mimicking viral components and architectures have been well constructed and succeed in enhancement of bioactive molecules delivery efficiency.Hyaluronic acid(HA)is a type of polyanionic polysaccharide that is widely distributed in the extracellular matrix.Studies have found that most cancer cell surfaces overexpress HA receptors such as CD44,RHAMM,and LYVE-1.It is worth noting that the content of hyaluronidase is also high in various malignant tumor tissues,so HA could be degraded into low molecular weight glucuronic acid and disaccharide.Therefore,HA is not only a degradable protective layer of the carrier but also serves as a ligand to target specific cell receptors.Herein,a mimicking viral capsid based on pH-Sensitive polymeric micelles HA-Hyd-DOX with hyaluronic acid as the main body was reported.This viral mimic not only has virus-like parts and structures,but also embraces virus-like infections to tumor cells.Furthermore,HA-Hyd-DOX were effectively taken up by cancer cells via CD44 receptor-mediated endocytosis,but were rarely internalized into normal fibroblasts.In addition,hydrazone bond(Hyd)and the main body HA was destroyed under the conditions of pH=5 and hyaluronidase in cancer cell,so that DOX escaped from lysosomes to enhance anticancer efficacy.Such mimicking viral capsids based on polymeric micelles provided some remarkable benefits for drug delivery,including well-defined nanostructure,high drug loading,controlled release rate and low cytotoxicity.With the comparison of typical prodrug-based polymeric micelles mPEG-Hyd-DOX system,HA-Hyd-DOX showed greater inhibition to cancer cells due to the targeted and sensitive drug delivery.We synthesize HA-Hyd-DOX and mPEG-Hyd-DOX by amidation reaction.Their structures were identified by NMR and mass spectrometry.The morphology of the polymer was observed by transmission electron microscopy.Dynamic light scattering was used to measure the average diameter of the nanoparticles at various pH values.The cumulative release rate of DOX was measured by the dialysis bag method.The anti-tumor effect in vitro was tested by MTT assay.Cell uptake was measured by confocal and flow experiments.The results of NMR and MS indicated that HA-Hyd-DOX and mPEG-Hyd-DOX were successfully synthesized.The average particle size of nanoparticles was 112.6±1.33 and 74.41±4.45,respectively.The results of electron microscopy were uniform and stable spherical particles.The release results indicated that DOX could be released at pH 5 conditions.The uptake results showed that HA-Hyd-DOX had better uptake efficiency than mPEG-Hyd-DOX.The above result showsed HA-Hyd-DOX had better drug delivery efficiency than mPEG-Hyd-DOX.In addition,on the basis of the study of this topic,we have studied the drug delivery system of the multi-biosensory imitation viral capsid.In this study,viral mimicking drug delivery systems use a well-known ―Trojan Horse‖ strategy to invade tumor cells and sequentially unpack the capsid(HA-PLGAG-DSPE),and accessory the inner core(mPEG-PDPA)to release the drug.