Preparation Of Nanomedicine Constructed With Gold Cage Or Small Molecule Carrier And Their Applications In Disease Treatment

In this study,three stimuli-responsive nanodrug systems have been designed and fabricated for combination treatment for diseases using gold nanocage or aggregated small molecules as the carriers.These nanodrugs can accumulate in disease lesions and release active drugs by responding to stimuli from the microenvironment of the lesions.The combined treatment achieved by the activated drugs exhibited high therapeutic efficacies.This work is divided into the following three parts:1)A nanodrug with the gold nanocage(Au NC)/gold nanocluster(Au Cluster)complex as the carrier was designed for tumor inhibition via the delivery of an EGFR inhibitor and photothermal effects.For this nanodrug,an EGFR inhibitor erlotinib(EB)was loaded into Au NCs,which were then capped and functionalized by highly biocompatible Au Cluster@BSA conjugates via electrostatic interaction.Upon cell internalization,the lysosomal proteases and lower p H triggered the release of the EB from the Au NC.The lower p H also induced the fluorescence restoration of Au Cluster for imaging.Irradiation with NIR light further promotes the drug release and also affords PTT effect.The Au NC-based nanodrug is optoacoustically active,and its biodistribution and metabolic process have been successfully monitored by the whole-body and three-dimensional multispectral optoacoutic tomography(MSOT)imaging.Owing to the combined actions of PTT and EGFR pathway blocking,the nanodrug exhibited marked tumor inhibition efficacy in vivo.2)A p H and GSH dual-responsive nanodrug was fabricated for treatment of metastatic breast cancer.To realize the dual stimuli-response to p H and GSH,two cinnamaldehyde molecules were connected by a linkage containing a disulfide bond and an imine bond,and the resultant molecules could self-assembled into nanoparticles in aqueous media.Further,a cysteine channel protein x CT inhibitor sulfasalazine was loaded into the nanoparticles,and the mouse macrophage membrane was wrapped on the surface of the particles using the nano-extrusion method to produce the nanodrug system.After injection into the in situ/metastatic breast cancer mice,the nanodrug actively targeted to the tumor regions,and released cinnamaldehyde and sulfasalazine molecules therein.Upon release,the two drugs could not only enhance the level of reactive oxygen species in the tumor cells,but also inhibited the GSH synthesis,thereby destroyed the redox balance in tumor cells and cause the cell apoptosis.As a result,this nanodrug system has shown a significant tumor suppressing effect in orthotopic and metastatic tumors in a mouse model.3)A diselenide-based nanodrug nanodrug for acute liver failure treatment through inhibiting NLRP3 inflammasome activation and enhancing liver regeneration.A diselenide-containing molecule(DSe Se D)has been synthesized via covalently linking two L-Dopa molecules to a diselenide linker,and the resultant molecules form stable nanoparticles in aqueous media and encapsulate SW033291(an inhibitor of prostaglandin-degrading enzyme that hampers liver regeneration)to produce the nanodrug(SW@DSe Se D).As a nanoscale prodrug,SW@DSe Se D protects its payloads from decomposition in bloodstream upon administration,accumulates in liver of ALF mice,then responds to the overexpressed ROS and thereby releases SW033291 as well as a stable dopamine precursor that can transform into dopamine in hepatic cells,thus achieving significant therapeutic efficacy against ALF through inhibiting NLRP3 inflammasome activation and enhancing hepatic regeneration.Moreover,multiple contrast agents have been loaded onto the nanodrug to achieve fluorescence,optoacoustic and magnetic resonance imaging for nanodrug location and disease evaluation.