Supramolecular Chemistry-based Surface Engineering Of Nanoparticles For Targeted Biomedical Imaging

Biomedical imaging technique plays a vital role in disease diagnosis and monitoring.Nowadays,various nano-contrast agents have been developed to enhance the contrast of imaging signals between normal tissues and the lesions,thereby improving the accuracy of diagnosis.To achieve the effective biologcial applications of nano-contrast agents,the development of efficient surface engineering method is need to endow them with high biocompatibility,long-term colloidal stability,and precise targeting performance.However,there are still some limitations on the current surface engineering strategies,for instance,some methods are not versatile for different nanoparticles,also the random attachment and disorientation of modified targeting ligands would lead to poor bioactivities.Therefore,it is necessary to develop a versatile surface ligand modification method to improve the targeted biomedical imaging effect of nano-contrast agents.Nowadays,supramolecular containers have achieved much attention in biological applications.The supramolecular compound,cucurbituril can be used as an intermediate to connect diverse nanoparticles and targeting ligands through host-guest complexation,and orderly arrange the targeting ligands on the surface of nanoparticles.Based on above,a universal surface engineering approach based on supramolecular chemistry is designed to improve the colloidal stability and biotargeting of nano contrast agents.In this work,firstly,inorganic nanoparticles with uniform morphology(e.g.iron oxide nanoparticles,manganese oxide nanoparticles and gold nanorods)were prepared,and the nanoparticles were endowed with excellent solubility and biocompatibility via ligand-exchange with functionalized polyethylene glycol(PEG);After further conjugated with spermidine,the acyclic cucurbituril(a CB)molecular containers were connected with the nanoparticles through host-guest complexation;Finally,spermidine modified targeting ligand was accommodated regularly in a CB molecule via host-guest complexation,whereafter a series of targeted nano-contrast agents(XNP-CR TCAs)based on the surface engineering of supramolecular chemistry were achieved.The morphology and size of XNP-CR TCAs were characterized by transmission electron microscope(TEM)and dynamic light scattering;the successful modification of a CB and RGD were verified by UV-vis and Zeta potential;the magnetic resonance imaging(MRI)performance or photoacoustic imaging(PAI)performance of XNP-CR TCAs were investigated by MR scanner or PA scanner;the orientation of RGD was studied by molecular dynamic simulation.The results show that the three kinds of XNP-CR TCAs are highly monodispersed in aqueous solution.The a CB and RGD are successfully modified on the surface of nanoparticles,and the active targeting ligands face outward.All the results prove the successful fabrication of nano-contrast agents based on surface engineering method of supramolecular chemistry.Furthermore,the stability of XNP-CR TCAs was investigated in different solutions.The results indicate that this surface engineering approach can endow the nano-contrast agents with good colloidal stability.Subsequently,the targeting properties of XNP-CR TCAs were studied at the cellular level.The differences of cellular uptake between XNP-CR TCAs and XNP-R TCAs(conventional RGD peptide conjugated nanoparticles without a CB),were studied with confocal laser scanning microscopy(CLSM),inductively coupled plasma mass spectrometry(ICP-MS)and in vitro cell imaging.The results show that all the three XNPCR TCAs exhibit better targeting effects to tumor cells.Furthermore,the binding of supramolecular targeted ligand to corresponding receptor was studied through molecular dynamics simulation.The results suggest that a CB molecule can assist in the effective binding between targeting ligand and corresponding receptor by forming hydrogen bonds with the receptor,which is beneficial for targeted delivery of nano-contrast agents.Finally,the in vivo MRI and tumor targeting properties of XNP-CR TCAs based on iron oxide nanoparticles(IONP-CR TCAs)were investigated at the animal level.By comparing the signal changes of MRI and the accumulation of nano-contrast agents at the tumor site,the differences of targeting effect between IONP-CR TCAs and IONP-R TCAs were evaluated.The results show that IONP-CR TCAs exhibit excellent tumor targeting efficiency and T2 MRI effect.Therefore,supramolecular chemistry-based surface engineering approach can significantly improve the imaging effect of nano-contrast agents on the lesions.Furthermore,the in vivo biocompatibility studies verify that IONPCR TCAs exhibit excellent biosafety.In conclusion,the surface engineering of nanomaterials based on the bilateral hostguest complexation of supramolecular chemistry is universal for diverse nanoparticles.It can endow the nano-contrast agents with colloidal stability and accurately control the orientation of targeting ligands.In vivo and in vitro studies have proved that the targeted nano-contrast agents based on this surface engineering approach possess excellent tumor targeting effect and targeted biomedical imaging effect,which is conducive to effective disease diagnosis.Furthermore,supramolecular chemistry-based surface engineering approach can provide a new method for the design and development of targeted nano drugs in the future.