Multifunctional Ruthenium-based Nanoplatforms With Drug Controlled Release Characteristic For Simultaneous Tumor Imaging And Therapy

Cancer,as one of the most mortal diseases worldwide,remains a serious public health concern.The diversity,complexity,and heterogeneity of tumors seriously undermine the therapeutic outcomes of traditional clinical treatment.The inherent limitation of conventional therapies have promoted the development and application of nano-biotechnology.The rapid development of nanotechnology provides theoretical and technical support for nanomedicine.Therefore,the current trend in nanomedicine research has gradually shifted from monotherapy to synergistic combination therapy,and the synergistic enhancement interactions between two or more monotherapies helps to achieve better therapeutic effects(namely “1+1>2”).More importantly,the greatest advantage of nanomedicine lies in the ability to load multiple drugs on the same nanoplatform for the coordinated treatment of tumors.It could even be used in combination with biomedicine imaging technology for affording both therapeutic and diagnostic functions.Drug delivery systems(DDS)are the most critical components of nanomedicines,which determines the intrinsic properties and treatment of nanomedicines.DDS can be divided into the following types: liposome carriers,polymer carriers,inorganic nanocarriers,etc.Particularly,in addition to serving as a drug carrier,inorganic nanoparticles can also perform different functions on their own,such as iron-based nanomaterials(contrast agents of magnetic resonance imaging),gold-based nanomaterials(photothermal agents).The loading capacity of DDS determines the efficacy of nanomedicines.Therefore,nanocarriers with high loading capacity have received extensive attention.In recent years,mesoporous material is now considered a potential DDS in the field of biomedical engineering,because of the uniform pore volume and easily modified pore structure to achieve drug loading and controlled release.In addition,two-dimensional nanomaterials are increasingly recognized for their drug delivery owing to their high specific surface area and special optical properties.The solid tumor is composed of cancer cells and many other types of stromal cells including fibroblasts,macrophages,lymphocytes etc.Each type of cell has its own functions,which are embedded in the extracellular matrix consisted of collagen and proteoglycans.This provides a hydrated matrix to promote tumor growth.Compared with the normal tissues,the tumor microenvironment(TME)has some distinctive properties,such as hypoxia,acidic pH and vascular abnormalities.Tumor-associated macrophages(TAMs)play an important role in the tumors where they could alter the TME to accelerate tumor progression.TAM-targeting therapy has proven to be a promising strategy for an indirect cancer therapy.Thanks to the rapid development of biomedicine imaging technology,many researchers have developed a variety of probes that can not only detect the solid tumors accurately,but also combine small molecules drugs on the same nanocarrier to perform simultaneous diagnostics and therapeutic functions,called “theranostic”.Based on the considerable body of literature,we developed a series of multifunctional nanomaterials for tumor theranostic which provided a new strategy for precision cancer therapy.The thesis consists of three chapters.In chapter 1,we briefly introduced the TME and the nanomedicine design strategies by exploiting the TME.And we further described the physiological and pathological barriers within body's complex conditions.Finally,we focuse on the current multimodality combination therapy and the latest research advances based on the nanomedicines.In chapter 2,we first synthesized the pRuNPs with mesoporous structure via the polyol reducing method.And then developed a theranostic system,pRu-pNIPAM@RBT,composed of pNIPAM as the thermal-response switch and of Ru complex(RBT).We studied the photothermal/photodynamic properties,drug loading capability/drug controlled release and the mechanism of apoptosis of pRu-pNIPAM@RBT.To monitor the drug biodistribution and detect the tumor,the fluorescence and photoacoustic dual-mode imaging were carried out.Finally,the in vivo anticancer efficacy of pRu-pNIPAM@RBT for simultaneous PTT/PDT was studied in HepG2 tumor-bearing nude mice.The therapy outcomes confirmed that the pRu-pNIPAM@RBT could be used as a multifunctional anticancer agent with good biocompatibility.In chapter 3,based on our previous works,two-dimensional Ru nanosheet with high loading capacity was prepared.And then we developed a delivery system RuNPs@ICG-BLZ that can be activated by the inflammatory microenvironment.RuNPs@ICG-BLZ can substantially passively target the tumor tissue with the enhanced permeability and retention(EPR)effect.RuNPs@ICG-BLZ can perform a better simultaneous PTT/PDT with the suppression of M2 TAMs.We demonstrated that Ru nanosheet has high drug loading capacity and sensitive inflammatory response.Second,the ability of RuNPs@ICG-BLZ to induce apoptosis and penetrate was studied by the cell experiments.Finally,the anticancer efficacy and mechanism of RuNPs@ICG-BLZ were studied by xenograft mice and immunofluorescence,respectively.