Cell Plasma Membrane-based Nanosystems For Tumor Therapy And Imaging

Cells as the fundamental structural and functional units of natural organisms play important roles in the whole process of life.Cell plasma membrane,the most essential component in cells,can protect cells from outer stimuli and keep the stability of cells.It can also regulate lots of physiological activities in cells,including mediating substances and energy exchanges between cells and the surrounding environments,selectively absorbing nutrients,excreting metabolites,secreting and transporting functional proteins.Tumor cell plasma membrane possesses the same structure and similar functions as normal cells,which can be used for designing functional nanosystems for precise tumor imaging and therapy.Thus,we developed a series of cell plasma membrane-based nanosystems for tumor imaging and therapy.Detailed contents are as follows:In chapter one,we reviewed the important functions of cell plasma membrane in the physiological activities of cells,summarized a series of nanosystems which can interact with cell plasma membrane(including cell plasma membrane targeting,response,fusing,encapsulating and regulating)for tumor imaging and therapy,and further introduced lots of multifunctional tumor theragnosis strategies by utilizing plasma membrane of various cells(including specific tumor cells,red blood cells,blood platelets,macrophages and neutrophils).In chapter two,we designed a transformable chimeric peptide for cell encapsulation to overcome multidrug resistance.This chimeric peptide(CTGP)was comprised of cathepsin B-responsive Gly-Phe-Leu-Gly(GFLG)sequence,hydrophilic PEG₈ and Gly-Gly-Gly-His(GGGH)sequence,cell membrane-targeted hydrophobic 16-carbon alkyl chain and aggregation-induced emission probe.In aqueous solution,CTGP could self-assemble into nanomicelles and further encapsulate DOX to form peptide-based drug delivery nanosystem(CTGP@DOX).Once accumulated at tumor regions,CTGP@DOX could be disassociated and cleaved by tumor pericellular hypersecreted cathepsin B and further reassembled into nanofibers on the cell membrane via the cell membrane-targeting hydrophobic16-carbon alkyl chain.These pericellularly self-assembled nanofibers would greatly restrict DOX efflux and efficiently overcome tumor multidrug resistance.We studied a series of processes including cathepsin B-induced DOX release,pericellular nanofiber self-assembly and enhanced intracellular DOX retention,and further verified in vivo tumor imaging and therapeutic effects.In chapter three,we constructed a tumor cell plasma membrane-targeted chimeric peptide for enhanced tumor photodynamic-immunotherapy.This chimeric peptide(PCPK)was comprised of a plasma membrane-targeted K-Ras-derived peptide KKKKKKSKTKC-OMe,a hydrophilic PEG₈ chain,a hydrophobic 6-carbon alkyl chain and the photosensitizer protoporphyrin IX(PpIX).The plasma membrane-targeted K-Ras-derived peptide was derived from cellular K-Ras signalling protein exclusively driving corresponding proteins to cell inner plasma membrane.After conjugated with PpIX,this K-Ras-derived peptide could generate ROS under light irradiation and specifically destroy tumor cell plasma membrane.Afterwards,intracellular HMGB1 and ATP could be fast released,inducing dendritic cells(DCs)maturation,tumor antigen presentation and T lymphocytes activation.After cooperated with checkpoint blockade agent anti-PD-1(a PD-1)to alleviate the immunosuppression of tumor microenvironment,PCPK could further improve antitumor immune responses and realize enhanced photodynamic-immunotherapy.Both in vitro and in vivo experiments demonstrated the excellent cell plasma membrane targeted antitumor effects.In chapter four,artificial“super neutrophils”were designed and constructed to simulate the inflammation targeting and HCl O generation functions of natural neutrophils for antitumor,antimetastasis and antibiosis.The artificial neutrophils(GCZM)were prepared by embedding two enzymes(glucose oxidase and chloroperoxidase)into metal-organic frameworks ZIF-8,and further encapsulating natural neutrophil membrane on the surface via biomimetic modification.GCZM could target to inflammation sites and utilize intracellular glucose and Cl^-to generate HCl O for antitumor and antibiosis.In vitro and in vivo results indicated that these artificial“super neutrophils”could generate 7 times higher reactive HCl O than the natural neutrophils for targeting and eradicating tumors and infections.