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Objective: Development of chemotherapeutic drugs targeted delivery to tumor cells remains a challenge due to the lower uptake by tumor tissue,and higher exposure of other body compartments to the drug.Polymer nanoparticles are efficient delivery vehicles for cancer therapy such as doxorubicin (DOX).In this study,we constructed a DOX-loaded PEG-PLGA nanotechnology-based delivery systems with surface modified various ratios of spermidine (SPD) for offer the system function of active targeting (SPD-DOX-NPs) (Fig.1.A),with the ability of SPD to bind to the polyamine transport system (PTS) specifically overexpressed on the tumor cell surface.Methods: The nanoparticles were prepared by a typical emulsion-solvent evaporation method.The size distribution,zeta potential,drug encapsulation efficiency (EE %),drug loading capacity (LC) and in vitro drug release were systematically studied.Fluorescence microscopy and flow cytometry were utilized to investigate the cellular uptake of SPD-DOX-NPs in A549 cells.And the in vitro cytotoxicity of nanoparticles were evaluated with A549 cells by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay.Results:The resultant SPD-DOX-NPs showed a uniform particle size (~150 nm) with typical spherical shapes and well dispersed.And the surface charge was near electric neutrality.The encapsulation efficiency (EE %) and drug loading ratio (DL %) were characterized to 50.08±1.28 % and 0.88±0.06 %,respectively.In addition,the in vitro drug release pattern can be plotted into the double exponential kinetic model.After SPD modification,the cellular uptake of nanoparticles in A549 cells was concentration dependent with surface density of SPD (Fig.1.B),and the uptake efficiency was further increased by eflomithine (DMFO) (~1.2-fold) or competitively be inhibited by free SPD pre-treatment (~1.4-fold).Furthermore,the SPD-DOX-NPs exhibits a significantly enhanced cytotoxicity for A549 cells than the free DOX solution and DOX-NPs (Fig.1.C).Conclusion: With favorable characteristics in stability,cellular uptake,cytotoxicity,safety and efficacy,SPD-PEG-PLGA seems highlypotential as a nanocarrier for specifically deliver DOX to tumor cells through the PTS and thus enhance the anti-tumor efficiency in vitro.