Preparation And Anti-Breast Cancer Evaluation Of Active Targeted PLAG Nanoparticles Incorporated With PTX And UFH

Objective:To improve the therapeutic effect against breast cancer by killing cancer cells directly and inhibiting their metastasis as the same time,via constructing an active tumor targeted nano-scale drug delivery system incorporating both paclitaxel?PTX?and unfractionated heparin?UFH?.Methods:PLGA-UFH and PLGA-HA were obtained by conjugating terminal amino-based lactic acid glycolic acid copolymer?PLGA-NH₂?with UFH or hyaluronic acid?HA?,and confirmed by IR and NMR spectroscopy.The active tumor targeted nano-scale drug delivery system incorporating both PTX and UFH,[PLGA-?HA+UFH?+PTX]-NPs,was prepared by modified emulsion solvent evaporation method.The PTX,UFH alone loaded,and passive tumor targeted nano-scale drug delivery systems,?PLGA-HA+PTX?-NPs,[PLGA-?HA+UFH?]-NPs and?PLGA-UFH+PTX?-NPs,were prepared as control.These drug delivery systems were characterized.At in vitro level,the cytotoxic effect,uptake behavior and mechanism and anti-metastasis effect of[PLGA-?HA+UFH?+PTX]-NPs were evaluated in cultured4T1 cells,using CCK-8 method,scratch healing,migration and invasion methods,respectively.At in vivo level,the anti-tumor and anti-metastasis effect of[PLGA-?HA+UFH?+PTX]-NPs were evaluated in 4T1 breast cancer bearing mouse model.Results and discussion:The successful synthesis of conjugates of drug or ligand with vehicle material?PLGA-UFH and PLGA-HA?was confirmed by infrared and nuclear magnetic resonance spectroscopy.The[PLGA-?HA+UFH?+PTX]-NPs were relatively uniform in size,with the average particle size,polydispersity coefficient?PDI?and zeta potential being 89.4±0.7 nm,0.12±0.2,and-35.5±1.3 m V,separately.The encapsulation efficiency?EE?and drug loading?DL?of PTX in[PLGA-?HA+UFH?+PTX]-NPs were 98.97±0.55%and 1.97±0.11%,respectively.The in vitro release of PTX from[PLGA-?HA+UFH?+PTX]-NPs was speeded up to some extent in the tumor microenvironment?p H 6.8?,in comparison with the normal body fluid environment?p H 7.4?.These results suggested that[PLGA-?HA+UFH?+PTX]-NPs might exhibit a tumor microenvironment response release prosperity.The toxicity of PTX against in vitro cultured 4T1 cells were increased obviously by constructing[PLGA-?HA+UFH?+PTX]-NPs.Theuptakeof[PLGA-?HA+UFH?+PTX]-NPs by 4T1 cells was facilitated by HA modification?P<0.05?.The in vitro anti-metastasis effect of[PLGA-?HA+UFH?+PTX]-NPs might be attributed to the incorporation of UFH.In comparison with blank control group,the growth of 4T1 tumor was inhibited by free PTX or?PLGA-HA+PTX?-NPs?P<0.05?,the metastasis of 4T1 tumor was inhibited by free UFH or[PLGA-?HA+UFH?]-NPs?P<0.05?,whereas both the growth and metastasis of 4T1 tumor were inhibited by[PLGA-?HA+UFH?+PTX]-NPs.Conclusion:The therapeutic effect against 4T1 breast cancer might be improved by constructing an active tumor targeted nano-scale drug delivery system incorporating both PTX and UFH,through killing cancer cells directly and inhibiting their metastasis as the same time.This strategy might be used to construct novel and high efficient nano-scale delivery systems for Chinese herbal medicine.