Preparation And Pharmacokinetic Study Of Stellate Pentaerythritol Polyester Nanoparticles

In this study,a novel enzyme sensitive nanoparticles consisting of functional polymer mPEG-Peptide-PET-PCL and Curcumin as a drug model,were prepared through emulsion-solvent evaporation method.The investigation on their safety,cell uptake,pharmacokinetics,tissue distribution and antitumor activity were preformed and the experimental details and the corresponding results are as following:(1)In aspect of synthesis and characterization of mPEG-Peptide-PET-PCL,mPEG-Peptide-PET-PCL was synthesized using mPEG-NHS,hydrophobic star fragment PET-PCL and matrix metalloproteinase cleavable peptide(XGPLGIAGQr9X).The structure of obtained mPEG-Peptide-PET-PCL was characterized by FT-IR spectroscopy,and nuclear magnetic resonance spectroscopy.The mean molecular weight of the copolymer was determined via gel permeation chromatography.The protein concentration of BCA the copolymer was determined via method.(2)In terms of preparation,characterization and in vitro pharmacokinetics of nanoparticles,Polymeric curcumin nanoparticles were prepared by emulsion-solvent evaporation method and the optimal preparation conditions were obtained.The nanoparticles were spherical and intact observed via transmission electron microscopy(TEM)and Fourier transform infrared spectroscopy(FT-IR)with high drug encapsulation efficiency.Moreover,the Cur-P-NPs suspensions maintained good storage stability and in vitro release study revealed that the cumulative release amount of Cur from the nanoparticles could achieve up to 89.39% after 84 h.(3)For safety evaluation,the cytotoxicity test of the enzyme sensitive blank nanoparticles(P-NPs)to normal fibroblast L929 cells was performed through MTT assay.The result showed that the nanoparticles were cell viable,which confirmed the safety of this formulation.In vitro pharmacodynamics and cell uptake study,the antitumor activity and cell uptake of Cur-NPs and enzyme sensitive Cur nanoparticles(Cur-P-NPs)against breast cancer cells MCF-7were investigated using free curcumin(Cur-DMSO)as positive control.The antitumor activity and cell uptake observed in all three test groups exhibit dose dependent,in which Cur-P-NPs revealed the highest cell inhibition effect with enhanced cell uptake.(4)In vivo Pharmacokinetics: Compared with free Cur-DMSO,theplasma concentration of Cur-P-NPs showed significant increment with prolonged residence time of curcumin in vivo.In vivo distribution study: The In vivo distribution of Cur-DMSO was observed mainly in the liver.In contrast,a majority of Cur-P-NPs were distributed in tumor site,without accumulation in other main organs.These results give a clear hint that the enzyme sensitive nano drug delivery systempossess a good targeting function.(5)Antitumor activity: the anti-tumor effect of saline,Cur-DMSO,Cur-NPs and Cur-P-NPs was investigated using MCF-7 nude mouse model.The results showed that Cur-P-NPsshowed the highest inhibition efficiency on tumor growth.Histopathological study: Compared with Cur-DMSO,Cur-P-NPs group showed a lesser lesion in main organ tissues but a mass necrosis in tumor tissue.These results demonstrated our Cur-P-NPs can decrease the toxic side effects and increase drug targeting delivery.