| Due to the fact that the enhanced permeability and retention effect(EPR)can improve the accumulation of nanoparticles in tumors which first introduced by Maeda,Nanoparticle based delivery formulations are widely used in cancer therapy.Nanoparticulate delivery system refers to the dispersion of fine particle size of 10-1000 nm which can improve drug solubility and tumor targeting.Liposome,polymer nanoparticle,polymeric micelle and macromolecular covalent conjugates are four kinds of the most studied nano drug delivery system.Paclitaxel(PTX)is effective in treating metastatic breast cancer,ovarian cancer,non-small cell lung cancer and stomach cancer.Taxol,Abraxane and Genexol-PM are the current clinical dosage form of PTX.Due to Cremophor EL,Taxol can cause serious side-effects,Abraxane and Genexol-PM eliminate the adverse effects associated with Cremophor but do not improve the pharmacokinetics of PTX.we had prepared three types of nano drug delivery systems : paclitaxel liposome(PTX-Lip)?paclitaxel self-assembled nanoparticles(PTX-SNPs)andpaclitaxel albumin nanoparticle(PTX-HSA)to improve the pharmacokinetics.The pharmacokinetics,biodistribution and pharmacodynamics were systematic comparative investigated.First of all,PTX-Lip was prepared using egg phosphatidylcholine,cholesterol,TPGS as carrier materials.The effects of drug/lipid ratio and the amount of TPGS were investigated to get a suitable particle size,encapsulation efficiency and physical stability of PTX-Lip.The results showed that when the drug lipid ratio was 1:20(w/w)and the concentration of TPGS was 5.5 mg/mL,liposome can be prepared with appropriate particle size of about 100 nm,good encapsulation efficiency up to 90% and good stability(it can be stabled at 4 °C for 6 days).Secondly,PTX-SNPs were prepared using Soluplus as carrier material.The effects of drug/polymer ratio,organic solvent species,ionic strength,pH value and media types on particle size and encapsulation efficiency were evaluated.The results showed that PTX-NPs could be prepared with particle size of approximately100 nm,spherical morphology and good encapsulation efficiency up to 90% when the drug/polymer ratio was 1/10,organic solvent was ethanol and the medium was water.The organic solvent species,ionic strength,pH value and media types had no effect on the particle size and encapsulation efficiency.Freeze-drying technique was utilized to prepare freeze-dried PTX-SNPs for facilitate storage.Through inspect the freeze-dryingprocess,5% mannitol was determined as lyoprotectant finally.In vitro release showed that PTX-Lip and PTX-SNPsmexhibited a sustained release behavior.Then the toxicity of PTX-Lip and PTX-SNPs on MCF-7 and A549 cells was investigated,PTX-HSA and paclitaxel solution were tested in parallel as control.No cytotoxicity was observed for blank polymeric micelles with either cell line,the toxicity of blank liposome and Cremophor EL-ethanol mixed solvent show concentration and time dependent manner.The IC50 values of Taxol solution,PTX-Lip,PTX-SNPs and PTX-HSA of MCF-7 cells were 14.7 ± 0.6,13.3 ±0.1,22.9 ± 1.9,38.8 ± 0.4?M at 24h;6.8 ± 0.2,6.7 ± 0.1,16.8 ± 0.4,17.4 ±1.1?M at 48h;were 5.0 ± 0.4,3.6 ± 0.1,11.4 ± 0.2,12.9 ± 1.2?M at 72h;the IC50 values of A549 cells were 11.2 ± 0.7,8.0 ± 0.7,11.8 ± 0.5,32.1 ±0.7?M at 24h;6.5 ± 0.1,4.1 ± 0.2,7.5 ± 0.7,20.6 ± 0.8?M at 48h;5.1 ± 0.5,3.1 ± 0.1,7.5 ± 0.2,18.4 ± 1.4?M at 72 h,respectively.The IC50 values of two cell lines of four formulations were PTX-Lip <paclitaxel solution < PTX-SNPs < PTX-HSA,showed that the strongest toxicity of PTX-Lip.Cellular uptake studies showed that all of the four formulations uptake cells in a concentration-dependent manner.At last in vivo studies were carried out of four PTX formulations.The AUC of paclitaxel solution?PTX-SNPs?PTX-Lip and PTX-HSA was18.502?13.944?10.373?4.887 mg/L*h,the clearance(CL)was 0.483?0.615?0.927?2.21 L/h/kg,the mean residence time(MRT)was 0.842?0.71?0.749?1.858 h,respectively.These parameters showed similar pharmacokinetic results of PTX-Lip,PTX-SNPs with paclitaxel solution with the characteristics of rapid eliminate in vivo and PTX-HSA had a long cycle effect.The biodistribution results showed three nano formulations in the distribution of mice were different with paclitaxel solution.PTX-Lip and PTX-HSA improved the targeting efficiency of heart,liver,kidney and tumour,TPX-SNPs was mostly distributed in the plasma.S180 tumor-bearing mices were set up to assess the therapeutic potential of four paclitaxel formulations,PTX-HSA showed the best antitumor effect,the inhibition was up to 82.8%,the inhibition of paclitaxel solution?PTX-Lip and TPX-PMs was 76.7%?65.4%?76%(2%Soluplus)and 69.1%(8%Soluplus),respectively.Survival time was24.5±4.7?25.8±5.6?22.3±7.3?22.3±5.9 and 24.8±3.4 days,and had no significant difference. |
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