| In recent years,nanostructured lipid carriers(NLCs)have attracted broader concerns because of their ideal biocompatibility,high drug loading,good stability and easy-release,etc.Paclitaxel(PTXL)and gemcitabine(GEM)showed independent mechanism and nonoverlapping toxicity in the treatment of non-small cell lung cancer(NSCLC).Therefore,PTXL and GEM are effective combination anticancer drugs against NSCLC.In this paper,two kinds of GEM/PTXL dual-drug NLCs were designed and synthesized,and in vivo and in vitro antitumor activities were studied in detail.(1)Tumor-targeted polymeric nanostructured lipid carriers with precise ratiometric control over GEM/PTXL dual-drug loading for combination therapyAt present,one of the main challenges of combined administration is precision ratiometric control,which can optimize the effect of combined action.In this study,hydrophilic GEM and hydrophobic PTXL were inserted into tumor targeting NLCs to accurately control the ratio of the two drugs.These two drugs are covalently conjugated by hydrolyzable ester bond to form drug conjugates.N-acetyl-d-glucosamine(NAG)as a glucose receptor-targeted ligand,which could target to cancer cells,was added in the preparation of NAG-NLCs.We have designed and synthesized the poly(6-O-methacryloyl-D-galactopyranose)-GEM/PTXL(PMAGP-GEM/PTXL)conjugate and prepared NAG-NLCs by emulsification and solvent evaporation.NAG-NLCs was spherical,with an average particle size of 120.3 ± 1.3 nm and a polydispersity index of 0.233 ±0.04,and showed a precise proportional control for both drugs.Cytotoxicity test showed that NAG-NLCs had good antitumor activity on NSCLC cells.In addition,we found the optimal ratio of two drugs in the experiment,which showed the best cytotoxicity and combinatorial effect.PMAGP-GEM/PTXL NAG-NLCs(3:1)had better synergistic effects than free drug combination and separately nanopackaged drug conjugates.Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis.This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC.(2)Stimulus-responsive GEM/PTXL dual-drug targeting nanostructured lipid carriersGemcitabine(GEM)and paclitaxel(PTXL)were proved to have a more remarkable therapeutic effect on non-small-cell lung cancer(NSCLC)than any of the individuals alone,and PTXL administered prior to GEM might be preferable than the reverse order.In this paper,stimuli-sensitive nanostructured lipid carriers(NLCs)were prepared to enhance synergistical efficiency of GEM and PTXL.PTXL-ss-poly(6-O-methacryloyl-d-galactopyranose)-GEM(PTXL-ss-PMAGP-GEM)was prepared by grafting hydrophilic GEM via succinic anhydride and hydrophobic PTXL via redox-sensitive 3,3'-dithiodipropionic acid to PMAGP,respectively.An amphiphilic block copolymer NAG-poly(styrene-alt-maleic anhydride)58-b-polystyrene130(NAG-P(St-alt-MA)58-b-PSt130)was added as a targeting material to prepared nanostructured lipid carriers(PTXL-ss-PMAGP-GEM/NAG NLCs)using emulsification and solvent evaporation.The PTXL-ss-PMAGP-GEM/NAG NLCs had homogeneous size and high drug encapsulation efficiency.In vitro drug release experiments reinforced that PTXL possessed intracellular GSH-triggered release characteristics,and discovered that the drugs were released sequentially with PTXL prior to GEM.The targeting effects of PTXL-ss-PMAGP-GEM/NAG NLCs were demonstrated by in vitro and in vivo analysis.In vitro cytotoxicity analysis and in vivo antitumor assay showed that PTXL-ss-PMAGP-GEM/NAG NLCs exhibited dramatic antitumor effect and optimal synergistic effect.These results may offer an effective combination drug delivery system for NSCLC targeting therapy. |
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