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. 2016 Nov 2:6:36281.
doi: 10.1038/srep36281.

Tumour microenvironment-responsive lipoic acid nanoparticles for targeted delivery of docetaxel to lung cancer

Fenfen Gu  1 , Chuling Hu  1 , Zhongguang Tai  1 , Chong Yao  1 , Jing Tian  1 , Lijuan Zhang  1 , Qingming Xia  1 , Chunai Gong  1 , Yuan Gao  1   2 , Shen Gao  1
Affiliations

Tumour microenvironment-responsive lipoic acid nanoparticles for targeted delivery of docetaxel to lung cancer

Fenfen Gu et al. Sci Rep. .

Abstract

In the present study, we developed a novel type of reduction-sensitive nanoparticles (NPs) for docetaxel (DTX) delivery based on cross-linked lipoic acid NPs (LANPs). The physicochemical properties, cellular uptake and in vitro cytotoxicity of DTX loaded LANPs (DTX-LANPs) on A549 cells were investigated. Furthermore, the in vivo distribution and in vivo efficacy of DTX-LANPs was evaluated. The results showed that DTX-LANPs had a particle size of 110 nm and a negative zeta potential of -35 mv with excellent colloidal stability. LANPs efficiently encapsulated DTX with a high drug loading of 4.51% ± 0.49% and showed remarkable reduction-sensitive drug release in vitro. Cellular uptake experiments demonstrated that LANPs significantly increased intracellular DTX uptake by about 10 fold as compared with free DTX. The cytotoxicity of DTX-LANPs showed significantly higher potency in inhibiting A549 cell growth than free DTX, while blank LANPs had a good biocompatibility. In addition, in vivo experiments demonstrated that DTX-LANPs could enhance tumour targeting and anti-tumour efficacy with low systemic toxicity. In conclusion, LANPs may prove to be a potential tumour microenvironment-responsive delivery system for cancer treatment, with the potential for commercialization due to the simple component, controllable synthesis, stability and economy.

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Figures

Figure 1
Figure 1
The syntheic scheme of cross-linked lipoic acid (A), and the action mechanism of LANPs (B).
Figure 2
Figure 2
The graph of ultraviolet and visible absorption of cross-linked lipoic acid and non- cross-linked lipoic acid (A), and GPC of crosslinked lipoic acid (B).
Figure 3
Figure 3
The size distribution and zeta potential of LANPs (A,B). The morphology of LANPs observed by TEM (C).
Figure 4
Figure 4
The effect of concentrations (A), 10% FBS (B), and pH (C) on the size and PDI of LANPs. The stability of LANPs was evaluated by size and zeta potential within 15 days in PBS (pH = 5.5 or 7.4) (D). Data are represented as mean  ± SD (n = 3).
Figure 5
Figure 5. In vitro DTX release of DTX-LANPs in PBS containing 0.5% Tween-80 (B).
Data are shown as mean ± SD (n = 3).
Figure 6
Figure 6. Cellular uptake of free coumarin 6 (C-6), coumarin-6 loaded LANPs (C-6/LANPs), and coumarin-6 loaded PLGANPs (C-6/PLGA) in A549 cells.
CLAM images were observed after 4 h incubation with 60 ng/ml C-6 (A). C-6/NPs exhibited green, and the lysosome was stained by LysoTracker® Red. The quantitative research of different concentrations of C-6 was tested by FCM in A549 cells. Data are shown as mean ± SD (n = 3). The comparison between two groups is analyzed by Independent Sample’s T test (ns. p > 0.05, ***p < 0.001).
Figure 7
Figure 7. The endocytosis mechanism of LANPs.
The flow cytometric data of LANPs uptake handled with different endocytosis inhibitors (A). Effects of different endocytic inhibitors of LANPs uptake on A549 cells (B). Data are shown as mean ± SD. (n = 3). *p < 0.05, **p < 0.01. Comparison between two groups is analyzed by Independent Sample’s T test.
Figure 8
Figure 8. In vitro cytotoxicity of the NPs in A549cells at 24 and 48 h.
The cytotoxicity of blank LANPs and PLGANPs (A,B), and free DTX-loaded LANPs (DTX-LANPs) and DTX-loaded PLGANPs (DTX-PLGANPAs) (C,D). Data are shown as mean ± SD (n = 3).
Figure 9
Figure 9. Cell apoptosis of A549 cells treated with free DTX, DTX-LANPs and DTX-PLGANPs at a DTX concentration of 10 ng/ml for 48 h.
Flow cytometry data of different treatment groups (A). Quantitative analysis of cells apoptosis (B). a, p < 0.0 vs. control; b, p < 0.01 vs. DTX; c, p < 0.05 vs. DTX-PLGANPs (n = 3).
Figure 10
Figure 10. Cell cycle of A549 cells after treatment at a DTX concentration of 10 ng/ml with free DTX, DTX-LANPs and DTX-PLGANPs for 48 h.
Flow cytometry data of different groups (A). Quantitative analysis of cell cycle (B). a, p < 0.0 vs. control; b, p < 0.01 vs. DTX; c, p < 0.05 vs. DTX-PLGANPs (n = 3).
Figure 11
Figure 11. In vivo images of A549 transplantation tumour-bearing nude mice after injection with PBS, DiR loaded LANPs (LA-DiR) or DiR loaded (PLGA-DiR) through the tail vein.
The images of flourescence distribution in the whole body at different time points (A). The images of excised organs and tumors ex vivo after 24-h injection (B).
Figure 12
Figure 12. The anti-tumor efficiency in vivo in different treatment groups in A549 bearing nude mice.
The change of tumor volume indicated tumor growth curves (A). The enlarged exhibition of tumor growth in free DTX, DTX-LANPs and DTX-PLGANPs treatment groups (B). The images of excised tumors (C). The tumor weighed at the end of test (D). The change of body weight of A549 bearing nude mice after treatment (E). The decrease rate of body weight was measured at the end of the test, “-” indicating body weight increase (F). The tumor inhibitory rate measured with excised tumor weight.
Figure 13
Figure 13. H&E stained tumors from A549 tumor-bearing nude mice treated with PBS, blank LANPs, DTX, DTX-PLGANPs or DTX-LANPs.
The images were observed with a Leica microscope at 200X magnification.
See this image and copyright information in PMC

References

    1. Rashmi H. P., Vandana B. P. & Medha D. J. Polymeric nanoparticles for targeted treatment in oncology: current insights. Int J Nanomedicine 10, 1001–1018 (2015). - PMC - PubMed
    1. Lee A. L., Wang Y., Cheng H. Y., Pervaiz S. & Yang Y. Y. The codelivery of paclitaxel and Herceptin using cationic micellar nanoparticles. Biomaterials 30, 919–927 (2009). - PubMed
    1. Wang H. et al.. Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterial 32, 8281–8890 (2011). - PubMed
    1. Chen M. C., Sonaje K., Chen K. J. & Sung H. W. A review of the prospects for polymeric nanoparticle platforms in oral insulin delivery. Biomaterials 32, 9826–9838 (2011). - PubMed
    1. Park S. et al.. Tumor suppression via paclitaxel-loaded drug carriers that target inflammation marker upregulated in tumor vasculature and macrophages. Biomaterials 34, 598–605 (2013). - PubMed

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