SCIENCE CHINA Materials, Volume 60, Issue 10: 995-1007(2017) https://doi.org/10.1007/s40843-017-9107-x

Curcumin-encapsulated polymeric nanoparticles for metastatic osteosarcoma cells treatment

More info
  • ReceivedJul 11, 2017
  • AcceptedAug 27, 2017
  • PublishedSep 27, 2017


Osteosarcoma is a high-class malignant bone cancer with a less than 20% five-year survival rate due to its early metastasis potential. There is an urgent need to develop a versatile and innoxious drug to treat metastatic osteosarcoma. Curcumin (Cur) has shown its potential for the treatment of many cancers; however, the clinical implication of native curcumin is severely hindered by its intrinsic property. In this study, a mixed system of monomethoxy (polyethylene glycol)-poly(d, l-lactide-co-glycolide)/poly(ε-caprolactone) (mPEG-PLGA/PCL) was used to build a formulation of curcumin-encapsulated nanoparticles (Cur-NPs), which significantly improved the solubility, stability and cellular uptake of curcumin. Moreover, the Cur-NPs were superior to free curcumin in the matter of inhibition on the proliferation, migration and invasion of osteosarcoma 143B cells. It was found that both free curcumin and Cur-NPs could decrease the expressions of c-Myc and MMP7 in the level of mRNA and protein, which explained why free curcumin and Cur-NPs could inhibit the proliferation and invasion of metastatic osteosarcoma 143B cells. The Cur-NPs provided a promising strategy for metastatic osteosarcoma treatment.

Funded by

National Natural Science Foundation of China(51520105004,51673189,51390484,51403204,51673185,51473029,51503202)

Science and Technology Service Network Initiative(KFJ-SW-STS-166)

and the Chinese Academy of Sciences Youth Innovation Promotion Association.


This work was supported by the National Natural Science Foundation of China (51520105004, 51673189, 51390484, 51403204, 51673185, 51473029 and 51503202), Science and Technology Service Network Initiative (KFJ-SW-STS-166), and the Chinese Academy of Sciences Youth Innovation Promotion Association.

Interest statement

The authors declare that there is no conflict of interest.

Contributions statement

Wang G, Song W conceived and designed the reported research. Wang G mainly performed the whole experiments. Shen N provided related reagents. Yu H assisted to lyophilizate samples. Deng M, Tang Z and Fu X analyzed the data. Wang G wrote the manuscript. All authors discussed the results and commented on the manuscript. Tang Z revised the manuscript.

Author information

Guanyi Wang was born in 1990, a PhD candidate in Jilin university. Currently she is a joint PhD student in Professor Zhaohui Tang and Xuesi Chen’s group. She is majoring in biochemistry and molecular biology. Her research interests mainly focus on anti-tumor therapeutics.

Zhaohui Tang was born in 1976. Currently he is a professor at the Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences. His research interests include fabrication of nano-medicine, anti-tumor therapeutics and industrial development of biodegradable medical polymer materials.

Xueqi Fu was born in 1960. Currently he is a professor at Edmond H. Fischer Signal Transduction Laboratory, School of Life Sciences, Jilin University. His research interests focus on the cell signal transduction and anti-tumor drug screening.


[1] Kansara M, Teng MW, Smyth MJ, et al. Translational biology of osteosarcoma. Nat Rev Cancer, 2014, 14: 722-735 CrossRef PubMed Google Scholar

[2] Grimer RJ. Surgical options for children with osteosarcoma. Lancet Oncology, 2005, 6: 85-92 CrossRef Google Scholar

[3] Luetke A, Meyers PA, Lewis I, et al. Osteosarcoma treatment–Where do we stand? A state of the art review. Cancer Treatment Rev, 2014, 40: 523-532 CrossRef PubMed Google Scholar

[4] Li Y, Rogoff HA, Keates S, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA, 2015, 112: 1839-1844 CrossRef PubMed ADS Google Scholar

[5] Benjamin RS. Osteosarcoma: better treatment through better trial design. Lancet Oncology, 2015, 16: 12-13 CrossRef Google Scholar

[6] Kunnumakkara AB, Anand P, Aggarwal BB. Curcumin inhibits proliferation, invasion, angiogenesis and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett, 2008, 269: 199-225 CrossRef PubMed Google Scholar

[7] Heger M, van Golen RF, Broekgaarden M, et al. The molecular basis for the pharmacokinetics and pharmacodynamics of curcumin and its metabolites in relation to cancer. Pharmacol Rev, 2014, 66: 222-307 CrossRef PubMed Google Scholar

[8] Cheng AL, Hsu HC, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res, 2001, 21: 2895–2900. Google Scholar

[9] Dhillon N, Aggarwal BB, Newman RA, et al. Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res, 2008, 14: 4491-4499 CrossRef PubMed Google Scholar

[10] Liu L, Sun L, Wu Q, et al. Curcumin loaded polymeric micelles inhibit breast tumor growth and spontaneous pulmonary metastasis. Int J Pharm, 2013, 443: 175-182 CrossRef PubMed Google Scholar

[11] Gao X, Zheng F, Guo G, et al. Improving the anti-colon cancer activity of curcumin with biodegradable nano-micelles. J Mater Chem B, 2013, 1: 5778 CrossRef Google Scholar

[12] Yallapu MM, Nagesh PKB, Jaggi M, et al. Therapeutic applications of curcumin nanoformulations. AAPS J, 2015, 17: 1341-1356 CrossRef PubMed Google Scholar

[13] Chang Z, Xing J, Yu X. Curcumin induces osteosarcoma MG63 cells apoptosis via ROS/Cyto-C/Caspase-3 pathway. Tumor Biol, 2014, 35: 753-758 CrossRef PubMed Google Scholar

[14] Chang R, Sun L, Webster TJ. Selective inhibition of MG-63 osteosarcoma cell proliferation induced by curcumin-loaded self-assembled arginine-rich-RGD nanospheres. Int J Nanomedicine, 2015, 1: 3351 CrossRef PubMed Google Scholar

[15] Chen P, Wang H, Yang F, et al. Curcumin promotes osteosarcoma cell death by activating MiR-125a/ERRα signal pathway. J Cell Biochem, 2017, 118: 74-81 CrossRef PubMed Google Scholar

[16] Walters DK, Muff R, Langsam B, et al. Cytotoxic effects of curcumin on osteosarcoma cell lines. Invest New Drugs, 2008, 26: 289-297 CrossRef PubMed Google Scholar

[17] Jin S, Xu H, Shen J, et al. Apoptotic effects of curcumin on human osteosarcoma U2OS cells. Orthop Surg, 2009, 1: 144-152 CrossRef PubMed Google Scholar

[18] Fossey SL, Bear MD, Lin J, et al. The novel curcumin analog FLLL32 decreases STAT3 DNA binding activity and expression, and induces apoptosis in osteosarcoma cell lines. BMC Cancer, 2011, 11: 112 CrossRef PubMed Google Scholar

[19] Peng SF, Lee CY, Hour MJ, et al. Curcumin-loaded nanoparticles enhance apoptotic cell death of U2OS human osteosarcoma cells through the Akt-Bad signaling pathway. Int J Oncol, 2014, 44: 238-246 CrossRef PubMed Google Scholar

[20] Fatima MT, Chanchal A, Yavvari PS, et al. Cell permeating nano-complexes of amphiphilic polyelectrolytes enhance solubility, stability, and anti-cancer efficacy of curcumin. Biomacromolecules, 2016, 17: 2375-2383 CrossRef PubMed Google Scholar

[21] Si M, Zhao J, Li X, et al. Reversion effects of curcumin on multidrug resistance of MNNG/HOS human osteosarcoma cells in vitro and in vivo through regulation of P-glycoprotein. Chin Med J, 2013, 126: 4116–4123. Google Scholar

[22] Dhule SS, Penfornis P, Frazier T, et al. Curcumin-loaded γ-cyclodextrin liposomal nanoparticles as delivery vehicles for osteosarcoma. Nanomed-Nanotech Biol Med, 2012, 8: 440-451 CrossRef PubMed Google Scholar

[23] Luu HH, Kang Q, Park JK, et al. An orthotopic model of human osteosarcoma growth and spontaneous pulmonary metastasis. Clin Exp Metastasis, 2005, 22: 319-329 CrossRef PubMed Google Scholar

[24] He N, Zhang Z. Baicalein suppresses the viability of MG-63 osteosarcoma cells through inhibiting c-MYC expression via Wnt signaling pathway. Mol Cell Biochem, 2015, 405: 187-196 CrossRef PubMed Google Scholar

[25] Lin CY, Lovén J, Rahl PB, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell, 2012, 151: 56-67 CrossRef PubMed Google Scholar

[26] Dang CV. MYC on the path to cancer. Cell, 2012, 149: 22-35 CrossRef PubMed Google Scholar

[27] Wu CH, van Riggelen J, Yetil A, et al. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci USA, 2007, 104: 13028-13033 CrossRef PubMed ADS Google Scholar

[28] Lin L, Zhang JH, Panicker LM, et al. The parafibromin tumor suppressor protein inhibits cell proliferation by repression of the c-myc proto-oncogene. Proc Natl Acad Sci USA, 2008, 105: 17420-17425 CrossRef PubMed ADS Google Scholar

[29] Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 2010, 141: 52-67 CrossRef PubMed Google Scholar

[30] Szarvas T, Becker M, vom Dorp F, et al. Matrix metalloproteinase-7 as a marker of metastasis and predictor of poor survival in bladder cancer. Cancer Sci, 2010, 101: 1300-1308 CrossRef PubMed Google Scholar

[31] Hu XT, Zhang FB, Fan YC, et al. Phospholipase C delta 1 is a novel 3p22.3 tumor suppressor involved in cytoskeleton organization, with its epigenetic silencing correlated with high-stage gastric cancer. Oncogene, 2009, 28: 2466-2475 CrossRef PubMed Google Scholar

[32] Sakamoto N, Naito Y, Oue N, et al. MicroRNA-148a is downregulated in gastric cancer, targets MMP7, and indicates tumor invasiveness and poor prognosis. Cancer Sci, 2014, 105: 236-243 CrossRef PubMed Google Scholar

[33] Song N, Liu H, Ma X, et al. Placental growth factor promotes metastases of ovarian cancer through MiR-543-regulated MMP7. Cell Physiol Biochem, 2015, 37: 1104-1112 CrossRef PubMed Google Scholar

[34] Han G, Wang Y, Bi W. c-Myc overexpression promotes osteosarcoma cell invasion via activation of MEK-ERK pathway. Oncol Res Feat Preclin Clin Cancer Therap, 2012, 20: 149-156 CrossRef Google Scholar

[35] Song W, Tang Z, Li M, et al. Polypeptide-based combination of paclitaxel and cisplatin for enhanced chemotherapy efficacy and reduced side-effects. Acta Biomater, 2014, 10: 1392-1402 CrossRef PubMed Google Scholar

[36] Song W, Tang Z, Lei T, et al. Stable loading and delivery of disulfiram with mPEG-PLGA/PCL mixed nanoparticles for tumor therapy. Nanomed-Nanotech Biol Med, 2016, 12: 377-386 CrossRef PubMed Google Scholar

[37] Franken NAP, Rodermond HM, Stap J, et al. Clonogenic assay of cells in vitro. Nat Protoc, 2006, 1: 2315-2319 CrossRef PubMed Google Scholar

[38] Yallapu MM, Khan S, Maher DM, et al. Anti-cancer activity of curcumin loaded nanoparticles in prostate cancer. Biomaterials, 2014, 35: 8635-8648 CrossRef PubMed Google Scholar

[39] Tian J, Min Y, Rodgers Z, et al. Nanoparticle delivery of chemotherapy combination regimen improves the therapeutic efficacy in mouse models of lung cancer. Nanomed-Nanotech Biol Med, 2017, 13: 1301-1307 CrossRef PubMed Google Scholar

[40] Wang Z, Tan J, McConville C, et al. Poly lactic-co-glycolic acid controlled delivery of disulfiram to target liver cancer stem-like cells. Nanomed-Nanotech Biol Med, 2017, 13: 641-657 CrossRef PubMed Google Scholar

[41] Shen Y. Elastin-like polypeptide fusion for precision design of protein-polymer conjugates with improved pharmacology. Sci China Mater, 2015, 58: 767-768 CrossRef Google Scholar

[42] Zhang Y, Xiao CS, Li MQ, et al. Co-delivery of doxorubicin and paclitaxel with linear-dendritic block copolymer for enhanced anti-cancer efficacy. Sci China Chem, 2014, 57: 624-632 CrossRef Google Scholar

[43] Xu C, Tian H, Chen X. Recent progress in cationic polymeric gene carriers for cancer therapy. Sci China Chem, 2017, 60: 319-328 CrossRef Google Scholar

[44] Wang J, Liu Y, Ma Y, et al. NIR-activated supersensitive drug release using nanoparticles with a flow core. Adv Funct Mater, 2016, 26: 7516-7525 CrossRef Google Scholar

[45] Li D, Ma Y, Du J, et al. Tumor acidity/NIR controlled interaction of transformable nanoparticle with biological systems for cancer therapy. Nano Lett, 2017, 17: 2871-2878 CrossRef PubMed ADS Google Scholar

[46] Leung MHM, Kee TW. Effective stabilization of curcumin by association to plasma proteins: human serum albumin and fibrinogen. Langmuir, 2009, 25: 5773-5777 CrossRef PubMed Google Scholar

[47] Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotech, 2011, 6: 815-823 CrossRef PubMed ADS Google Scholar

[48] Li Y. Realize molecular surgical knife in tumor therapy by nanotechnology. Sci China Mater, 2015, 58: 851-851 CrossRef Google Scholar

[49] Zhen M, Shu C, Li J, et al. A highly efficient and tumor vascular-targeting therapeutic technique with size-expansible gadofullerene nanocrystals. Sci China Mater, 2015, 58: 799-810 CrossRef Google Scholar

[50] Yang X, Li Z, Wang N, et al. Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo. Sci Rep, 2015, 5: 10322 CrossRef PubMed ADS Google Scholar

[51] Wang YJ, Pan MH, Cheng AL, et al. Stability of curcumin in buffer solutions and characterization of its degradation products. J Pharm Biomed Anal, 1997, 15: 1867-1876 CrossRef Google Scholar

[52] Kaur K, Kumar R, Mehta SK. Nanoemulsion: a new medium to study the interactions and stability of curcumin with bovine serum albumin. J Mol Liquids, 2015, 209: 62-70 CrossRef Google Scholar

[53] Mohanty C, Acharya S, Mohanty AK, et al. Curcumin-encapsulated MePEG/PCL diblock copolymeric micelles: a novel controlled delivery vehicle for cancer therapy. Nanomedicine, 2010, 5: 433-449 CrossRef PubMed Google Scholar

[54] Li C, Luo T, Zheng Z, et al. Curcumin-functionalized silk materials for enhancing adipogenic differentiation of bone marrow-derived human mesenchymal stem cells. Acta Biomater, 2015, 11: 222-232 CrossRef PubMed Google Scholar

  • Figure 1

    Preparation of Cur-encapsulated mPEG-PLGA/PCL nanoparticles. (a) Schematic diagram of the prepared Cur-NPs; (b) appearance of free Cur in DMSO, free Cur in water, Cur-NPs in water, 2 mg mL−1 pure Cur equivalent.

  • Figure 2

    Properties of Cur-NPs. (a) Particle size of Cur-NPs measured by DLS; (b) TEM image of Cur-NPs; (c) CAC; (d) in vitro drug release of Cur-NPs.

  • Figure 3

    The stability of Cur-NPs and Cur in water and PBS with 10% FBS. (a, b) Particle sizes and intensities of Cur-NPs determined by DLS (n=3); (c, d) residual curcumin of free curcumin (Cur) and Cur-NPs (n=3).

  • Figure 4

    In vitro cytotoxicity and cellular uptakes of Cur and Cur-NPs. (a, b) Cytotoxicity of free Cur and Cur-NPs after 24 or 48 h treatment (n=4); (c) CLSM observations (A: Cur, B: Cur-NPs, Scale bars, 100 μm) and (d, e) FCM analysis for cellular uptakes of Cur and Cur-NPs by 143B cells after treatment with free Cur or Cur-NPs for 1 or 3 h.

  • Figure 5

    Suppression of colony formation of 143B cells by free Cur and Cur-NPs (n=5). (a) Observations under an inverted microscope; (b) the counted cloning efficiencies (* p<0.05, * * p<0.01).

  • Figure 6

    The inhibition effect of Cur and Cur-NPs on cell migration and invasion. (a, b) Inhibitory effect on 143B cells migration by free Cur or Cur-NPs (scale bars, 200 μm; n=3, Mean±SD, * p<0.05, * * p<0.01); (c, d) changes of 143B cells invasion after treatment with free Cur and Cur-NPs (Scale bars, 100 μm; n=5, mean±SD, * p<0.05, ** p<0.01).

  • Figure 7

    Cell apoptosis analysis of 143B cells by FCM.

  • Figure 8

    The c-Myc and MMP7 expressions. (a, b) Relative mRNA level of c-Myc and MMP7; (c) western blotting of c-Myc protein and MMP7 protein ( * p<0.05, * * p<0.01).

Copyright 2020 Science China Press Co., Ltd. 《中国科学》杂志社有限责任公司 版权所有

京ICP备18024590号-1       京公网安备11010102003388号