Journal of Materials Science

, Volume 55, Issue 4, pp 1702–1714 | Cite as

Drug carrier for sustained release of withaferin A for pancreatic cancer treatment

  • Qi Shao
  • Yechen Feng
  • Wenwu Wang
  • Min Wang
  • Binbin Li
  • Mario El Tahchi
  • Yixia YinEmail author
Materials for life sciences


Chemotherapeutic drugs have shown some limitations in anti-tumor treatment, such as drug resistance, high toxicity and limited regime of clinical uses. Natural products have attracted extensive attention as potential source of unmodified chemical compounds for disease treatment. Withaferin A (WA) has the potential to inhibit multiple human tumors, but it is hardly available for oral administration due to its low water solubility and its side effects. We developed a methoxy poly(ethylene glycol) (mPEG) conjugated poly(d,l-lactide-co-glycolide) (PLGA) drug carrier particles to encapsulate WA for pancreatic cancer treatment. The results showed that WA does not lose its physicochemical properties after encapsulation, and our drug carriers are completely degraded within 1 month. We used the WA-loaded mPEG–PLGA particles for pancreatic cancer cell treatment where it exhibited stronger inhibition than free drug (WA) at the early treatment stage. Our formulation of the drug carriers provides an efficient encapsulation of WA that allows it bonding with heat shock proteins, thereby reducing the expression of AKT and CDK4 proteins to induce apoptosis in cancer cells. Together, our data demonstrate that mPEG–PLGA loaded with WA can achieve the design goals for cancer therapy given its advantages of sustained release and degradation property to reduce the side effect of WA, which provides a possibility for WA to be used in clinical applications.



This work was supported by National Key Research and Development Program of China (No. 2016YFC1101302), and the National Natural Science Foundation of China (81773160, 51572206), HUBEI Natural Science Foundation (2017CFB467) to MW, and Tongji Hospital Science Fund for Distinguished Young Scholars (2017) to MW.

Compliance with ethical standards

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Supplementary material

10853_2019_4139_MOESM1_ESM.docx (616 kb)
Supplementary material 1 (DOCX 616 kb)


  1. 1.
    Kumar M, Liu ZR, Thapa L, Wang DY, Tian R, Qin RY (2004) Mechanisms of inhibition of growth of human pancreatic carcinoma implanted in nude mice by somatostatin receptor subtype 2. Pancreas 29(2):141–151Google Scholar
  2. 2.
    Michl P, Gress TM (2013) Current concepts and novel targets in advanced pancreatic cancer. Gut 62(2):317–326Google Scholar
  3. 3.
    Siegel R, Naishadham D, Jemal A (2012) Cancer statistics. CA Cancer J Clin 62(1):10–29Google Scholar
  4. 4.
    Nd MW (2006) Ancient medicine, modern use: withania somnifera and its potential role in integrative oncology. Altern Med Rev 11:269–278Google Scholar
  5. 5.
    Kumar M, Liu ZR, Thapa L, Qin RY (2004) Anti-angiogenic effects of somatostatin receptor subtype 2 on human pancreatic cancer xenografts. Carcinogenesis 25(11):2075–2081Google Scholar
  6. 6.
    Okamoto S, Tsujioka T, Suemori S, Kida J, Kondo T, Tohyama Y, Tohyama K (2016) Withaferin A suppresses the growth of myelodysplasia and leukemia cell lines by inhibiting cell cycle progression. Cancer Sci 107(9):1302–1314Google Scholar
  7. 7.
    Wang Z, Dabrosin C, Yin X et al (2015) Broad targeting of angiogenesis for cancer prevention and therapy. Semin Cancer Biol 35(Suppl):S224–S243Google Scholar
  8. 8.
    Debernardi S, Massat NJ, Radon TP, Sangaralingam A, Banissi A, Ennis DP, Dowe T, Chelala C et al (2015) Noninvasive urinary miRNA biomarkers for early detection of pancreatic adenocarcinoma. Am J Cancer Res 5(11):3455–3466Google Scholar
  9. 9.
    Li X, Zhu F, Jiang JX, Sun CY, Wang X, Shen M, Tian R, Shi CJ et al (2015) Synergistic antitumor activity of withaferin A combined with oxaliplatin triggers reactive oxygen species-mediated inactivation of the PI3 K/AKT pathway in human pancreatic cancer cells. Cancer Lett 357(1):219–230Google Scholar
  10. 10.
    Matsuda Y, Naito Z, Kawahara K, Nakazawa N, Korc M, Ishiwata T (2011) Nestin is a novel target for suppressing pancreatic cancer cell migration, invasion and metastasis. Cancer Biol Ther 11(5):512–523Google Scholar
  11. 11.
    Aqil F, Jeyabalan J, Kausar H, Bansal SS, Sharma RJ, Singh IP, Vadhanam MV, Gupta RC (2012) Multi-layer polymeric implants for sustained release of chemopreventives. Cancer Lett 326(1):33–40Google Scholar
  12. 12.
    Han YC, Li SP, Cao XY, Yuan L, Wang YF, Yin YX, Qiu T, Dai HL, Wang XY (2014) Different inhibitory effect and mechanism of hydroxyapatite nanoparticles on normal cells and cancer cells in vitro and in vivo. Sci Rep 4:7134Google Scholar
  13. 13.
    Wang H, Zhao Y, Wu Y, Hu YL, Nan KH, Nie GJ, Chen H (2011) Enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG–PLGA copolymer nanoparticles. Biomaterials 32(32):8281–8290Google Scholar
  14. 14.
    Bhatnagar P, Kumari M, Pahuja R, Pant AB, Shukla Y, Kumar P, Gupta KC (2018) Hyaluronic acid-grafted PLGA nanoparticles for the sustained delivery of berberine chloride for an efficient suppression of Ehrlich ascites tumors. Drug Deliv Transl Res 8(3):565–579Google Scholar
  15. 15.
    Park J, Fong PM, Lu J, Russell KS, Booth CJ, Saltzman WM, Fahmy TM (2009) PEGylated PLGA nanoparticles for the improved delivery of doxorubicin. Nanomed Nanotechnol Biol Med 5(4):410–418Google Scholar
  16. 16.
    Shen M, Xu YY, Sun Y, Han BS, Duan YR (2015) Preparation of a thermosensitive gel composed of a mPEG–PLGA–PLL–cRGD nanodrug delivery system for pancreatic tumor therapy. ACS Appl Mater Interfaces 7(37):20530–20537Google Scholar
  17. 17.
    Cu Y, Saltzman WM (2009) Controlled surface modification with poly(ethylene)glycol enhances diffusion of PLGA nanoparticles in human cervical mucus. Mol Pharm 6(1):173–181Google Scholar
  18. 18.
    Danhier F, Lecouturier N, Vroman B, Jerome C, Marchand-Brynaert J, Feron O, Preat V (2009) Paclitaxel-loaded PEGylated PLGA-based nanoparticles: in vitro and in vivo evaluation. J Control Release 133(1):11–17Google Scholar
  19. 19.
    Zhang KR, Tang X, Zhang J, Lu W, Lin X, Zhang Y, Tian B, Yang H et al (2014) PEG–PLGA copolymers: their structure and structure-influenced drug delivery applications. J Control Release 183:77–86Google Scholar
  20. 20.
    Li J, Jiang GQ, Ding FX (2008) The effect of pH on the polymer degradation and drug release from PLGA–mPEG microparticles. J Appl Polym Sci 109(1):475–482Google Scholar
  21. 21.
    Guo Y, He W, Yang S, Zhao D, Li Z, Luan Y (2017) Co-delivery of docetaxel and verapamil by reduction-sensitive PEG–PLGA–SS–DTX conjugate micelles to reverse the multi-drug resistance of breast cancer. Colloids Surf B Biointerfaces 151:119–127Google Scholar
  22. 22.
    Liu P, Yu H, Sun Y, Zhu M, Duan Y (2012) A mPEG–PLGA–b-PLL copolymer carrier for adriamycin and siRNA delivery. Biomaterials 33(17):4403–4412Google Scholar
  23. 23.
    Qureshi WA, Zhao RF, Wang H, Ji TJ, Ding YP, Ihsan A, Mujeeb A, Nie GJ et al (2016) Co-delivery of doxorubicin and quercetin via mPEG–PLGA copolymer assembly for synergistic anti-tumor efficacy and reducing cardio-toxicity. Sci Bull 61(21):1689–1698Google Scholar
  24. 24.
    Wang L, Hu Y, Hao Y, Li L, Zheng C, Zhao H et al (2018) Tumor-targeting core-shell structured nanoparticles for drug procedural controlled release and cancer sonodynamic combined therapy. J Control Release 286:74–84Google Scholar
  25. 25.
    Zhang X, Wang Q, Qin L, Fu H, Fang Y, Han B, Duan Y (2016) EGF-modified mPEG–PLGA–PLL nanoparticle for delivering doxorubicin combined with Bcl-2 siRNA as a potential treatment strategy for lung cancer. Drug Deliv 23(8):2936–2945Google Scholar
  26. 26.
    Mosquera J, Garcia I, Liz-Marzan LM (2018) Cellular uptake of nanoparticles versus small molecules: a matter of size. Accounts Chem Res 51(9):2305–2313Google Scholar
  27. 27.
    Zhou YQ, Peng ZL, Seven ES, Leblanc RM (2018) Crossing the blood-brain barrier with nanoparticles. J Control Release 270:290–303Google Scholar
  28. 28.
    He Z, Sun Y, Cao J, Duan Y (2016) Degradation behavior and biosafety studies of the mPEG–PLGA–PLL copolymer. Phys Chem Chem Phys 18(17):11986–11999Google Scholar
  29. 29.
    Teng Y, Bai M, Sun Y, Wang Q, Li F, Duan Y et al (2015) Enhanced delivery of PEAL nanoparticles with ultrasound targeted microbubble destruction mediated siRNA transfection in human MCF-7/S and MCF-7/ADR cells in vitro. Int J Nanomed 10:5447–5457Google Scholar
  30. 30.
    Hanson JA, Chang CB, Graves SM, Li Z, Mason TG, Deming TJ (2008) Nanoscale double emulsions stabilized by single-component block copolypeptides. Nature 455(7209):85–88Google Scholar
  31. 31.
    Dinsmore AD, Hsu MF, Nikolaides MG, Marquez M, Bausch AR, Weitz DA (2002) Colloidosomes: selectively permeable capsules composed of colloidal particles. Science 298(5595):1006–1009Google Scholar
  32. 32.
    Moussa EM, Panchal JP, Moorthy BS, Blum JS, Joubert MK, Narhi LO, Topp EM (2016) Immunogenicity of therapeutic protein aggregates. J Pharm Sci 105(2):417–430Google Scholar
  33. 33.
    Nunes C, Suryanarayanan R, Botez CE, Stephens PW (2004) Characterization and crystal structure of d-mannitol hemihydrate. J Pharm Sci 93(11):2800–2809Google Scholar
  34. 34.
    Garidel P, Pevestorf B, Bahrenburg S (2015) Stability of buffer-free freeze-dried formulations: a feasibility study of a monoclonal antibody at high protein concentrations. Eur J Pharm Biopharm 97:125–139Google Scholar
  35. 35.
    Nicoud L, Owczarz M, Arosio P, Morbidelli M (2015) A multiscale view of therapeutic protein aggregation: a colloid science perspective. Biotechnol J 10(3):367–378Google Scholar
  36. 36.
    Wen L, Zheng X, Wang X, Lan H, Yin Z (2017) Bilateral effects of excipients on protein stability: preferential interaction type of excipient and surface aromatic hydrophobicity of protein. Pharm Res 34(7):1378–1390Google Scholar
  37. 37.
    Aryal S, Prabaharan M, Pilla S, Gong S (2009) Biodegradable and biocompatible multi-arm star amphiphilic block copolymer as a carrier for hydrophobic drug delivery. Int J Biol Macromol 44(4):346–352Google Scholar
  38. 38.
    Decuzzi P, Godin B, Tanaka T, Lee SY, Chiappini C, Liu X, Ferrari M (2010) Size and shape effects in the biodistribution of intravascularly injected particles. J Control Release 141(3):320–327Google Scholar
  39. 39.
    Gu M, Yu Y, Gunaherath G, Gunatilaka A, Li D, Sun D (2014) Structure–activity relationship (SAR) of withanolides to inhibit Hsp90 for its activity in pancreatic cancer cells. Invest New Drugs 32(1):68–74Google Scholar
  40. 40.
    Liu X, Qi W, Cooke LS, Kithsiri Wijeratne EM, Xu Y, Marron MT, Leslie Gunatilaka AA, Mahadevan D (2011) An analog of withaferin A activates the MAPK and glutathione “stress” pathways and inhibits pancreatic cancer cell proliferation. Cancer Invest 29(10):668–675Google Scholar
  41. 41.
    Yoneyama T, Arai MA, Sadhu SK, Ahmed F, Ishibashi M (2015) Hedgehog inhibitors from Withania somnifera. Bioorg Med Chem Lett 25(17):3541–3544Google Scholar
  42. 42.
    Bauer TW, Liu W, Fan F, Camp ER, Yang A, Somcio RJ et al (2005) Targeting of urokinase plasminogen activator receptor in human pancreatic carcinoma cells inhibits c-Met- and insulin-like growth factor-I receptor-mediated migration and invasion and orthotopic tumor growth in mice. Cancer Res 65(17):7775–7781Google Scholar
  43. 43.
    Bi Y, Min M, Shen W, Liu Y (2016) Numb/Notch signaling pathway modulation enhances human pancreatic cancer cell radiosensitivity. Tumour Biol 37(11):15145–15155Google Scholar
  44. 44.
    Gu WJ, Liu HL (2013) Induction of pancreatic cancer cell apoptosis, invasion, migration, and enhancement of chemotherapy sensitivity of gemcitabine, 5-FU, and oxaliplatin by hnRNP A2/B1 siRNA. Anticancer Drugs 24(6):566–576Google Scholar
  45. 45.
    Kikuta K, Masamune A, Watanabe T, Ariga H, Itoh H, Hamada S et al (2010) Pancreatic stellate cells promote epithelial–mesenchymal transition in pancreatic cancer cells. Biochem Biophys Res Commun 403(3–4):380–384Google Scholar
  46. 46.
    Sun XD, Liu XE, Huang DS (2013) Curcumin reverses the epithelial–mesenchymal transition of pancreatic cancer cells by inhibiting the Hedgehog signaling pathway. Oncol Rep 29(6):2401–2407Google Scholar
  47. 47.
    Xu WT, Bian ZY, Fan QM, Li G, Tang TT (2009) Human mesenchymal stem cells (hMSCs) target osteosarcoma and promote its growth and pulmonary metastasis. Cancer Lett 281(1):32–41Google Scholar
  48. 48.
    Yin Y, Lin Q, Sun H, Chen D, Wu Q, Chen X, Li S (2012) Cytotoxic effects of ZnO hierarchical architectures on RSC96 Schwann cells. Nanoscale Res Lett 7:439Google Scholar
  49. 49.
    Sun HL, Dai XW, Han B (2014) TRIM29 as a novel biomarker in pancreatic adenocarcinoma. Dis Markers. CrossRefGoogle Scholar
  50. 50.
    Yu Y, Hamza A, Zhang T, Gu M, Zou P, Newman B et al (2010) Withaferin A targets heat shock protein 90 in pancreatic cancer cells. Biochem Pharmacol 79(4):542–551Google Scholar
  51. 51.
    Xia Y, Rocchi P, Iovanna JL, Peng L (2012) Targeting heat shock response pathways to treat pancreatic cancer. Drug Discov Today 17(1–2):35–43Google Scholar
  52. 52.
    Xia S, Miao Y, Liu S (2018) Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells. Biochem Biophys Res Commun 503(4):2363–2369Google Scholar
  53. 53.
    Sherr CJ, McCormick F (2002) The RB and p53 pathways in cancer. Cancer Cell 2:103–112Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.State Key Laboratory of Advanced Technology for Materials Synthesis and ProcessingWuhan University of TechnologyWuhanPeople’s Republic of China
  2. 2.Brigham and Women’s HospitalHarvard Medical SchoolBostonUSA
  3. 3.Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  4. 4.LBMI, Department of Physics, Faculty of Sciences 2Lebanese UniversityJdeidetLebanon

Personalised recommendations