Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Silk nanoparticles—an emerging anticancer nanomedicine

1 Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, UK
2 Leibniz Institute of Polymer Research Dresden, Max Bergmann Center of Biomaterials Dresden, Hohe Strasse 6, 01069 Dresden, Germany

Topical Section: Drug delivery

Silk is a sustainable and ecologically friendly biopolymer with a robust clinical track record in humans for load bearing applications, in part due to its excellent mechanical properties and biocompatibility. Our ability to take bottom-up and top-down approaches for the generation of silk (inspired) biopolymers has been critical in supporting the evolution of silk materials and formats, including silk nanoparticles for drug delivery. Silk nanoparticles are emerging as interesting contenders for drug delivery and are well placed to advance the nanomedicine field. This review covers the use of Bombyx mori and recombinant silks as an anticancer nanomedicine, highlighting the emerging trends and developments as well as critically assessing the current opportunities and challenges by providing a context specific assessment of this multidisciplinary field.
  Article Metrics


1. Vollrath F, Porter D (2009) Silks as ancient models for modern polymers. Polymer 50: 5623–5632.    

2. Lubec G, Holaubek J, Feldl C, et al. (1993) Use of silk in ancient Egypt. Nature 362: 25.

3. Altman GH, Diaz F, Jakuba C, et al. (2003) Silk-based biomaterials. Biomaterials 24: 401–416.    

4. Omenetto FG, Kaplan DL (2010) New opportunities for an ancient material. Science 329: 528–531.    

5. Elices M, Plaza GR, Perez RJ, et al. (2011) The hidden link between supercontraction and mechanical behavior of spider silks. J Mech Behav Biomed Mater 4: 658–669.    

6. Cranford SW, Tarakanova A, Pugno NM, et al. (2012) Nonlinear material behaviour of spider silk yields robust webs. Nature 482: 72–76.    

7. Vollrath F, Porter D, Holland C (2013) The science of silks. MRS Bull 38: 73–80.    

8. Kluge JA, Rabotyagova O, Leisk GG, et al. (2008) Spider silks and their applications. Trends Biotechnol 26: 244–251.    

9. Gatesy J, Hayashi C, Motriuk D, et al. (2001) Extreme diversity, conservation, and convergence of spider silk fibroin sequences. Science 291: 2603–2605.    

10. Hardy JG, Scheibel TR (2009) Silk-inspired polymers and proteins. Biochem Soc T 37: 677–681.    

11. Rising A, Johansson J (2015) Toward spinning artificial spider silk. Nat Chem Biol 11: 309–315.    

12. Kim S, Marelli B, Brenckle MA, et al. (2014) All-water-based electron-beam lithography using silk as a resist. Nat Nanotechnol 9: 306–310.    

13. Omenetto FG, Kaplan DL (2008) A new route for silk. Nature Photonic 2: 641–643.    

14. Zhu B, Wang H, Leow WR, et al. (2016) Silk fibroin for flexible electronic devices. Adv Mater 22: 4250–4265.

15. Doblhofer E, Schmid J, Riess M, et al. (2016) Structural insights into water-based spider silk protein-nanoclay composites with excellent gas and water vapor barrier properties. ACS Appl Mater Interface 8: 25535–25543.    

16. Marelli B, Brenckle MA, Kaplan DL, et al. (2016) Silk fibroin as edible coating for perishable food preservation. Sci Rep 6: 25263–25273.    

17. Abbott RD, Kimmerling EP, Cairns DM, et al. (2016) Silk as a biomaterial to support long-term three-dimensional tissue cultures. ACS Appl Mater Interface 8: 21861–21868.    

18. Jao D, Mou X, Hu X (2016) Tissue regeneration: a silk road. J Funct Biomater 7: 22–39.    

19. Kasoju N, Bora U (2012) Silk fibroin in tissue engineering. Adv Healthc Mater 1: 393–412.    

20. Werner V, Meinel L (2015) From silk spinning in insects and spiders to advanced silk fibroin drug delivery systems. Eur J Pharm Biopharm 97: 392–399.    

21. Yucel T, Lovett ML, Kaplan DL (2014) Silk-based biomaterials for sustained drug delivery. J Control Release 190: 381–397.    

22. Seib FP, Kaplan DL (2013) Silk for drug delivery applications: opportunities and challenges. Israel J Chem 53: 756–766.

23. Thurber AE, Omenetto FG, Kaplan DL (2015) In vivo bioresponses to silk proteins. Biomaterials 71: 145–157.    

24. Pritchard EM, Dennis PB, Omenetto FG, et al. (2012) Physical and chemical aspects of stabilization of compounds in silk. Biopolymers 97: 479–498.    

25. Chiu B, Coburn J, Pilichowska M, et al. (2014) Surgery combined with controlled-release doxorubicin silk films as a treatment strategy in an orthotopic neuroblastoma mouse model. Brit J Cancer 111: 708–715.    

26. Seib FP, Coburn J, Konrad I, et al. (2015) Focal therapy of neuroblastoma using silk films to deliver kinase and chemotherapeutic agents in vivo. Acta Biomater 20: 32–38.    

27. Coburn J, Harris J, Zakharov AD, et al. (2017) Implantable chemotherapy-loaded silk protein materials for neuroblastoma treatment. Int J Cancer 140: 726–735.    

28. Seib FP, Pritchard EM, Kaplan DL (2013) Self-assembling doxorubicin silk hydrogels for the focal treatment of primary breast cancer. Adv Funct Mater 23: 58–65.    

29. Jastrzebska K, Kucharczyk K, Florczak A, et al. (2015) Silk as an innovative biomaterial for cancer therapy. Rep Pract Oncol Radiother 20: 87–98.    

30. Coleman RE (2012) Bone cancer in 2011: prevention and treatment of bone metastases. Nat Rev Clin Oncol 9: 76–78.

31. Gupta GP, Massague J (2006) Cancer metastasis: building a framework. Cell 127: 679–695.    

32. Ehrlich P (1913) Address in pathology, on chemiotherapy: delivered before the seventeenth international congress of medicine. Brit Med J 2: 353–359.    

33. Mottaghitalab F, Farokhi M, Shokrgozar MA, et al. (2015) Silk fibroin nanoparticle as a novel drug delivery system. J Control Release 206: 161–176.    

34. Zhao Z, Li Y, Xie MB (2015) Silk fibroin-based nanoparticles for drug delivery. Int J Mol Sci 16: 4880–4903.    

35. Ebrahimi D, Tokareva O, Rim NG, et al. (2015) Silk-its mysteries, how it is made, and how it is used. ACS Biomater Sci Eng 1: 864–876.    

36. Eisoldt L, Thamm C, Scheibel T (2012) Review the role of terminal domains during storage and assembly of spider silk proteins. Biopolymers 97: 355–361.    

37. Xu G, Gong L, Yang Z, et al. (2014) What makes spider silk fibers so strong? From molecular-crystallite network to hierarchical network structures. Soft Mat 10: 2116–2123.

38. Ha SW, Gracz HS, Tonelli AE, et al. (2005) Structural study of irregular amino acid sequences in the heavy chain of bombyx mori silk fibroin. Biomacromolecules 6: 2563–2569.    

39. Asakura T, Ohgo K, Ishida T, et al. (2005) Possible implications of serine and tyrosine residues and intermolecular interactions on the appearance of silk istructure of bombyx mori silk fibroin-derived synthetic peptides: high-resolution 13c cross-polarization/magic-angle spinning NMR study. Biomacromolecules 6: 468–474.    

40. Asakura T, Okushita K, Williamson MP (2015) Analysis of the structure of bombyx mori silk fibroin by NMR. Macromolecules 48: 2345–2357.    

41. Zhou CZ, Confalonieri F, Jacquet M, et al. (2001) Silk fibroin: structural implications of a remarkable amino acid sequence. Proteins 44: 119–122.    

42. Zhou CZ, Confalonieri F, Medina N, et al. (2000) Fine organization of bombyx mori fibroin heavy chain gene. Nucleic Acids Res 28: 2413–2419.    

43. Jin HJ, Kaplan DL (2003) Mechanism of silk processing in insects and spiders. Nature 424: 1057–1061.    

44. Greving I, Dicko C, Terry A, et al. (2010) Small angle neutron scattering of native and reconstituted silk fibroin. Soft Mat 6: 4389–4395.    

45. Lu Q, Zhu H, Zhang C, et al. (2012) Silk self-assembly mechanisms and control from thermodynamics to kinetics. Biomacromolecules 13: 826–832.    

46. Wang X, Yucel T, Lu Q, et al. (2010) Silk nanospheres and microspheres from silk/pva blend films for drug delivery. Biomaterials 31: 1025–1035.    

47. Myung SJ, Kim HS, Kim Y, et al. (2008) Fluorescent silk fibroin nanoparticles prepared using a reverse microemulsion. Macromol Res 16: 604–608.    

48. Gupta V, Aseh A, Rios CN, et al. (2009) Fabrication and characterization of silk fibroin-derived curcumin nanoparticles for cancer therapy. Int J Nanomed 4: 115–122.

49. Lammel AS, Hu X, Park SH, et al. (2010) Controlling silk fibroin particle features for drug delivery. Biomaterials 31: 4583–4591.    

50. Kundu J, Chung YI, Kim YH, et al. (2010) Silk fibroin nanoparticles for cellular uptake and control release. Int J Pharm 388: 242–250.    

51. Seib FP, Jones GT, Rnjak KJ, et al. (2013) pH-dependent anticancer drug release from silk nanoparticles. Adv Healthc Mater 2: 1606–1611.    

52. Wongpinyochit T, Johnston BF, Seib FP (2016) Manufacture and drug delivery applications of silk nanoparticles. J Vis Exp DOI: 10.3791/54669.

53. Zhang YQ, Shen WD, Xiang RL, et al. (2007) Formation of silk fibroin nanoparticles in water-miscible organic solvent and their characterization. J Nanopart Res 9: 885–900.    

54. Zhao Z, Xie M, Li Y, et al. (2015) Formation of curcumin nanoparticles via solution-enhanced dispersion by supercritical CO2. Int J Nanomed 10: 3171–3181.

55. Lozano PAA, Montalban MG, Aznar CSD, et al. (2015) Production of silk fibroin nanoparticles using ionic liquids and high-power ultrasounds. J Appl Polym Sci 132: 41702–41709.

56. Gholami A, Tavanai H, Moradi AR (2010) Production of fibroin nanopowder through electrospraying. J Nanopart Res 13: 2089–2098.

57. Wenk E, Wandrey AJ, Merkle HP, et al. (2008) Silk fibroin spheres as a platform for controlled drug delivery. J Control Release 132: 26–34.    

58. Lu Q, Huang Y, Li M, et al. (2011) Silk fibroin electrogelation mechanisms. Acta Biomater 7: 2394–2400.    

59. Rajkhowa R, Wang L, Wang X (2008) Ultra-fine silk powder preparation through rotary and ball milling. Powder Technol 185: 87–95.    

60. Mathur AB, Gupta V (2010) Silk fibroin-derived nanoparticles for biomedical applications. Nanomedicine 5: 807–820.    

61. Xiao L, Lu G, Lu Q, et al. (2016) Direct formation of silk nanoparticles for drug delivery. ACS Biomater Sci Eng 2: 2050–2057.    

62. Wongpinyochit T, Uhlmann P, Urquhart AJ, et al. (2015) PEGylated silk nanoparticles for anticancer drug delivery. Biomacromolecules 16: 3712–3722.    

63. Subia B, Chandra S, Talukdar S, et al. (2014) Folate conjugated silk fibroin nanocarriers for targeted drug delivery. Integr Biol 6: 203–214.    

64. Rabanel JM, Hildgen P, Banquy X (2014) Assessment of PEG on polymeric particles surface, a key step in drug carrier translation. J Control Release 185: 71–87.    

65. Pasut G, Veronese FM (2012) State of the art in PEGylation: the great versatility achieved after forty years of research. J Control Release 161: 461–472.    

66. Wang S, Xu T, Yang Y, et al. (2015) Colloidal stability of silk fibroin nanoparticles coated with cationic polymer for effective drug delivery. ACS Appl Mater Interface 7: 21254–21262.    

67. Tian Y, Jiang X, Chen X, et al. (2014) Doxorubicin-loaded magnetic silk fibroin nanoparticles for targeted therapy of multidrug-resistant cancer. Adv Mater 26: 7393–7398.    

68. Chung H, Kim TY, Lee SY (2012) Recent advances in production of recombinant spider silk proteins. Curr Opin Biotech 23: 957–964.    

69. Lammel A, Schwab M, Hofer M, et al. (2011) Recombinant spider silk particles as drug delivery vehicles. Biomaterials 32: 2233–2240.    

70. Humenik M, Smith AM, Scheibel T (2011) Recombinant spider silks-biopolymers with potential for future applications. Polymers 3: 640–661.    

71. Schierling MB, Doblhofer E, Scheibel T (2016) Cellular uptake of drug loaded spider silk particles. Biomater Sci 4: 1515–1523.    

72. Doblhofer E, Scheibel T (2015) Engineering of recombinant spider silk proteins allows defined uptake and release of substances. J Pharm Sci 104: 988–994.    

73. Elsner MB, Herold HM, Muller HS, et al. (2015) Enhanced cellular uptake of engineered spider silk particles. Biomater Sci 3: 543–551.    

74. Florczak A, Mackiewicz A, Dams KH (2014) Functionalized spider silk spheres as drug carriers for targeted cancer therapy. Biomacromolecules 15: 2971–2981.    

75. Neubauer MP, Blüm C, Agostini E, et al. (2013) Micromechanical characterization of spider silk particles. Biomater Sci 1: 1160–1165.    

76. Anselmo AC, Zhang M, Kumar S, et al. (2015) Elasticity of nanoparticles influences their blood circulation, phagocytosis, endocytosis, and targeting. ACS Nano 9: 3169–3177.    

77. Numata K, Kaplan DL (2010) Silk-based delivery systems of bioactive molecules. Adv Drug Deliver Rev 62: 1497–1508.    

78. Numata K, Subramanian B, Currie HA, et al. (2009) Bioengineered silk protein-based gene delivery systems. Biomaterials 30: 5775–5784.    

79. Numata K, Hamasaki J, Subramanian B, et al. (2010) Gene delivery mediated by recombinant silk proteins containing cationic and cell binding motifs. J Control Release 146: 136–143.    

80. Numata K, Kaplan DL (2010) Silk-based gene carriers with cell membrane destabilizing peptides. Biomacromolecules 11: 3189–3195.    

81. Numata K, Reagan MR, Goldstein RH, et al. (2011) Spider silk-based gene carriers for tumor cell-specific delivery. Bioconjugate Chem 22: 1605–1610.    

82. Seib FP, Herklotz M, Burke KA, et al. (2014) Multifunctional silk-heparin biomaterials for vascular tissue engineering applications. Biomaterials 35: 83–91.    

83. Seib FP, Maitz MF, Hu X, et al. (2012) Impact of processing parameters on the haemocompatibility of bombyx mori silk films. Biomaterials 33: 1017–1023.    

84. Murphy AR, Kaplan DL (2009) Biomedical applications of chemically-modified silk fibroin. J Mater Chem 19: 6443–6450.    

85. Kambe Y, Yamamoto K, Kojima K, et al. (2010) Effects of RGDS sequence genetically interfused in the silk fibroin light chain protein on chondrocyte adhesion and cartilage synthesis. Biomaterials 31: 7503–7511.    

86. Teule F, Miao YG, Sohn BH, et al. (2012) Silkworms transformed with chimeric silkworm/spider silk genes spin composite silk fibers with improved mechanical properties. P Natl Acad Sci USA 109: 923–928.    

87. Xia XX, Qian ZG, Ki CS, et al. (2010) Native-sized recombinant spider silk protein produced in metabolically engineered Escherichia coli results in a strong fiber. P Natl Acad Sci USA 107: 14059–14063.    

88. Wray LS, Hu X, Gallego J, et al. (2011) Effect of processing on silk-based biomaterials: reproducibility and biocompatibility. J Biomed Mater Res 99: 89–101.

89. Rockwood DN, Preda RC, Yucel T, et al. (2011) Materials fabrication from bombyx mori silk fibroin. Nat Protoc 6: 1612–1631.    

90. Duncan R, Gaspar R (2011) Nanomedicine(s) under the microscope. Mol Pharm 8: 2101–2141.    

91. Sheridan C (2012) Proof of concept for next-generation nanoparticle drugs in humans. Nature Biotechnol 30: 471–473.    

92. Shi J, Kantoff PW, Wooster R, et al. (2017) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17: 20–37.

93. Maeda H, Nakamura H, Fang J (2013) The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliver Rev 65: 71–79.    

94. Duncan R (2006) Polymer conjugates as anticancer nanomedicines. Nat Rev Cancer 6: 688–701.    

95. Juliano R (2013) Nanomedicine: is the wave cresting? Nat Rev Drug Discov 12: 171–172.    

96. Venditto VJ, Szoka FC (2013) Cancer nanomedicines: so many papers and so few drugs! Adv Drug Deliver Rev 65: 80–88.

97. Wilhelm S, Tavares AJ, Dai Q, et al. (2016) Analysis of nanoparticle delivery to tumours. Nature Rev Mater 1: 1–12.

98. Cleal K, He L, Watson PD, et al. (2013) Endocytosis, intracellular traffic and fate of cell penetrating peptide based conjugates and nanoparticles. Curr Pharm Design 19: 2878–2894.    

99. Duncan R, Richardson SC (2012) Endocytosis and intracellular trafficking as gateways for nanomedicine delivery: opportunities and challenges. Mol Pharm 9: 2380–2402.    

100. Whitehead KA, Langer R, Anderson DG (2009) Knocking down barriers: advances in siRNA delivery. Nat Rev Drug Discov 8: 129–138.    

101. Gratton SE, Ropp PA, Pohlhaus PD, et al. (2008) The effect of particle design on cellular internalization pathways. P Natl Acad Sci USA 105: 11613–11618.    

102. Herd H, Daum N, Jones AT, et al. (2013) Nanoparticle geometry and surface orientation influence mode of cellular uptake. ACS Nano 7: 1961–1973.    

103. Rejman J, Oberle V, Zuhorn IS, et al. (2004) Size-dependent internalization of particles via the pathways of clathrin- and caveolae-mediated endocytosis. Biochem J 377: 159–169.    

104. Oh P, Borgstrom P, Witkiewicz H, et al. (2007) Live dynamic imaging of caveolae pumping targeted antibody rapidly and specifically across endothelium in the lung. Nat Biotechnol 25: 327–337.    

105. Sabharanjak S, Mayor S (2004) Folate receptor endocytosis and trafficking. Adv Drug Deliver Rev 56: 1099–1109.    

106. Mosesson Y, Mills GB, Yarden Y (2008) Derailed endocytosis: an emerging feature of cancer. Nat Rev Cancer 8: 835–850.    

107. Vercauteren D, Vandenbroucke RE, Jones AT, et al. (2010) The use of inhibitors to study endocytic pathways of gene carriers: optimization and pitfalls. Mol Ther 18: 561–569.    

Copyright Info: © 2017, F. Philipp Seib, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved