Engineering of Targeted Nanoparticles by Using Self-Assembled Biointegrated Block Copolymers

  • Shoaib Iqbal
  • M. Naveed YasinEmail author
  • Heather Sheardown


Polymer-based nanoparticle delivery systems have attracted a lot of attention recently due to their chemical versatility offering precise engineering for targeted drug delivery. However, surface functionalization of these nanoparticles could lead to poor control over their properties. A strategy to overcome this shortcoming is synthesis of self-assembled biointegrated block copolymers which offer reproducible preparation, quantitative control over ligand density and easy production. These polymers are prepared by well-established polymerization and conjugation chemistries. The resultant nanoparticles are prepared by self-assembly of these polymers in a single step where fine tuning of these nanoparticles is accomplished by varying the composition of block polymers.


Self-assembled nanoparticles Targeted drug delivery Bio-inspired nanoparticles 


  1. 1.
    Langer, R. (1998). Drug delivery and targeting. Nature-London, 5–10.Google Scholar
  2. 2.
    Gu, F. X., Karnik, R., Wang, A. Z., Alexis, F., Levy-Nissenbaum, E., Hong, S., et al. (2007). Targeted nanoparticles for cancer therapy. Nano Today, 2(3), 14–21.Google Scholar
  3. 3.
    Alexis, F., Pridgen, E., Molnar, L. K., & Farokhzad, O. C. (2008). Factors affecting the clearance and biodistribution of polymeric nanoparticles. Molecular Pharmaceutics, 5(4), 505–515.Google Scholar
  4. 4.
    Gad, A., Kydd, J., Piel, B., & Rai, P. (2016). Targeting cancer using polymeric nanoparticle mediated combination chemotherapy. International Journal of Nanomedicine and Nanosurgery, 2(3).Google Scholar
  5. 5.
    Petros, R. A., & DeSimone, J. M. (2010). Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews Drug Discovery, 9(8), 615.Google Scholar
  6. 6.
    Albanese, A., Tang, P. S., & Chan, W. C. (2012). The effect of nanoparticle size, shape, and surface chemistry on biological systems. Annual Review of Biomedical Engineering, 14, 1–16.Google Scholar
  7. 7.
    Yuan, H., & Zhang, S. (2010). Effects of particle size and ligand density on the kinetics of receptor-mediated endocytosis of nanoparticles. Applied Physics Letters, 96(3), 033704.Google Scholar
  8. 8.
    Verma, A., & Stellacci, F. (2010). Effect of surface properties on nanoparticle–cell interactions. Small, 6(1), 12–21.Google Scholar
  9. 9.
    Leamon, C. P., Cooper, S. R., & Hardee, G. E. (2003). Folate-liposome-mediated antisense oligodeoxynucleotide targeting to cancer cells: Evaluation in vitro and in vivo. Bioconjugate Chemistry, 14(4), 738–747.Google Scholar
  10. 10.
    Popielarski, S. R., Pun, S. H., & Davis, M. E. (2005). A nanoparticle-based model delivery system to guide the rational design of gene delivery to the liver. 1. Synthesis and characterization. Bioconjugate Chemistry, 16(5), 1063–1070.Google Scholar
  11. 11.
    Chiu, S.-J., Liu, S., Perrotti, D., Marcucci, G., & Lee, R. J. (2006). Efficient delivery of a Bcl-2-specific antisense oligodeoxyribonucleotide (G3139) via transferrin receptor-targeted liposomes. Journal of Controlled Release, 112(2), 199–207.Google Scholar
  12. 12.
    Farokhzad, O. C., Jon, S., Khademhosseini, A., Tran, T.-N. T., LaVan, D. A., & Langer, R. (2004). Nanoparticle-aptamer bioconjugates: A new approach for targeting prostate cancer cells. Cancer Research, 64(21), 7668–7672.Google Scholar
  13. 13.
    Sun, B., Ranganathan, B., & Feng, S.-S. (2008). Multifunctional poly (D, L-lactide-co-glycolide)/montmorillonite (PLGA/MMT) nanoparticles decorated by Trastuzumab for targeted chemotherapy of breast cancer. Biomaterials, 29(4), 475–486.Google Scholar
  14. 14.
    Farokhzad, O. C., Cheng, J., Teply, B. A., Sherifi, I., Jon, S., Kantoff, P. W., et al. (2006). Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proceedings of the National Academy of Sciences, 103(16), 6315–6320.Google Scholar
  15. 15.
    Cheng, J., Teply, B. A., Sherifi, I., Sung, J., Luther, G., Gu, F. X., et al. (2007). Formulation of functionalized PLGA–PEG nanoparticles for in vivo targeted drug delivery. Biomaterials, 28(5), 869–876.Google Scholar
  16. 16.
    Kubowicz, S., Baussard, J. F., Lutz, J. F., Thünemann, A. F., von Berlepsch, H., & Laschewsky, A. (2005). Multicompartment micelles formed by self-assembly of linear ABC triblock copolymers in aqueous medium. Angewandte Chemie International Edition, 44(33), 5262–5265.Google Scholar
  17. 17.
    Li, G., Shi, L., Ma, R., An, Y., & Huang, N. (2006). Formation of complex micelles with double-responsive channels from self-assembly of two diblock copolymers. Angewandte Chemie International Edition, 45(30), 4959–4962.Google Scholar
  18. 18.
    Reynhout, I. C., Cornelissen, J. J., & Nolte, R. J. (2007). Self-assembled architectures from biohybrid triblock copolymers. Journal of the American Chemical Society, 129(8), 2327–2332.Google Scholar
  19. 19.
    Lee, H., Hu, M., Reilly, R. M., & Allen, C. (2007). Apoptotic epidermal growth factor (EGF)-conjugated block copolymer micelles as a nanotechnology platform for targeted combination therapy. Molecular Pharmaceutics, 4(5), 769–781.Google Scholar
  20. 20.
    Xu, Q., Liu, Y., Su, S., Li, W., Chen, C., & Wu, Y. (2012). Anti-tumor activity of paclitaxel through dual-targeting carrier of cyclic RGD and transferrin conjugated hyperbranched copolymer nanoparticles. Biomaterials, 33(5), 1627–1639.Google Scholar
  21. 21.
    Gu, F., Zhang, L., Teply, B. A., Mann, N., Wang, A., Radovic-Moreno, A. F., et al. (2008). Precise engineering of targeted nanoparticles by using self-assembled biointegrated block copolymers. Proceedings of the National Academy of Sciences, 105(7), 2586–2591.Google Scholar
  22. 22.
    Xu, W., Siddiqui, I. A., Nihal, M., Pilla, S., Rosenthal, K., Mukhtar, H., et al. (2013). Aptamer-conjugated and doxorubicin-loaded unimolecular micelles for targeted therapy of prostate cancer. Biomaterials, 34(21), 5244–5253.Google Scholar
  23. 23.
    Zhan, C., Gu, B., Xie, C., Li, J., Liu, Y., & Lu, W. (2010). Cyclic RGD conjugated poly (ethylene glycol)-co-poly (lactic acid) micelle enhances paclitaxel anti-glioblastoma effect. Journal of Controlled Release, 143(1), 136–142.Google Scholar
  24. 24.
    Jiang, X., Sha, X., Xin, H., Chen, L., Gao, X., Wang, X., et al. (2011). Self-aggregated pegylated poly (trimethylene carbonate) nanoparticles decorated with c(RGDyK) peptide for targeted paclitaxel delivery to integrin-rich tumors. Biomaterials, 32(35), 9457–9469.Google Scholar
  25. 25.
    Zhou, D., Zhang, G., & Gan, Z. (2013). C(RGDfK) decorated micellar drug delivery system for intravesical instilled chemotherapy of superficial bladder cancer. Journal of Controlled Release, 169(3), 204–210.Google Scholar
  26. 26.
    Christie, R. J., Matsumoto, Y., Miyata, K., Nomoto, T., Fukushima, S., Osada, K., et al. (2012). Targeted polymeric micelles for siRNA treatment of experimental cancer by intravenous injection. ACS Nano, 6(6), 5174–5189.Google Scholar
  27. 27.
    Zhang, Y., Zhang, H., Wang, X., Wang, J., Zhang, X., & Zhang, Q. (2012). The eradication of breast cancer and cancer stem cells using octreotide modified paclitaxel active targeting micelles and salinomycin passive targeting micelles. Biomaterials, 33(2), 679–691.Google Scholar
  28. 28.
    Wu, X. L., Kim, J. H., Koo, H., Bae, S. M., Shin, H., Kim, M. S., et al. (2010). Tumor-targeting peptide conjugated pH-responsive micelles as a potential drug carrier for Cancer therapy. Bioconjugate Chemistry, 21(2), 208–213.Google Scholar
  29. 29.
    Liu, P., Qin, L., Wang, Q., Sun, Y., Zhu, M., Shen, M., et al. (2012). cRGD-functionalized mPEG-PLGA-PLL nanoparticles for imaging and therapy of breast cancer. Biomaterials, 33(28), 6739–6747.Google Scholar
  30. 30.
    Sun, C.-Y., Shen, S., Xu, C.-F., Li, H.-J., Liu, Y., Cao, Z.-T., et al. (2015). Tumor acidity-sensitive polymeric vector for active targeted siRNA delivery. Journal of the American Chemical Society, 137(48), 15217–15224.Google Scholar
  31. 31.
    Huang, C. K., Lo, C. L., Chen, H. H., & Hsiue, G. H. (2007). Multifunctional micelles for cancer cell targeting, distribution imaging, and anticancer drug delivery. Advanced Functional Materials, 17(14), 2291–2297.Google Scholar
  32. 32.
    Zhong, Y., Yang, W., Sun, H., Cheng, R., Meng, F., Deng, C., et al. (2013). Ligand-directed reduction-sensitive shell-sheddable biodegradable micelles actively deliver doxorubicin into the nuclei of target cancer cells. Biomacromolecules, 14(10), 3723–3730.Google Scholar
  33. 33.
    Yang, R., Meng, F., Ma, S., Huang, F., Liu, H., & Zhong, Z. (2011). Galactose-decorated cross-linked biodegradable poly (ethylene glycol)-b-poly (ε-caprolactone) block copolymer micelles for enhanced hepatoma-targeting delivery of paclitaxel. Biomacromolecules, 12(8), 3047–3055.Google Scholar
  34. 34.
    Tao, Y., He, J., Zhang, M., Hao, Y., Liu, J., & Ni, P. (2014). Galactosylated biodegradable poly(ε-caprolactone-co-phosphoester) random copolymer nanoparticles for potent hepatoma-targeting delivery of doxorubicin. Polymer Chemistry, 5(10), 3443–3452.Google Scholar
  35. 35.
    Lee, H., Lee, K., & Park, T. G. (2008). Hyaluronic acid-paclitaxel conjugate micelles: Synthesis, characterization, and antitumor activity. Bioconjugate Chemistry, 19(6), 1319–1325.Google Scholar
  36. 36.
    Yadav, A. K., Mishra, P., Mishra, A. K., Mishra, P., Jain, S., & Agrawal, G. P. (2007). Development and characterization of hyaluronic acid–anchored PLGA nanoparticulate carriers of doxorubicin. Nanomedicine: Nanotechnology, Biology and Medicine, 3(4), 246–257.Google Scholar
  37. 37.
    Li, J., Huo, M., Wang, J., Zhou, J., Mohammad, J. M., Zhang, Y., et al. (2012). Redox-sensitive micelles self-assembled from amphiphilic hyaluronic acid-deoxycholic acid conjugates for targeted intracellular delivery of paclitaxel. Biomaterials, 33(7), 2310–2320.Google Scholar
  38. 38.
    Yoo, H. S., & Park, T. G. (2004). Folate receptor targeted biodegradable polymeric doxorubicin micelles. Journal of Controlled Release, 96(2), 273–283.Google Scholar
  39. 39.
    Yang, X., Chen, Y., Yuan, R., Chen, G., Blanco, E., Gao, J., et al. (2008). Folate-encoded and Fe3O4-loaded polymeric micelles for dual targeting of cancer cells. Polymer, 49(16), 3477–3485.Google Scholar
  40. 40.
    Wang, W., Cheng, D., Gong, F., Miao, X., & Shuai, X. (2012). Design of multifunctional micelle for tumor-targeted intracellular drug release and fluorescent imaging. Advanced Materials, 24(1), 115–120.Google Scholar
  41. 41.
    Guo, X., Shi, C., Wang, J., Di, S., & Zhou, S. (2013). pH-triggered intracellular release from actively targeting polymer micelles. Biomaterials, 34(18), 4544–4554.Google Scholar
  42. 42.
    Hu, J., He, J., Cao, D., Zhang, M., & Ni, P. (2015). Core cross-linked polyphosphoester micelles with folate-targeted and acid-cleavable features for pH-triggered drug delivery. Polymer Chemistry, 6(17), 3205–3216.Google Scholar
  43. 43.
    Li, H., Miteva, M., Kirkbride, K. C., Cheng, M. J., Nelson, C. E., Simpson, E. M., et al. (2015). Dual MMP7-proximity-activated and folate receptor-targeted nanoparticles for siRNA delivery. Biomacromolecules, 16(1), 192–201.Google Scholar
  44. 44.
    Patil, Y., Sadhukha, T., Ma, L., & Panyam, J. (2009). Nanoparticle-mediated simultaneous and targeted delivery of paclitaxel and tariquidar overcomes tumor drug resistance. Journal of Controlled Release, 136(1), 21–29.Google Scholar
  45. 45.
    Patil, Y. B., Swaminathan, S. K., Sadhukha, T., Ma, L., & Panyam, J. (2010). The use of nanoparticle-mediated targeted gene silencing and drug delivery to overcome tumor drug resistance. Biomaterials, 31(2), 358–365.Google Scholar
  46. 46.
    Hrkach, J., Von Hoff, D., Ali, M. M., Andrianova, E., Auer, J., Campbell, T., et al. (2012). Preclinical development and clinical translation of a PSMA-targeted docetaxel nanoparticle with a differentiated pharmacological profile. Science Translational Medicine, 4(128), 128ra39–128ra39.Google Scholar
  47. 47.
    Prosperi-Porta, G., Kedzior, S., Muirhead, B., & Sheardown, H. (2016). Phenylboronic-acid-based polymeric micelles for Mucoadhesive anterior segment ocular drug delivery. Biomacromolecules, 17(4), 1449–1457.Google Scholar
  48. 48.
    Feng, H., Lu, X., Wang, W., Kang, N.-G., & Mays, J. W. (2017). Block copolymers: Synthesis, self-assembly, and applications. Polymers, 9(10), 494.Google Scholar
  49. 49.
    Hawker, C. J., & Wooley, K. L. (2005). The convergence of synthetic organic and polymer chemistries. Science, 309(5738), 1200–1205.Google Scholar
  50. 50.
    Matyjaszewski, K., & Spanswick, J. (2005). Controlled/living radical polymerization. Materials Today, 8(3), 26–33.Google Scholar
  51. 51.
    Egli, S., Schlaad, H., Bruns, N., & Meier, W. (2011). Functionalization of block copolymer vesicle surfaces. Polymers, 3(1), 252–280.Google Scholar
  52. 52.
    Jérôme, C., & Lecomte, P. (2008). Recent advances in the synthesis of aliphatic polyesters by ring-opening polymerization. Advanced Drug Delivery Reviews, 60(9), 1056–1076.Google Scholar
  53. 53.
    Kim, J. K., Yang, S. Y., Lee, Y., & Kim, Y. (2010). Functional nanomaterials based on block copolymer self-assembly. Progress in Polymer Science, 35(11), 1325–1349.Google Scholar
  54. 54.
    Zhang, G., Zhang, M., He, J., & Ni, P. (2013). Synthesis and characterization of a new multifunctional polymeric prodrug paclitaxel-polyphosphoester-folic acid for targeted drug delivery. Polymer Chemistry, 4(16), 4515–4525.Google Scholar
  55. 55.
    Matsumoto, A., Sato, N., Kataoka, K., & Miyahara, Y. (2009). Noninvasive sialic acid detection at cell membrane by using phenylboronic acid modified self-assembled monolayer gold electrode. Journal of the American Chemical Society, 131(34), 12022–12023.Google Scholar
  56. 56.
    Liu, S., Jones, L., & Gu, F. X. (2012). Development of Mucoadhesive drug delivery system using Phenylboronic acid functionalized poly (D, L-lactide)-b-dextran nanoparticles. Macromolecular Bioscience, 12(12), 1622–1626.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Shoaib Iqbal
    • 1
  • M. Naveed Yasin
    • 2
    Email author
  • Heather Sheardown
    • 2
  1. 1.Department of Chemical and Biomolecular EngineeringClemson UniversityClemsonUSA
  2. 2.Department of Chemical Engineering, Faculty of EngineeringMcMaster UniversityHamiltonCanada

Personalised recommendations