Skip to main content

Advertisement

SpringerLink
Log in

A Self-assembled Nanoparticle Platform Based on Amphiphilic Oleanolic Acid Polyprodrug for Cancer Therapy

  • Article
  • Published:
Chinese Journal of Polymer Science Aims and scope Submit manuscript

Abstract

Oleanolic acid (OA) is a pentacyclic triterpenoid compound with extensive biological effects, such as anti-inflammatory and anticancer activities. However, the application of OA in chemotherapy is hampered by its poor solubility and severe adverse effects. To solve the problems, we developed a self-assembled nanoparticle platform based on amphiphilic oleanolic acid polyprodrug, poly[oligo(ethylene glycol) methyl ether methacrylate]-b-poly[oleanolic acid methacrylate] (POEGMA-b-POAMA), encapsulating 10-hydroxycamptothecin (HCPT) to achieve efficient cancer therapy. The polyprodrug was prepared via reversible addition-fragmentation chain transfer polymerization (RAFT), and could self-assemble to prepare POEGMA-b-POAMA/HCPT nanoparticles (NPs). The obtained nanoparticles exhibited appropriate particle size, excellent drug stability, good drug loading capacity, and high drug loading efficiency. In vitro drug release indicated that the drug release was prolonged to 132 h. The POEGMA-b-POAMA/HCPT NPs enhanced cell cytotoxicity in 4T1 cells and MCF-7 cells and could be efficiently uptaken by 4T1 cells. Furthermore, in vivo antitumor efficiency showed that the POEGMA-b-POAMA/HCPT NPs had great antitumor efficiency with considerably low adverse effects in the treatment of the 4T1 mouse breast tumor xenograft tumor. Therefore, POEGMA-b-POAMA/HCPT NPs provide great potential as a platform for drug delivery applications.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Tao, X. G.; Gou, J. X.; Zhang, Q. Y.; Tan, X. Y.; Ren, T. Y.; Yao, Q.; Tian, B.; Kou, L. F.; Zhang, L.; Tang, X., Synergistic breast tumor cell killing achieved by intracellular co-delivery of doxorubicin and disulfiram via core-shell-corona nanoparticles. Biomater. Sci., 2018, 6, 1869–1881.

    CAS  PubMed  Google Scholar 

  2. Gao, S. T.; Tang, G. S.; Hua, D. W.; Xiong, R. H.; Han, J. Q.; Jiang, S. H.; Zhang, Q. L.; Huang, C. B., Stimuli-responsive bio-based polymeric systems and their applications. J. Mater. Chem. B, 2019, 7, 709–729.

    CAS  PubMed  Google Scholar 

  3. Pei, P.; Sun, C. Y.; Tao, W.; Li, J.; Yang, X. Z.; Wang, J., ROS-sensitive thioketal-linked polyphosphoester-doxorubicin conjugate for precise phototriggered locoregional chemotherapy. Biomaterials, 2019, 188, 74–82.

    CAS  PubMed  Google Scholar 

  4. Gupta, P. K.; Pappuru, S.; Gupta, S.; Patra, B.; Chakraborty, D.; Verma, R. S., Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics. Mater. Sci. Eng. C-Mater. Biol. Appl., 2019, 101, 448–463.

    CAS  PubMed  Google Scholar 

  5. Kumari, A.; Yadav, S. K.; Yadav, S. C., Biodegradable polymeric nanoparticles based drug delivery systems. Colloid Surf. B-Biointerfaces, 2010, 75, 1–18.

    CAS  Google Scholar 

  6. Oh, J. K., Disassembly and tumor-targeting drug delivery of reduction-responsive degradable block copolymer nanoassemblies. Polym. Chem., 2019, 10, 1554–1568.

    CAS  Google Scholar 

  7. Dong, S. X.; Sun, Y.; Liu, J.; Li, L.; He, J. L.; Zhang, M. Z.; Ni, P. H., Multifunctional polymeric prodrug with simultaneous conjugating camptothecin and doxorubicin for pH/reduction dual-responsive drug delivery. ACS Appl. Mater. Interfaces, 2019, 11, 8740–8748.

    CAS  PubMed  Google Scholar 

  8. Wang, X. M.; Xu, K. Y.; Yao, H. C.; Chang, L. M.; Wang, Y.; Li, W. J.; Zhao, Y. L.; Qin, J. L., Temperature-regulated aggregation-induced emissive self-healable hydrogels for controlled drug delivery. Polym. Chem., 2018, 9, 5002–5013.

    CAS  Google Scholar 

  9. Pound-Lana, G. E. N.; Garcia, G. M.; Trindade, I. C.; Capelari-Oliveira, P.; Pontifice, T. G.; Vilela, J. M. C.; Andrade, M. S.; Nottelet, B.; Postacchini, B. B.; Mosqueira, V. C. F., Phthalocyanine photosensitizer in polyethylene glycol-block-poly(lactide-co-benzyl glycidyl ether) nanocarriers: probing the contribution of aromatic donor-acceptor interactions in polymeric nanospheres. Mater. Sci. Eng. C-Mater. Biol. Appl., 2019, 94, 220–233.

    CAS  PubMed  Google Scholar 

  10. Zabihi, F.; Koeppe, H.; Achazi, K.; Hedtrich, S.; Haag, R., One-pot synthesis of poly(glycerol-co-succinic acid) nanogels for dermal delivery. Biomacromolecules, 2019, 20, 1867–1875.

    CAS  PubMed  Google Scholar 

  11. Liang, K.; Chung, J. E.; Gao, S. J.; Yongvongsoontorn, N.; Kurisawa, M., Highly augmented drug loading and stability of micellar nanocomplexes composed of doxorubicin and poly(ethylene glycol)-green tea catechin conjugate for cancer therapy. Adv. Mater., 2018, 30, 8.

    Google Scholar 

  12. You, C. Q.; Wu, H. S.; Gao, Z. G.; Sun, K.; Chen, F. H.; Tao, W. A.; Sun, B. W., Subcellular co-delivery of two different site-oriented payloads based on multistage targeted polymeric nanoparticles for enhanced cancer therapy. J. Mater. Chem. B, 2018, 6, 6752–6766.

    CAS  PubMed  Google Scholar 

  13. Shao, L. H.; Wan, K. W.; Wang, H.; Cui, Y. K.; Zhao, C. Y.; Lu, J. Q.; Li, X. L.; Chen, L.; Cui, X. Y.; Wang, X.; Deng, X. W.; Shi, X. H.; Wu, Y., A non-conjugated polyethylenimine copolymer-based unorthodox nanoprobe for bioimaging and related mechanism exploration. Biomater. Sci., 2019, 7, 3016–3024.

    CAS  PubMed  Google Scholar 

  14. Yao, J. K.; Kang, S. S.; Zhang, J.; Du, J.; Zhang, Z.; Li, M., Amphiphilic near-infrared conjugated polymer for photothermal and chemo combination therapy. ACS Biomater. Sci. Eng., 2017, 3, 2230–2234.

    CAS  Google Scholar 

  15. Matsumura, Y.; Maeda, H., A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res., 1986, 46, 6387–6392.

    CAS  PubMed  Google Scholar 

  16. Zhou, L. Y.; Qiu, T.; Lv, F. T.; Liu, L. B.; Ying, J. M.; Wang, S., Self-assembled nanomedicines for anticancer and antibacterial applications. Adv. Healthc. Mater., 2018, 7, 29.

    Google Scholar 

  17. Pierini, F.; Nakielski, P.; Urbanek, O.; Pawlowska, S.; Lanzi, M.; De Sio, L.; Kowalewski, T. A., Polymer-based nanomaterials for photothermal therapy: from light-responsive to multifunctional nanoplatforms for synergistically combined technologies. Biomacromolecules, 2018, 19, 4147–4167.

    CAS  PubMed  Google Scholar 

  18. Tao, R.; Gao, M.; Liu, F.; Guo, X. L.; Fan, A. P.; Ding, D.; Kong, D. L.; Wang, Z.; Zhao, Y. J., Alleviating the liver toxicity of chemotherapy via pH-responsive hepatoprotective prodrug micelles. ACS Appl. Mater. Interfaces, 2018, 10, 21836–21846.

    CAS  PubMed  Google Scholar 

  19. Ma, X. Q.; Shi, X. X.; Bai, S.; Gao, Y. E.; Hou, M. L.; Han, M. Y.; Xu, Z. G., Acid-activatable doxorubicin prodrug micelles with folate-targeted and ultra-high drug loading features for efficient antitumor drug delivery. J. Mater. Sci., 2018, 53, 892–907.

    CAS  Google Scholar 

  20. Dai, L.; Cao, X.; Liu, K. F.; Li, C. X.; Zhang, G. F.; Deng, L. H.; Si, C. L.; He, J.; Lei, J. D., Self-assembled targeted folate-conjugated eight-arm-polyethylene glycol-betulinic acid nanoparticles for co-delivery of anticancer drugs. J. Mater. Chem. B, 2015, 3, 3754–3766.

    CAS  PubMed  Google Scholar 

  21. Palvai, S.; Anandi, L.; Sarkar, S.; Augustus, M.; Roy, S.; Lahiri, M.; Basu, S., Drug-triggered self-assembly of linear polymer into nanoparticles for simultaneous delivery of hydrophobic and hydrophilic drugs in breast cancer cells. ACS Omega, 2017, 2, 8730–8740.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhou, Z.; Ma, X.; Jin, E.; Tang, J.; Sui, M.; Shen, Y.; van Kirk, E. A.; Murdoch, W. J.; Radosz, M., Linear-dendritic drug conjugates forming long-circulating nanorods for cancer-drug delivery. Biomaterials, 2013, 34, 5722–5735.

    CAS  PubMed  Google Scholar 

  23. Yar, Y.; Khodadust, R.; Akkoc, Y.; Utkur, M.; Saritas, E. U.; Gozuacik, D.; Acar, H. Y., Development of tailored SPION-PNIPAM nanoparticles by ATRP for dually responsive doxorubicin delivery and mr imaging. J. Mater. Chem. B, 2018, 6, 289–300.

    CAS  PubMed  Google Scholar 

  24. Cheng, G. Q.; Xu, D.; Lu, Z. Y.; Liu, K., Chiral self-assembly of nanoparticles induced by polymers synthesized via reversible addition-fragmentation chain transfer polymerization. ACS Nano, 2019, 13, 1479–1489.

    CAS  PubMed  Google Scholar 

  25. Guegain, E.; Tran, J.; Deguettes, Q.; Nicolas, J., Degradable polymer prodrugs with adjustable activity from drug-initiated radical ring-opening copolymerization. Chem. Sci., 2018, 9, 8291–8306.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Lomkova, E. A.; Chytil, P.; Janouskova, O.; Mueller, T.; Lucas, H.; Filippov, S. K.; Trhlikova, O.; Aleshunin, P. A.; Skorik, Y. A.; Ulbrich, K.; Etrych, T., Biodegradable micellar HPMA-based polymer-drug conjugates with betulinic acid for passive tumor targeting. Biomacromolecules, 2016, 17, 3493–3507.

    CAS  PubMed  Google Scholar 

  27. Hu, X.; Hu, J.; Tian, J.; Ge, Z.; Zhang, G.; Luo, K.; Liu, S., Polyprodrug amphiphiles: hierarchical assemblies for shape-regulated cellular internalization, trafficking, and drug delivery. J. Am. Chem. Soc., 2013, 135, 17617–17629.

    CAS  PubMed  Google Scholar 

  28. Hu, X.; Liu, G.; Li, Y.; Wang, X.; Liu, S., Cell-penetrating hyperbranched polyprodrug amphiphiles for synergistic reductive milieu-triggered drug release and enhanced magnetic resonance signals. J. Am. Chem. Soc., 2015, 137, 362–368.

    CAS  PubMed  Google Scholar 

  29. Hu, X. L.; Zhai, S. D.; Liu, G. H.; Xing, D.; Liang, H. J.; Liu, S. Y., Concurrent drug unplugging and permeabilization of polyprodrug-gated crosslinked vesicles for cancer combination chemotherapy. Adv. Mater., 2018, 30, 7.

    Google Scholar 

  30. Zhu, K. N.; Liu, G. H.; Hu, J. M.; Liu, S. Y., Near-infrared light-activated photochemical internalization of reduction-responsive polyprodrug vesicles for synergistic photodynamic therapy and chemotherapy. Biomacromolecules, 2017, 18, 2571–2582.

    CAS  PubMed  Google Scholar 

  31. Tan, J. J.; Deng, Z. Y.; Liu, G. H.; Hu, J. M.; Liu, S. Y., Anti-inflammatory polymersomes of redox-responsive polyprodrug amphiphiles with inflammation-triggered indomethacin release characteristics. Biomaterials, 2018, 178, 608–619.

    CAS  PubMed  Google Scholar 

  32. Zhang, W. J.; Hu, X. L.; Shen, Q.; Xing, D., Mitochondria-specific drug release and reactive oxygen species burst induced by polyprodrug nanoreactors can enhance chemotherapy. Nat. Commun., 2019, 10, 14.

    Google Scholar 

  33. Pusuluri, A.; Krishnan, V.; Lensch, V.; Sarode, A.; Bunyan, E.; Vogus, D. R.; Menegatti, S.; Soh, H. T.; Mitragotri, S., Treating tumors at low drug doses using an aptamer-peptide synergistic drug conjugate. Angew. Chem. Int. Ed., 2019, 58, 1437–1441.

    CAS  Google Scholar 

  34. Duan, X. P.; Xiao, J. S.; Yin, Q.; Zhang, Z. W.; Yu, H. J.; Mao, S. R.; Li, Y. P., Smart pH-sensitive and temporal-controlled polymeric micelles for effective combination therapy of doxorubicin and disulfiram. ACS Nano, 2013, 7, 5858–5869.

    CAS  PubMed  Google Scholar 

  35. He, Y.; Li, X. L.; Ma, J. K.; Ni, G. L.; Yang, G.; Zhou, S. B., Programmable codelivery of doxorubicin and apatinib using an implantable hierarchical-structured fiber device for overcoming cancer multidrug resistance. Small, 2019, 15, 14.

    Google Scholar 

  36. Qin, J. W.; Wei, X. J.; Chen, H. Y.; Lv, F.; Nan, W. B.; Wang, Y. X.; Zhang, Q. Q.; Chen, H. L., mPEG-g-CS-modified PLGA nanoparticle carrier for the codelivery of paclitaxel and epirubicin for breast cancer synergistic therapy. ACS Biomater. Sci. Eng., 2018, 4, 1651–1660.

    CAS  Google Scholar 

  37. Lee, W.; Yang, E. J.; Ku, S. K.; Song, K. S.; Bae, J. S., Anti-inflammatory effects of oleanolic acid on LPS-induced inflammation in vitro and in vivo. Inflammation, 2013, 36, 94–102.

    CAS  PubMed  Google Scholar 

  38. Wang, X.; Ye, X. L.; Liu, R.; Chen, H. L.; Bai, H.; Liang, X.; Zhang, X. D.; Wang, Z.; Li, W. L.; Hai, C. X., Antioxidant activities of oleanolic acid in vitro: possible role of Nrf2 and MAP kinases. Chem. Biol. Interact., 2010, 184, 328–337.

    CAS  PubMed  Google Scholar 

  39. Yu, Z. J.; Sun, W. Z.; Peng, W. B.; Yu, R. L.; Li, G. Q.; Jiang, T., Pharmacokinetics in vitro and in vivo of two novel prodrugs of oleanolic acid in rats and its hepatoprotective effects against liver injury induced by CCl4. Mol. Pharm., 2016, 13, 1699–1710.

    CAS  PubMed  Google Scholar 

  40. Niu, S. W.; Williams, G. R.; Wu, J. R.; Wu, J. Z.; Zhang, X. J.; Zheng, H.; Li, S. D.; Zhu, L. M., A novel chitosan-based nanomedicine for multi-drug resistant breast cancer therapy. Chem. Eng. J., 2019, 369, 134–149.

    CAS  Google Scholar 

  41. Fontana, G.; Bruno, M.; Notarbartolo, M.; Labbozzetta, M.; Poma, P.; Spinella, A.; Rosselli, S., Cytotoxicity of oleanolic and ursolic acid derivatives toward hepatocellular carcinoma and evaluation of NF-κB involvement. Bioorg. Chem., 2019, 90, 103054.

    CAS  PubMed  Google Scholar 

  42. Pollier, J.; Goossens, A., Oleanolic acid. Phytochemistry, 2012, 77, 10–15.

    CAS  PubMed  Google Scholar 

  43. Jeong, D. W.; Kim, Y. H.; Kim, H. H.; Ji, H. Y.; Yoo, S. D.; Choi, W. R.; Lee, S. M.; Han, C. K.; Lee, H. S., Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats. Biopharm. Drug Disposition, 2007, 28, 51–57.

    CAS  Google Scholar 

  44. Jiang, Q. K.; Yang, X. X.; Du, P.; Zhang, H. F.; Zhang, T. H., Dual strategies to improve oral bioavailability of oleanolic acid: enhancing water-solubility, permeability and inhibiting cytochrome P450 isozymes. Eur. J. Pharm. Biopharm., 2016, 99, 65–72.

    CAS  PubMed  Google Scholar 

  45. Ghosh, S.; Kar, N.; Bera, T., Oleanolic acid loaded poly lactic coglycolic acid-vitamin E TPGS nanoparticles for the treatment of leishmania donovani infected visceral leishmaniasis. Int. J. Biol. Macromol., 2016, 93, 961–970.

    CAS  PubMed  Google Scholar 

  46. Zhang, L.; Chen, Y.; Shi, R.; Rang, T. G.; Pang, G. S.; Wang, B. R.; Zhao, Y.; Zeng, X.; Zou, C. X.; Wu, P.; Li, J. Y., Synthesis of hollow nanocages MOF-5 as drug delivery vehicle to solve the load-bearing problem of insoluble antitumor drug oleanolic acid (OA). Inorg. Chem. Commun., 2018, 96, 20–23.

    CAS  Google Scholar 

  47. Hornig, S.; Heinze, T.; Becer, C. R.; Schubert, U. S., Synthetic polymeric nanoparticles by nanoprecipitation. J. Mater. Chem., 2009, 19, 3838–3840.

    CAS  Google Scholar 

  48. Modi, S.; Anderson, B. D., Determination of drug release kinetics from nanoparticles: overcoming pitfalls of the dynamic dialysis method. Mol. Pharm., 2013, 10, 3076–3089.

    CAS  PubMed  Google Scholar 

  49. Guo, Y. F.; Hao, C. Y.; Wang, X. K.; Zhao, Y. N.; Han, M. H.; Wang, M. C.; Wang, X. T., Well-defined podophyllotoxin polyprodrug brushes: preparation via raft polymerization and evaluation as drug carriers. Polym. Chem., 2017, 8, 901–909.

    CAS  Google Scholar 

  50. Xu, M. Z.; Zhang, C. Y.; Wu, J. G.; Zhou, H. G.; Bai, R.; Shen, Z. Y.; Deng, F. L.; Liu, Y.; Liu, J., PEG-detachable polymeric micelles self-assembled from amphiphilic copolymers for tumor-acidity-triggered drug delivery and controlled release. ACS Appl. Mater. Interfaces, 2019, 11, 5701–5713.

    CAS  PubMed  Google Scholar 

  51. Du, J. Z.; Du, X. J.; Mao, C. Q.; Wang, J., Tailor-made dual pH-sensitive polymer-doxorubicin nanoparticles for efficient anticancer drug delivery. J. Am. Chem. Soc., 2011, 133, 17560–17563.

    CAS  PubMed  Google Scholar 

  52. Ke, W. D.; Yin, W.; Zha, Z. S.; Mukerabigwi, J. F.; Chen, W. J.; Wang, Y. H.; He, C. X.; Ge, Z. S., A robust strategy for preparation of sequential stimuli-responsive block copolymer prodrugs via thiolactone chemistry to overcome multiple anticancer drug delivery barriers. Biomaterials, 2018, 154, 261–274.

    CAS  PubMed  Google Scholar 

  53. Lin, J. T.; Ye, Q. B.; Yang, Q. J.; Wang, G. H., Hierarchical bioresponsive nanocarriers for codelivery of curcumin and doxorubicin. Colloids Surfaces B, 2019, 180, 93–101.

    CAS  Google Scholar 

  54. Yang, H.; Li, J.; Patel, S. K.; Palmer, K. E.; Devlin, B.; Rohan, L. C., Design of poly(lactic-co-glycolic acid) (PLGA) nanoparticles for vaginal co-delivery of griffithsin and dapivirine and their synergistic effect for HIV prophylaxis. Pharmaceutics, 2019, 11, 184.

    CAS  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (No. 21576029) and National Key R&D Program of China (No. 2017YFD0601205).

Author information

Authors and Affiliations

  1. Beijing Key Laboratory of Lignocellulosic Chemistry, Engineering Research Center of Forestry Biomass Materials and Bioenergy (Ministry of Education), Beijing Forestry University, Beijing, 100083, China

    Ying-Sa Wang, Gui-Liang Li, Shang-Bin Zhu, Fan-Chen Jing, Run-Dong Liu, Sai-Sai Li, Jing He & Jian-Du Lei

Authors
  1. Ying-Sa Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gui-Liang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shang-Bin Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fan-Chen Jing
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Run-Dong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sai-Sai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jing He
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jian-Du Lei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jing He.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, YS., Li, GL., Zhu, SB. et al. A Self-assembled Nanoparticle Platform Based on Amphiphilic Oleanolic Acid Polyprodrug for Cancer Therapy. Chin J Polym Sci 38, 819–829 (2020). https://doi.org/10.1007/s10118-020-2401-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10118-020-2401-2

Keywords

Search

Navigation