Skip to main content
SpringerLink
Log in

Phenylboronic Acid-conjugated Exosomes for Enhanced Anticancer Therapeutic Effect by Increasing Doxorubicin Loading Efficiency

  • Research Paper
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

Anticancer drugs, including doxorubicin (DOX), have been widely used for cancer treatment, but these chemotherapeutic drugs have some issues to address because of their associated side effects, such as cytotoxicity. Various synthetic delivery vehicles for anticancer drugs have been developed to encapsulate and transfer them to cancer cells. However, these delivery vehicles also have high cytotoxicity and immunogenicity. Recently, exosomes have been highlighted as candidates for anticancer drug delivery vehicles with fewer side effects. Exosomes are nanosized particles that are produced from cells, and high concentrations of exosomes are already present in the human body. To develop exosome-based anticancer therapeutics, high drug concentrations should be loaded into exosomes. In this context, phenylboronic acid (PBA) was introduced and chemically conjugated to the exosome surface to load DOX to exosomes. Consequently, a high amount of DOX was efficiently loaded onto the PBA-conjugated exosomes. The DOX-loaded PBA-conjugated exosomes were applied to MDA-MB-231 breast cancer cells and showed enhanced cancer cell cytotoxicity compared to free DOX and DOX-loaded non-conjugated exosomes. Therefore, using PBA-conjugated exosomes for delivering DOX to cancer cells can be a promising strategy for effectively killing cancer cells because a high amount of DOX can be loaded and delivered.

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. Liu, Z., A. C. Fan, K. Rakhra, S. Sherlock, A. Goodwin, X. Chen, Q. Yang, D. W. Felsher, and H. Dai (2009) Supramolecular stacking of doxorubicin on carbon nanotubes for in vivo cancer therapy. Angew. Chem. Int. Ed. Engl. 48: 7668–7672.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Takemura, G. and H. Fujiwara (2007) Doxorubicin-induced cardiomyopathy from the cardiotoxic mechanisms to management. Prog. Cardiovasc. Dis. 49: 330–352.

    Article  CAS  PubMed  Google Scholar 

  3. Davis, M. E., Z. G. Chen, and D. M. Shin (2008) Nanoparticle therapeutics: an emerging treatment modality for cancer. Nat. Rev. Drug Discov. 7: 771–782.

    Article  CAS  PubMed  Google Scholar 

  4. Peer, D., J. M. Karp, S. Hong, O. C. Farokhzad, R. Margalit, and R. Langer (2007) Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol. 2: 751–760.

    Article  CAS  Google Scholar 

  5. Tahover, E., Y. P. Patil, and A. A. Gabizon (2015) Emerging delivery systems to reduce doxorubicin cardiotoxicity and improve therapeutic index: focus on liposomes. Anticancer Drugs. 26: 241–258.

    Article  CAS  PubMed  Google Scholar 

  6. Kirtane, A. R., R. Langer, and G. Traverso (2016) Past, present, and future drug delivery systems for antiretrovirals. J. Pharm. Sci. 105: 3471–3482.

    Article  CAS  PubMed  Google Scholar 

  7. Omolo, C. A., R. S. Kalhapure, M. Jadhav, S. Rambharose, C. Mocktar, V. M. K. Ndesendo, and T. Govender (2016) Pegylated oleic acid: A promising amphiphilic polymer for nano-antibiotic delivery. Eur. J. Pharm. Biopharm. 112: 96–108.

    Article  PubMed  Google Scholar 

  8. Yang, X., J. Tong, L. Guo, Z. Qian, Q. Chen, R. Qi, and Y. Qiu (2017) Bundling potent natural toxin cantharidin within platinum (IV) prodrugs for liposome drug delivery and effective malignant neuroblastoma treatment. Nanomedicine. 13: 287–296.

    Article  CAS  PubMed  Google Scholar 

  9. Ying, M., C. Zhan, S. Wang, B. Yao, X. Hu, X. Song, M. Zhang, X. Wei, Y. Xiong, and W. Lu (2016) Liposome-based systemic glioma-targeted drug delivery enabled by all-d peptides. ACS Appl. Mater. Interfaces. 8: 29977–29985.

    Article  CAS  PubMed  Google Scholar 

  10. Lane, R. E., D. Korbie, W. Anderson, R. Vaidyanathan, and M. Trau (2015) Analysis of exosome purification methods using a model liposome system and tunable-resistive pulse sensing. Sci. Rep. 5: 7639.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Schageman, J., E. Zeringer, M. Li, T. Barta, K. Lea, J. Gu, S. Magdaleno, R. Setterquist, and A. V. Vlassov (2013) The complete exosome workflow solution: from isolation to characterization of RNA Cargo. Biomed. Res. Int. 2013: 253957.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Dragovic, R. A., C. Gardiner, A. S. Brooks, D. S. Tannetta, D. J. P. Ferguson, P. Hole, B. Carr, C. W. G. Redman, A. L. Harris, P. J. Dobson, P. Harrison, and I. L. Sargent (2011) Sizing and phenotyping of cellular vesicles using nanoparticle tracking analysis. Nanomedicine. 7: 780–788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cho, S., H. C. Yang, and W. J. Rhee (2019) Simultaneous multiplexed detection of exosomal microRNAs and surface proteins for prostate cancer diagnosis. Biosens. Bioelectron. 146: 111749.

    Article  CAS  PubMed  Google Scholar 

  14. Lee, J. H., J. A. Kim, S. Jeong, and W. J. Rhee (2016) Simultaneous and multiplexed detection of exosome microRNAs using molecular beacons. Biosens. Bioelectron. 86: 202–210.

    Article  CAS  PubMed  Google Scholar 

  15. Lee, J. H., J. A. Kim, M. H. Kwon, J. Y. Kang, and W. J. Rhee (2015) In situ single step detection of exosome microRNA using molecular beacon. Biomaterials. 54: 116–125.

    Article  CAS  PubMed  Google Scholar 

  16. Patil, A. A. and W. J. Rhee (2019) Exosomes: biogenesis, composition, functions, and their role in pre-metastatic niche formation. Biotechnol. Bioprocess Eng. 24: 689–701.

    Article  CAS  Google Scholar 

  17. Jeong, K., S. Jeong, J. A. Kim, and W. J. Rhee (2019) Exosome-based antisense locked nucleic acid delivery for inhibition of type II collagen degradation in chondrocyte. J. Ind. Eng. Chem. 74: 126–135.

    Article  CAS  Google Scholar 

  18. Han, S. and W. J. Rhee (2018) Inhibition of apoptosis using exosomes in Chinese hamster ovary cell culture. Biotechnol. Bioengin. 115: 1331–1339.

    Article  CAS  Google Scholar 

  19. Kim, Y. G., U. Park, B. J. Park, K. Kim (2019) Exosome-mediated bidirectional signaling between mesenchymal stem cells and chondrocytes for enhanced chondrogenesis. Biotechnol. Bioprocess Eng. 24: 734–744.

    Article  CAS  Google Scholar 

  20. Kim, H. and W. J. Rhee (2020) Exosome-mediated let7c-5p delivery for breast cancer therapeutic development. Biotechnol. Bioprocess Eng. 25: 513–520.

    Article  CAS  Google Scholar 

  21. Yang, T., P. Martin, B. Fogarty, A. Brown, K. Schurman, R. Phipps, V. P. Yin, P. Lockman, and S. Bai (2015) Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm. Res. 32: 2003–2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Lai, R. C., R. W. Y. Yeo, K. H. Tan, and S. K. Lim (2013) Exosomes for drug delivery — a novel application for the mesenchymal stem cell. Biotechnol. Adv. 31: 543–551.

    Article  CAS  PubMed  Google Scholar 

  23. Schindler, C., A. Collinson, C. Matthews, A. Pointon, L. Jenkinson, R. R. Minter, T. J. Vaughan, and N. J. Tigue (2019) Exosomal delivery of doxorubicin enables rapid cell entry and enhanced in vitro potency. PLoS One. 14: e0214545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang, J., X. Wang, J. Wen, X. Su, L. Weng, C. Wang, Y. Tian, Y. Zhang, J. Tao, P. Xu, G. Lu, Z. Teng, and L. Wang (2019) Size effect of mesoporous organosilica nanoparticles on tumor penetration and accumulation. Biomater. Sci. 7: 4790–4799.

    Article  CAS  PubMed  Google Scholar 

  25. Andersen, K. A., T. P. Smith, J. E. Lomax, and R. T. Raines (2016) Boronic acid for the traceless delivery of proteins into cells. ACS Chem. Biol. 11: 319–323.

    Article  CAS  PubMed  Google Scholar 

  26. Wang, X., H. Tang, C. Wang, J. Zhang, W. Wu, and X. Jiang (2016) Phenylboronic acid-mediated tumor targeting of chitosan nanoparticles. Theranostics. 6: 1378–1392.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Lee, J., J. Kim, Y. M. Lee, D. Park, S. Im, E. H. Song, H. Park, and W. J. Kim (2017) Self-assembled nanocomplex between polymerized phenylboronic acid and doxorubicin for efficient tumor-targeted chemotherapy. Acta Pharmacol. Sin. 38: 848–858.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Luo, C. Q., L. Xing, P. F. Cui, J. B. Qiao, Y. J. He, B. A. Chen, L. Jin, and H. L. Jiang (2017) Curcumin-coordinated nanoparticles with improved stability for reactive oxygen species-responsive drug delivery in lung cancer therapy. Int. J. Nanomedicine. 12: 855–869.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lee, J. Y., S. J. Chung, H. J. Cho, and D. D. Kim (2015) Phenylboronic acid-decorated chondroitin sulfate A-based theranostic nanoparticles for enhanced tumor targeting and penetration. Adv. Funct. Mater. 25: 3705–3717.

    Article  CAS  Google Scholar 

  30. Toffoli, G., M. Hadla, G. Corona, I. Caligiuri, S. Palazzolo, S. Semeraro, A. Gamini, V. Canzonieri, and F. Rizzolio (2015) Exosomal doxorubicin reduces the cardiac toxicity of doxorubicin. Nanomedicine. 10: 2963–2971.

    Article  CAS  PubMed  Google Scholar 

  31. Hadla, M., S. Palazzolo, G. Corona, I. Caligiuri, V. Canzonieri, G. Toffoli, and F. Rizzolio (2016) Exosomes increase the therapeutic index of doxorubicin in breast and ovarian cancer mouse models. Nanomedicine. 11: 2431–2441.

    Article  CAS  PubMed  Google Scholar 

  32. Otsuka, H., E. Uchimura, H. Koshino, T. Okano, and K. Kataoka (2003) Anomalous binding profile of phenylboronic acid with N-acetylneuraminic acid (Neu5Ac) in aqueous solution with varying pH. J. Am. Chem. Soc. 125: 3493–3502.

    Article  CAS  PubMed  Google Scholar 

  33. Deshayes, S., H. Cabral, T. Ishii, Y. Miura, S. Kobayashi, T. Yamashita, A. Matsumoto, Y. Miyahara, N. Nishiyama, and K. Kataoka (2013) Phenylboronic acid-installed polymeric micelles for targeting sialylated epitopes in solid tumors. J. Am. Chem. Soc. 135: 15501–15507.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Incheon National University Research Grant in 2017.

The authors declare no conflict of interest.

Neither ethical approval nor informed consent was required for this study.

Author information

Author notes

  1. Equal contribution.

Authors and Affiliations

  1. Department of Bioengineering and Nano-Bioengineering, Incheon National University, Incheon, 22012, Korea

    Haneul Kim, Su Jin Kang & Won Jong Rhee

  2. Division of Bioengineering, Incheon National University, Incheon, 22012, Korea

    Won Jong Rhee

Authors
  1. Haneul Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Su Jin Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Won Jong Rhee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Won Jong Rhee.

Additional information

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, H., Kang, S.J. & Rhee, W.J. Phenylboronic Acid-conjugated Exosomes for Enhanced Anticancer Therapeutic Effect by Increasing Doxorubicin Loading Efficiency. Biotechnol Bioproc E 26, 78–85 (2021). https://doi.org/10.1007/s12257-020-0107-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-020-0107-5

Keywords

Search

Navigation