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Balancing efficacy and safety of doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive doxorubicin-fatty acid prodrugs

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An Erratum to this article was published on 20 March 2024

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Abstract

Albumin nanoparticles (ANPs) offer unique advantages for antitumor drug delivery system, including non-immunogenicity and inherent tumor-targeting capacity. At present, only a few products, such as ABRAXANE® and FYARRO™, have been approved for clinical applications. The poor affinity of doxorubicin (DOX) for albumin, coupled with its numerous severe adverse reactions, poses challenges in the fabrication of desirable albumin nanoparticles loaded with DOX. In this study, we developed prodrugs by conjugating fatty acids of varying lengths with DOX. Our aim was to investigate the balance between efficacy and safety through the selection of appropriate modules. We synthesized five pH-sensitive doxorubicin-fatty acid prodrugs. Compared to free DOX, all DOX prodrug ANPs exhibited a uniform size distribution with desirable sizes of 150 nm. Additionally, DOX prodrugs with hydrazone bonds remained intact in blood circulation while releasing DOX within tumor cells. Significantly, the characteristics of prodrug ANPs were considerably influenced by the length of fatty acids, impacting their in vivo pharmacokinetics, antitumor effectiveness and tumor accumulation. This research offers a detailed understanding of the length of fatty acid influence on DOX-fatty acid prodrug-based ANPs, and it builds a good platform for creating ANPs which prioritize high drug loading, high efficiency, and minimal side effects.

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References

  1. Li, H.; Wei, W. Y.; Xu, H. X. Drug discovery is an eternal challenge for the biomedical sciences. Acta Mater. Med. 2022, 1, 1–3.

    Google Scholar 

  2. Zhao, N.; Woodle, M. C.; Mixson, A. J. Advances in delivery systems for doxorubicin. J. Nanomed. Nanotechnol. 2018, 9, 519.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Visscher, H.; Ross, C. J. D.; Rassekh, S. R.; Barhdadi, A.; Dubé, M. P.; Al-Saloos, H.; Sandor, G. S.; Caron, H. N.; van Dalen, E. C.; Kremer, L. C. et al. Pharmacogenomic prediction of anthracycline-induced cardiotoxicity in children. J. Clin. Oncol. 2012, 30, 1422–1428.

    Article  PubMed  Google Scholar 

  4. Wojnowski, L.; Kulle, B.; Schirmer, M.; Schlüter, G.; Schmidt, A.; Rosenberger, A.; Vonhof, S.; Bickeböller, H.; Toliat, M. R.; Suk, E. K. et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity. Circulation 2005, 112, 3754–3762.

    Article  CAS  PubMed  Google Scholar 

  5. Armstrong, J.; Dass, C. R. Doxorubicin action on mitochondria: Relevance to osteosarcoma therapy. Curr. Drug Targets 2018, 19, 432–438.

    Article  CAS  PubMed  Google Scholar 

  6. Swain, S. M.; Whaley, F. S.; Ewer, M. S. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003, 97, 2869–2879.

    Article  CAS  PubMed  Google Scholar 

  7. Regenold, M.; Steigenberger, J.; Siniscalchi, E.; Dunne, M.; Casettari, L.; Heerklotz, H.; Allen, C. Determining critical parameters that influence in vitro performance characteristics of a thermosensitive liposome formulation of vinorelbine. J. Control. Release 2020, 328, 551–561.

    Article  CAS  PubMed  Google Scholar 

  8. Vargason, A. M.; Anselmo, A. C.; Mitragotri, S. The evolution of commercial drug delivery technologies. Nat. Biomed. Eng. 2021, 5, 951–967.

    Article  PubMed  Google Scholar 

  9. Chatterjee, K.; Zhang, J. Q.; Honbo, N.; Karliner, J. S. Doxorubicin cardiomyopathy. Cardiology 2010, 115, 155–162.

    Article  CAS  PubMed  Google Scholar 

  10. Liu, Z. B.; Chen, X. Y. Simple bioconjugate chemistry serves great clinical advances: Albumin as a versatile platform for diagnosis and precision therapy. Chem. Soc. Rev. 2016, 45, 1432–1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang, G. B.; Phua, S. Z. F.; Lim, W. Q.; Zhang, R.; Feng, L. Z.; Liu, G. F.; Wu, H. W.; Bindra, A. K.; Jana, D.; Liu, Z. et al. A hypoxia-responsive albumin-based nanosystem for deep tumor penetration and excellent therapeutic efficacy. Adv. Mater. 2019, 31, 1901513.

    Article  Google Scholar 

  12. Bai, S. T.; Jiang, H.; Song, Y. S.; Zhu, Y. N.; Qin, M.; He, C. T.; Du, G. S.; Sun, X. Aluminum nanoparticles deliver a dual-epitope peptide for enhanced anti-tumor immunotherapy. J. Control. Release 2022, 344, 134–146.

    Article  CAS  PubMed  Google Scholar 

  13. Fan, N.; Zhao, J.; Zhao, W.; Zhang, X. Y.; Song, Q. C.; Shen, Y. T.; Shum, H. C.; Wang, Y.; Rong, J. H. Celastrol-loaded lactosylated albumin nanoparticles attenuate hepatic steatosis in non-alcoholic fatty liver disease. J. Control. Release 2022, 347, 44–54.

    Article  CAS  PubMed  Google Scholar 

  14. Kratz, F. WITHDRAWN: A clinical update of using albumin as a drug vehicle - a commentary. J. Control. Release, in press, DOI: https://doi.org/10.1016/j.jconrel.2014.04.022.

  15. Hao, L. Q.; Zhou, Q.; Piao, Y.; Zhou, Z. X.; Tang, J. B.; Shen, Y. Q. Albumin-binding prodrugs via reversible iminoboronate forming nanoparticles for cancer drug delivery. J. Control. Release 2021, 330, 362–371.

    Article  CAS  PubMed  Google Scholar 

  16. Chung, S. W.; Choi, J. U.; Lee, B. S.; Byun, J.; Jeon, O. C.; Kim, S. W.; Kim, I. S.; Kim, S. Y.; Byun, Y. Albumin-binding caspase-cleavable prodrug that is selectively activated in radiation exposed local tumor. Biomaterials 2016, 94, 1–8.

    Article  CAS  PubMed  Google Scholar 

  17. Hoogenboezem, E. N.; Duvall, C. L. Harnessing albumin as a carrier for cancer therapies. Adv. Drug Deliv. Rev. 2018, 130, 73–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li, G. T.; Sun, B. J.; Li, Y. Q.; Luo, C.; He, Z. G.; Sun, J. Small-molecule prodrug nanoassemblies: An emerging nanoplatform for anticancer drug delivery. Small 2021, 17, 2101460.

    Article  CAS  Google Scholar 

  19. Sun, B. J.; Luo, C.; Yu, H.; Zhang, X. B.; Chen, Q.; Yang, W. Q.; Wang, M. L.; Kan, Q. M.; Zhang, H. T.; Wang, Y. J. et al. Disulfide bond-driven oxidation- and reduction-responsive prodrug nanoassemblies for cancer therapy. Nano Lett. 2018, 18, 3643–3650.

    Article  ADS  CAS  PubMed  Google Scholar 

  20. Sun, B. J.; Luo, C.; Zhang, X. B.; Guo, M. R.; Sun, M. C.; Yu, H.; Chen, Q.; Yang, W. Q.; Wang, M. L.; Zuo, S. Y. et al. Probing the impact of sulfur/selenium/carbon linkages on prodrug nanoassemblies for cancer therapy. Nat. Commun. 2019, 10, 3211.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  21. Yang, Y. X.; Zuo, S. Y.; Zhang, J. X.; Liu, T.; Li, X. M.; Zhang, H. T.; Cheng, M. S.; Wang, S. J.; He, Z. G.; Sun, B. J. et al. Prodrug nanoassemblies bridged by Mono-/Di-/Tri-sulfide bonds: Exploration is for going further. Nano Today 2022, 44, 101480.

    Article  CAS  Google Scholar 

  22. Yang, Y. X.; Li, X. H.; Song, J. X.; Li, L. X.; Ye, Q.; Zuo, S. Y.; Liu, T.; Dong, F. D.; Liu, X. H.; He, Z. G. et al. Structure-activity relationship of pH-sensitive doxorubicin-fatty acid prodrug albumin nanoparticles. Nano Lett. 2023, 23, 1530–1538.

    Article  ADS  CAS  PubMed  Google Scholar 

  23. Callmann, C. E.; LeGuyader, C. L. M.; Burton, S. T.; Thompson, M. P.; Hennis, R.; Barback, C.; Henriksen, N. M.; Chan, W. C.; Jaremko, M. J.; Yang, J. et al. Antitumor activity of 1, 18-octadecanedioic acid-paclitaxel complexed with human serum albumin. J. Am. Chem. Soc. 2019, 141, 11765–11769.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Mo, R.; Gu, Z. Tumor microenvironment and intracellular signal-activated nanomaterials for anticancer drug delivery. Mater. Today 2016, 19, 274–283.

    Article  CAS  Google Scholar 

  25. El-Sawy, H. S.; Al-Abd, A. M.; Ahmed, T. A.; El-Say, K. M.; Torchilin, V. P. Stimuli-responsive Nano-architecture drug-delivery systems to solid tumor micromilieu: Past, present, and future perspectives. ACS Nano 2018, 12, 10636–10664.

    Article  CAS  PubMed  Google Scholar 

  26. Felber, A. E.; Dufresne, M. H.; Leroux, J. C. pH-sensitive vesicles, polymeric micelles, and nanospheres prepared with polycarboxylates. Adv. Drug Deliv. Rev. 2012, 64, 979–992.

    Article  CAS  PubMed  Google Scholar 

  27. Lu, T. L.; Wang, Z.; Ma, Y. F.; Zhang, Y.; Chen, T. Influence of polymer size, liposomal composition, surface charge, and temperature on the permeability of ph-sensitive liposomes containing lipid-anchored poly(2-ethylacrylic acid). Int. J. Nanomedicine 2012, 7, 4917–4926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee, E. S.; Oh, K. T.; Kim, D.; Youn, Y. S.; Bae, Y. H. Tumor pH-responsive flower-like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine). J. Control. Release 2007, 123, 19–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bae, Y. M.; Park, Y. I.; Nam, S. H.; Kim, J. H.; Lee, K.; Kim, H. M.; Yoo, B.; Choi, J. S.; Lee, K. T.; Hyeon, T. et al. Endocytosis, intracellular transport, and exocytosis of lanthanide-doped upconverting nanoparticles in single living cells. Biomaterials 2012, 33, 9080–9086.

    Article  CAS  PubMed  Google Scholar 

  30. Karve, S.; Bandekar, A.; Ali, M. R.; Sofou, S. The pH-dependent association with cancer cells of tunable functionalized lipid vesicles with encapsulated doxorubicin for high cell-kill selectivity. Biomaterials 2010, 31, 4409–4416.

    Article  CAS  PubMed  Google Scholar 

  31. Sonawane, S. J.; Kalhapure, R. S.; Govender, T. Hydrazone linkages in pH responsive drug delivery systems. Eur. J. Pharm. Sci. 2017, 99, 45–65.

    Article  CAS  PubMed  Google Scholar 

  32. Li, L.; Dai, S.; Liu, J. Y.; Wu, W.; Zhao, Q. X.; Wang, X.; Wang, N.; Xu, Z. H. Antagonistic effect and in vitro activity of dauricine on glucagon receptor. J. Nat. Prod. 2022, 85, 2035–2043.

    Article  CAS  PubMed  Google Scholar 

  33. Macari, G.; Toti, D.; Pasquadibisceglie, A.; Polticelli, F. DockingApp RF: A state-of-the-art novel scoring function for molecular docking in a user-friendly interface to AutoDock vina. Int. J. Mol. Sci. 2020, 21, 9548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Trott, O.; Olson, A. J. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem. 2010, 31, 455–461.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Key R&D Program of China (No. 2022YFE0111600), National Natural Science Foundation of China (Nos. 82272151 and 82204318).

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Author notes

  1. Yuanhao Yu, Shiyi Zuo, and Jiaxuan Song contributed equally to this work.

Authors and Affiliations

  1. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Yuanhao Yu, Danping Wang & Xiaohong Liu

  2. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Shiyi Zuo, Jiaxuan Song, Lingxiao Li, Tian Liu, Jiayu Guo, Yaqiao Li, Qi Lu, Helin Wang, Zhonggui He, Bingjun Sun & Jin Sun

  3. Department of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, China

    Dun Zhou

  4. Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang, 110016, China

    Bingjun Sun & Jin Sun

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  1. Yuanhao Yu
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Corresponding authors

Correspondence to Xiaohong Liu, Bingjun Sun or Jin Sun.

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12274_2024_6533_MOESM1_ESM.pdf

Electronic Supplementary Material: Balancing efficacy and safety of doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive doxorubicin-fatty acid prodrugs

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Yu, Y., Zuo, S., Song, J. et al. Balancing efficacy and safety of doxorubicin-loaded albumin nanoparticles utilizing pH-sensitive doxorubicin-fatty acid prodrugs. Nano Res. (2024). https://doi.org/10.1007/s12274-024-6533-5

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  • DOI: https://doi.org/10.1007/s12274-024-6533-5

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