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Research Article

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

Yuanhao Yu1,§, Shiyi Zuo2,§, Jiaxuan Song2,§, Lingxiao Li2, Tian Liu2, Jiayu Guo2, Yaqiao Li2, Danping Wang1, Qi Lu2, Helin Wang2, Dun Zhou3, Zhonggui He2, Xiaohong Liu1( ), Bingjun Sun2,4( ), Jin Sun2,4( )
School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China
Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
Department of Pharmacy, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, China
Joint International Research Laboratory of Intelligent Drug Delivery Systems, Ministry of Education, Shenyang 110016, China

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

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An erratum to this article is available online at:
https://doi.org/10.1007/s12274-024-6611-8

Graphical Abstract

Modification of doxorubicin (DOX) with fatty acids that bind well to albumin through pH-sensitive hydrazine bond can transform poor albumin-affinitive DOX into albumin-matched DOX prodrugs, with on-demand drug release behavior. Desirable DOX prodrug albumin nanoparticles (ANPs) with long chain (longer than C10) effectively improved the affinity to albumin, exhibiting high drug loading and encapsulation efficiency. In addition, with the increase of the fatty acid length, the cytotoxicity, blood circulation and tumor accumulation of DOX prodrug ANPs were improved, thus greatly facilitated their antitumor efficacy.

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.

Keywords

fatty acid prodrugalbumindoxorubicinpH-sensitive bondnanomedicines

Electronic Supplementary Material

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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.
Crossref Google Scholar
[2]

Zhao, N.; Woodle, M. C.; Mixson, A. J. Advances in delivery systems for doxorubicin. J. Nanomed. Nanotechnol. 2018, 9, 519.
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.
Crossref 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.
[5]

Armstrong, J.; Dass, C. R. Doxorubicin action on mitochondria: Relevance to osteosarcoma therapy. Curr. Drug Targets 2018, 19, 432–438.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref Google Scholar
[9]

Chatterjee, K.; Zhang, J. Q.; Honbo, N.; Karliner, J. S. Doxorubicin cardiomyopathy. Cardiology 2010, 115, 155–162.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref Google Scholar
[14]
Kratz, F. WITHDRAWN: A clinical update of using albumin as a drug vehicle - a commentary. J. Control. Release, in press, DOI: 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref Google Scholar
[24]

Mo, R.; Gu, Z. Tumor microenvironment and intracellular signal-activated nanomaterials for anticancer drug delivery. Mater. Today 2016, 19, 274–283.
Crossref 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.
Crossref 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.
Crossref 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.
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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref 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.
Crossref Google Scholar
Nano Research
Volume 17 Issue 6,
June 2024
Pages 5491-5500
DOI: 10.1007/s12274-024-6533-5
Cite this article:
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 Research, 2024, 17(6): 5491-5500. https://doi.org/10.1007/s12274-024-6533-5
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Received: 10 November 2023
Revised: 30 January 2024
Accepted: 31 January 2024
Published: 29 February 2024
© Tsinghua University Press, corrected publication 2024
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