Protein-based nanocarriers for efficient Etoposide delivery and cancer therapy
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Etoposide, a DNA damage-inducing agent, is widely used for malignant tumors. However, insufficient solubility, poor bioavailability and adverse events limited the treatment outcomes and prognosis. To address this, we here developed a novel biosynthetic and unfolded protein nanocarrier to load and deliver Etoposide. Compared with the pristine agent, the loading efficiency of the nanoformulated drug increased four times and the half-life time increased to 17.6 h with controlled release of the Etoposide for 6 days. The half-maximal inhibitory concentration at 48 h was lower than that at 24 h, suggesting a long-acting anti-tumor property. Moreover, the anti-tumor performance in rat models was significantly enhanced by improving solubility and cellular internalization. Additionally, immunogenicity and adverse toxicologic effects such as kidney and liver toxicity were significantly weakened. Therefore, the assembly strategy enables etoposide with higher efficacy, bioavailability, and safety, and has great potential in the comprehensive treatment of malignant tumors.
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Protein-based nanocarriers for efficient Etoposide delivery and cancer therapy
Abstract
Etoposide, a DNA damage-inducing agent, is widely used for malignant tumors. However, insufficient solubility, poor bioavailability and adverse events limited the treatment outcomes and prognosis. To address this, we here developed a novel biosynthetic and unfolded protein nanocarrier to load and deliver Etoposide. Compared with the pristine agent, the loading efficiency of the nanoformulated drug increased four times and the half-life time increased to 17.6 h with controlled release of the Etoposide for 6 days. The half-maximal inhibitory concentration at 48 h was lower than that at 24 h, suggesting a long-acting anti-tumor property. Moreover, the anti-tumor performance in rat models was significantly enhanced by improving solubility and cellular internalization. Additionally, immunogenicity and adverse toxicologic effects such as kidney and liver toxicity were significantly weakened. Therefore, the assembly strategy enables etoposide with higher efficacy, bioavailability, and safety, and has great potential in the comprehensive treatment of malignant tumors.
References(38)
Al-Ali, A. A. A.; Sandra, L.; Versweyveld, D.; Pijpers, I.; Dillen, L.; Vermeulen, A.; Snoeys, J.; Holm, R.; Nielsen, C. U. High-dose etoposide formulations do not saturate intestinal p-glycoprotein: Development, stability, and pharmacokinetics in sprague-dawley rats. Int. J. Pharm. 2020, 583, 119399.
Arumugam, S. P.; Balakrishnan, S. B.; Ganesan, V.; Munisamy, M.; Kuppu, S. V.; Narayanan, V.; Baskaralingam, V.; Jeyachandran, S.; Thambusamy, S. In-vitro dissolution and microbial inhibition studies on anticancer drug etoposide with β-cyclodextrin. Mater. Sci. Eng. C 2019, 102, 96–105.
Zhu, Y. J.; Zhu, R. R.; Wang, M.; Wu, B.; He, X. L.; Qian, Y. C.; Wang, S. L. Anti-metastatic and anti-angiogenic activities of core-shell SiO2@LDH loaded with etoposide in non-small cell lung cancer. Adv. Sci. 2016, 3, 1600229.
Beauté, L.; McClenaghan, N.; Lecommandoux, S. Photo-triggered polymer nanomedicines: From molecular mechanisms to therapeutic applications. Adv. Drug Deliv. Rev. 2019, 138, 148–166.
Abdel-Bar, H. M.; Walters, A. A.; Wang, J. T. W.; Al-Jamal, K. T. Combinatory delivery of etoposide and siCD47 in a lipid polymer hybrid delays lung tumor growth in an experimental melanoma lung metastatic model. Adv. Healthcare Mater. 2021, 10, 2001853.
Su, J. J.; Lu, S.; Wei, Z.; Li, B.; Li, J. J.; Sun, J.; Liu, K.; Zhang, H. J.; Wang, F. Biocompatible inorganic nanoagent for efficient synergistic tumor treatment with augmented antitumor immunity. Small 2022, 18, 2200897.
Liu, B.; Gu, X. Q.; Sun, Q. N.; Jiang, S. J.; Sun, J.; Liu, K.; Wang, F.; Wei, Y. Injectable in situ induced robust hydrogel for photothermal therapy and bone fracture repair. Adv. Funct. Mater. 2021, 31, 2010779.
Liu, B.; Sun, J.; Zhu, J. J.; Li, B.; Ma, C.; Gu, X. Q.; Liu, K.; Zhang, H. J.; Wang, F.; Su, J. J. et al. Injectable and NIR-responsive DNA-inorganic hybrid hydrogels with outstanding photothermal therapy. Adv. Mater. 2020, 32, 2004460.
Su, J. J.; Lu, S.; Jiang, S. J.; Li, B.; Liu, B.; Sun, Q. N.; Li, J. J.; Wang, F.; Wei, Y. Engineered protein photo-thermal hydrogels for outstanding in situ tongue cancer therapy. Adv. Mater. 2021, 33, 2100619.
Wang, N.; Cheng, X. J.; Li, N.; Wang, H.; Chen, H. Y. Nanocarriers and their loading strategies. Adv. Healthcare Mater. 2019, 8, 1801002.
Fenton, O. S.; Olafson, K. N.; Pillai, P. S.; Mitchell, M. J.; Langer, R. Advances in biomaterials for drug delivery. Adv. Mater. 2018, 30, 1705328.
Wei, G. Q.; Wang, Y.; Huang, X. H.; Hou, H. B.; Zhou, S. B. Peptide-based nanocarriers for cancer therapy. Small Methods 2018, 2, 1700358.
Jiang, Q.; Zhao, S.; Liu, J. B.; Song, L. L.; Wang, Z. G.; Ding, B. Q. Rationally designed DNA-based nanocarriers. Adv. Drug Deliv. Rev. 2019, 147, 2–21.
Ruman, U.; Fakurazi, S.; Masarudin, M. J.; Hussein, M. Z. Nanocarrier-based therapeutics and theranostics drug delivery systems for next generation of liver cancer nanodrug modalities. Int. J. Nanomedicine 2020, 15, 1437–1456.
Li, Y. X.; Sun, J.; Li, J. J.; Liu, K.; Zhang, H. J. Engineered protein nanodrug as an emerging therapeutic tool. Nano Res. 2022, 15, 5161–5172.
Bunschoten, A.; Buckle, T.; Kuil, J.; Luker, G. D.; Luker, K. E.; Nieweg, O. E.; Van Leeuwen, F. W. B. Targeted non-covalent self-assembled nanoparticles based on human serum albumin. Biomaterials 2012, 33, 867–875.
Pitek, A. S.; Jameson, S. A.; Veliz, F. A.; Shukla, S.; Steinmetz, N. F. Serum albumin ‘camouflage’ of plant virus based nanoparticles prevents their antibody recognition and enhances pharmacokinetics. Biomaterials 2016, 89, 89–97.
Su, J. J.; Liu, B. M.; He, H. N.; Ma, C.; Wei, B.; Li, M.; Li, J. J.; Wang, F.; Sun, J.; Liu, K. et al. Engineering high strength and super-toughness of unfolded structural proteins and their extraordinary anti-adhesion performance for abdominal hernia repair. Adv. Mater. 2022, 34, 2200842.
Zhao, K. L.; Liu, Y. W.; Ren, Y. B.; Li, B.; Li, J. J.; Wang, F.; Ma, C.; Ye, F. F.; Sun, J.; Zhang, H. J. et al. Molecular engineered crown-ether-protein with strong adhesion over a wide temperature range from -196 to 200 °C. Angew. Chem., Int. Ed. 2022, 61, e202207425.
Wang, Z. L.; Gu, X. Q.; Li, B.; Li, J. J.; Wang, F.; Sun, J.; Zhang, H. J.; Liu, K.; Guo, W. S. Molecularly engineered protein glues with superior adhesion performance. Adv. Mater. 2022, 34, 2204590.
Zhang, P.; Li, J. J.; Sun, J.; Li, Y. X.; Liu, K.; Wang, F.; Zhang, H. J.; Su, J. J. Bioengineered protein fibers with anti-freezing mechanical behaviors. Adv. Funct. Mater. 2022, 32, 2209006.
Wei, Z.; Sun, J.; Lu, S.; Liu, Y. W.; Wang, B.; Zhao, L.; Wang, Z. L.; Liu, K.; Li, J. J.; Su, J. J. et al. An engineered protein-Au bioplaster for efficient skin tumor therapy. Adv. Mater. 2022, 34, 2110062.
Li, J. J.; Li, B.; Sun, J.; Ma, C.; Wan, S. K.; Li, Y. X.; Göstl, R.; Herrmann, A.; Liu, K.; Zhang, H. J. Engineered near-infrared fluorescent protein assemblies for robust bioimaging and therapeutic applications. Adv. Mater. 2020, 32, 2000964.
Wan, S. K.; Cheng, W. H.; Li, J. J.; Wang, F.; Xing, X. W.; Sun, J.; Zhang, H. J.; Liu, K. Biological composite fibers with extraordinary mechanical strength and toughness mediated by multiple intermolecular interacting networks. Nano Res. 2022, 15, 9192–9198.
Zhao, X. Y.; Li, X.; Li, B.; Sun, Y.; Shi, Y. J.; Shen, H. X.; Wang, F.; Li, J. J.; Sharopov, F.; Mukhiddinov, Z. et al. A robust protein-peptide co-assembling nanoformulation (PePCAN) platform with significant cell-entry characteristics for targeted cancer therapy. Chem. Eng. J. 2023, 453, 139886.
Zhao, L.; Gu, X. Q.; Jiang, F. Q.; Li, B.; Lu, S.; Wang, F.; Sun, Y.; Liu, K.; Li, J. J. Long-lasting proteinaceous nanoformulation for tumor imaging and therapy. ACS Omega 2022, 7, 31299–31308.
Su, J. J.; Sun, Q. N.; Lin, S.; Lu, S.; Zhang, Q.; Li, Y. X.; Li, B.; Sun, Y.; Liu, K.; Zhang, H. J. et al. Biosynthetic and unfolded protein nanocarriers for chemotherapeutic drugs in oral cancers: Improved bioavailability and safety of chemotherapeutics. Adv. Funct. Mater. 2022, 32, 2204271.
Ma, C.; Li, B.; Zhang, J. R.; Sun, Y.; Li, J. J.; Zhou, H. C.; Shen, J. L.; Gu, R.; Qian, J. C.; Fan, C. H. et al. Significantly improving the bioefficacy for rheumatoid arthritis with supramolecular nanoformulations. Adv. Mater. 2021, 33, 2100098.
Wang, S. D.; Li, B.; Zhang, H. L.; Chen, J. Y.; Sun, X.; Xu, J.; Ren, T. T.; Zhang, Y. Y.; Ma, C.; Guo, W. et al. Improving bioavailability of hydrophobic prodrugs through supramolecular nanocarriers based on recombinant proteins for osteosarcoma treatment. Angew. Chem., Int. Ed. 2021, 60, 11252–11256.
Wang, C. Y.; Zhang, J. R.; Li, B.; Zuo, J. L.; Li, Y. X.; Sun, Y.; Wang, F.; Liu, K.; Li, J. J. High-efficiency treatment for osteoarthritis via self-assembled dual-functionalized nanobiologics. ACS Biomater. Sci. Eng. 2022, 8, 3320–3328.
Zhang, J. R.; Sun, Y.; Qu, Q.; Li, B.; Zhang, L. L.; Gu, R.; Zuo, J. L.; Wei, W.; Ma, C.; Liu, L. et al. Engineering non-covalently assembled protein nanoparticles for long-acting gouty arthritis therapy. J. Mater. Chem. B 2021, 9, 9923–9931.
Golombek, S. K.; May, J. N.; Theek, B.; Appold, L.; Drude, N.; Kiessling, F.; Lammers, T. Tumor targeting via EPR: Strategies to enhance patient responses. Adv. Drug Deliv. Rev. 2018, 130, 17–38.
Izci, M.; Maksoudian, C.; Manshian, B. B.; Soenen, S. J. The use of alternative strategies for enhanced nanoparticle delivery to solid tumors. Chem. Rev. 2021, 121, 1746–1803.
Lázaro, I. A.; Haddad, S.; Sacca, S.; Orellana-Tavra, C.; Fairen-Jimenez, D.; Forgan, R. S. Selective surface PEGylation of UiO-66 nanoparticles for enhanced stability, cell uptake, and pH-responsive drug delivery. Chem 2017, 2, 561–578.
You, X. R.; Wang, L. Y.; Wang, L.; Wu, J. Rebirth of aspirin synthesis by-product: Prickly poly(salicylic acid) nanoparticles as self-anticancer drug carrier. Adv. Funct. Mater. 2021, 31, 2100805.
Sengupta, S.; Tyagi, P.; Chandra, S.; Kochupillai, V.; Gupta, S. K. Encapsulation in cationic liposomes enhances antitumour efficacy and reduces the toxicity of etoposide, a topo-isomerase II inhibitor. Pharmacology 2001, 62, 163–171.
Zhu, J. W.; Chen, J. T.; Song, D. M.; Zhang, W. D.; Guo, J. P.; Cai, G. P.; Ren, Y. H.; Wan, C. Y.; Kong, L. Y.; Yu, W. Y. Real-time monitoring of etoposide prodrug activated by hydrogen peroxide with improved safety. J. Mater. Chem. B 2019, 7, 7548–7557.
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Acknowledgements
This work was supported by the National Key R&D Program of China (Nos. 2020YFA0712102, 2018YFA0902600, 2021YFF0701800, 2020YFA0211100), the National Natural Science Foundation of China (Nos. 52222214, 22020102003, 22125701, 21907088, 51922077, 51872205), the Youth Innovation Promotion Association of CAS (No. 2020228), Natural Science Foundation of Jilin Province (No. 20210101366JC), the Foundation of National Facility for Translational Medicine (Shanghai) (No. TMSK-2020-012). All animal experiments were conducted in compliance with the Animal Management Rules of the Ministry of Health of the People’s Republic of China and with the approval of the Institutional Animal Care and Use Committee of the Animal Experiment Center of Peking University (No. LA2019313).
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