Self-assembled vesicles containing podophyllotoxin covalently modified with polyoxometalates for antitumor therapy
(
), Teng Liu1 ()Graphical Abstract
Abstract
Several polyoxometalates (POMs) have been shown to possess antitumor activity. In this study, hydrophilic POMs were combined with the hydrophobic drug podophyllotoxin (PPT) to create an amphiphilic anti-cancer drug PPT-POM-PPT, which can self-assemble into hollow vesicles. The properties of these vesicles, such as the critical aggregation concentration, were characterized. These vesicles had low hemolytic activity and high stability. Cytotoxicity tests showed that the PTT-POM-PPT vesicles exhibit strong antitumor activity against lung and liver cancer cells without significantly affecting normal cells. Cell uptake experiments confirm that the PPT-POM-PPT vesicles can easily penetrate cell membranes and effectively enter tumor cells, thus exerting anti-tumor effects. Furthermore, these vesicles co-localized with lysosomes. Moreover, these PPT-POM-PPT vesicles exhibit synergistic effects of PPT and POMs. They are efficient drug delivery platforms that act as both the carrier and the active drug, avoiding the potential risks associated with additional carrier ingredients. In summary, due to their anticancer properties, POMs and PPT facilitate the generation of novel amphiphilic self-assembling vesicles, providing a theoretical basis and enabling clinical applications of POMs in cancer therapy.
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References
Liu, Q. D.; Zhang, Q. H.; Shi, W. X.; Hu, H. S.; Zhuang, J.; Wang, X. Self-assembly of polyoxometalate clusters into two-dimensional clusterphene structures featuring hexagonal pores. Nat. Chem. 2022, 14, 433–440.
Yu, C. Z.; Hu, Y.; Yang, J. L.; Huang, J. S.; Li, B.; Wu, L. X.; Li, F. H. Efficient and stable inverted perovskite solar cells with TOASiW12-modified AI as a cathode. Adv. Funct. Mater. 2023, 33, 2209290.
Li, K.; Liu, Y. F.; Yang, G. P.; Zheng, Z. L.; Lin, X. L.; Zhang, Z. B.; Li, S. J.; Liu, Y. H.; Wei, Y. G. Highly-stable silverton-type UIV-containing polyoxomolybdate frameworks for the heterogeneous catalytic synthesis of quinazolinones. Green Chem. 2024, 26, 6454–6460.
Huang, X. Q.; Liu, S.; Liu, G.; Tao, Y. W.; Wang, C. R.; Zhang, Y. L.; Li, Z.; Wang, H. W.; Zhou, Z.; Shen, G. D. et al. An unprecedented 2-fold interpenetrated lvt open framework built from Zn6 ring seamed trivacant polyoxotungstates used for photocatalytic synthesis of pyridine derivatives. Appl. Catal. B: Environ. 2023, 323, 122134.
Zhang, H. Y.; Zhao, W. L.; Li, H. Q.; Zhuang, Q. H.; Sun, Z. Q.; Cui, D. Y.; Chen, X. J.; Guo, A.; Ji, X.; An, S. et al. Latest progress in covalently modified polyoxometalates-based molecular assemblies and advanced materials. Polyoxometalates 2022, 1, 9140011.
Aureliano, M.; Gumerova, N. I.; Sciortino, G.; Garribba, E.; Rompel, A.; Crans, D. C. Polyoxovanadates with emerging biomedical activities. Coord. Chem. Rev. 2021, 447, 214143.
Shi, Y. H.; Zhang, J. J.; Huang, H.; Cao, C. Y.; Yin, J. J.; Xu, W. J.; Wang, W. J.; Song, X. J.; Zhang, Y. W.; Dong, X. C. Fe-doped polyoxometalate as acid-aggregated nanoplatform for NIR-II photothermal-enhanced chemodynamic therapy. Adv. Healthc. Mater. 2020, 9, 2000005.
Cheng, Y.; Qin, K. J.; Zang, D. J. Polyoxometalates based nanocomposites for bioapplications. Rare Met. 2023, 42, 3570–3600.
Garrido Ribó, E.; Bell, N. L.; Xuan, W. M.; Luo, J. C.; Long, D. L.; Liu, T. B.; Cronin, L. Synthesis, assembly, and sizing of neutral, lanthanide substituted molybdenum blue wheels {Mo90Ln10}. J. Am. Chem. Soc. 2020, 142, 17508–17514.
Hu, Q. L.; Liu, Y. F.; Lin, X. L.; Lin, Z. F.; Cao, J. W.; Yang, G. P. Two different three-dimensional uranium-containing polymolybdates based on Zn(II) for the heterogeneous catalytic construction of C–N bond. Inorg. Chem. 2024, 63, 8919–8924.
Xu, T. T.; Li, Y. W.; Wei, Z. Z.; Liu, S.; Sun, J. N.; Jin, R. C.; Song, Y. B. Controllable self-assembly of atomically precise Au31Cu32 nanoclusters into superstructures. Mater. Today Chem. 2024, 36, 101922.
Li, S. L.; Zhang, S. S.; Feng, N.; Zhang, N.; Zhu, Y.; Liu, Y. H.; Wang, W. J.; Xin, X. Chiral inversion and recovery of supramolecular luminescent copper nanocluster hydrogels triggered by polyethyleneimine and polyoxometalates. ACS Appl. Mater. Interfaces 2022, 14, 52324–52333.
Salazar Marcano, D. E.; Lentink, S.; Chen, J. J.; Anyushin, A. V.; Moussawi, M. A.; Bustos, J.; Van Meerbeek, B.; Nyman, M.; Parac-Vogt, T. N. Supramolecular self-assembly of proteins promoted by hybrid polyoxometalates. Small 2024, 20, 2312009.
Huo, Z. H.; Liang, Y. M.; Lv, Y. K.; Melin, F.; Hellwig, P.; Ibrahim, H.; Goldmann, M.; Boudon, C.; Badets, V.; Bonnefont, A. et al. Enhancement of photocurrent by incorporation of preyssler type polyoxometalate protected nanoparticles in polyporphyrin films. Chem. Commun. 2021, 57, 1482–1485.
Xiao, H. P.; Hao, Y. S.; Li, X. X.; Xu, P.; Huang, M. D.; Zheng, S. T. A water-soluble antimony-rich polyoxometalate with broad-spectrum antitumor activities. Angew. Chem., Int. Ed. 2022, 61, e202210019.
Qu, X. S.; Shi, D.; Fu, Y.; Chu, D. X.; Yang, Y. Y.; Liu, Y. Enhanced antitumor activity of polyoxometalates loaded solid lipid nanoparticles. Inorg. Chem. Commun. 2021, 124, 108411.
Dolbecq, A.; Dumas, E.; Mayer, C. R.; Mialane, P. Hybrid organic-inorganic polyoxometalate compounds: From structural diversity to applications. Chem. Rev. 2010, 110, 6009–6048.
Liu, G.; Chen, Y. F.; Chen, Y. L.; Shi, Y. Q.; Zhang, M. Y.; Shen, G. D.; Qi, P. F.; Li, J. K.; Ma, D. L.; Yu, F. et al. Indirect electrocatalysis S–N/S–S bond construction by robust polyoxometalate based foams. Adv. Mater. 2023, 35, 2304716.
Wang, Z. C.; Zhang, S. S.; Xie, H. Y.; Zhang, N.; Wang, W. J.; Li, S. L.; Xin, X. Dispersing hydrophobic copper nanoclusters in aqueous solutions triggered by polyoxometalate with aggregation-induced eimission properties. Colloids Surf. A: Physicochem. Eng. Asp. 2023, 664, 131147.
Chen, K.; Liu, S. Q.; Wei, Y. J. Sub-nanosized vanadate hybrid clusters maintain glucose homeostasis and restore treatment response in inflammatory disease in obese mice. Nano Res. 2024, 17, 1818–1826.
Xia, Z. Q.; Yang, Y.; Song, Y. F.; Shi, S. W. Self-assembly of polyoxometalate-based nanoparticle surfactants in solutions. ACS Macro Lett. 2024, 13, 99–104.
Huang, S.; Jin, Q.; Wang, Y.; Sun, Y. H.; Wang, F. Z. RETRACTED: Anti-liver cancer activity evaluation of a polyoxometalate-organic co-crystal compound and its related coordination polymer. Main Group Chem. 2019, 18, 231–238.
Liu, C.; Cheng, Z.; Xu, X. D.; Wang, N.; Luo, X. W.; Xin, X. Fluorescent nanocomposite prepared through supramolecular self-assembly of a tetraphenylethene derivative and polyoxometalate for light-emitting diodes. ACS Appl. Nano Mater. 2024, 7, 11455–11464.
She, S.; Bian, S. T.; Hao, J.; Zhang, J. W.; Zhang, J.; Wei, Y. G. Aliphatic organoimido derivatives of polyoxometalates containing a bioactive ligand. Chem.—Eur. J. 2014, 20, 16987–16994.
Wang, X. H.; Liu, J. F.; Li, J. X.; Yang, Y.; Liu, J. T.; Li, B.; Pope, M. T. Synthesis and antitumor activity of cyclopentadienyltitanium substituted polyoxotungstate [CoW11O39(CpTi)]7− (Cp = η5-C5H5). J. Inorg. Biochem. 2003, 94, 279–284.
Yang, H. K.; Cheng, Y. X.; Su, M. M.; Xiao, Y.; Hu, M. B.; Wang, W.; Wang, Q. Polyoxometalate-biomolecule conjugates: A new approach to create hybrid drugs for cancer therapeutics. Bioorg. Med. Chem. Lett. 2013, 23, 1462–1466.
Ding, J. H.; Liu, Y. F.; Tian, Z. T.; Lin, P. J.; Yang, F.; Li, K.; Yang, G. P.; Wei, Y. G. Uranyl-silicotungstate-containing hybrid building units {α-SiW9} and {γ-SiW10} with excellent catalytic activities in the three-component synthesis of dihydropyrimidin-2(1 H)-ones. Inorg. Chem. Front. 2023, 10, 3195–3201.
Chen, K.; Qin, Y. R.; Liu, S. Q.; Chen, R. L. Remission of iron overload in adipose tissue of obese mice by fatty acid-modified polyoxovanadates. Rare Met. 2025, 44, 461–471.
Cheng, X. H.; Sun, P. P.; Zhang, S. S.; Sun, D.; Jiang, B. L.; Wang, W. S.; Xin, X. Self-assembly of m-phenylenediamine and polyoxometalate into hollow-sphere and core-in-hollow-shell nanostructures for selective adsorption of dyes. J. Mol. Liq. 2019, 287, 110982.
Li, X.; Pillai, S. C.; Wei, L.; Liu, Z. Z.; Huang, L. X.; Huang, Q.; Jia, X. S.; Hou, D. Y.; Song, H.; Wang, H. L. Facile synthesis of polyoxometalate-modified metal organic frameworks for eliminating tetrabromobisphenol-A from water. J. Hazard. Mater. 2020, 399, 122946.
Hu, H. F.; Pang, J. J.; Gong, P. J.; Chen, L. J.; Zhao, J. W. Organic-inorganic two-dimensional hybrid networks constructed from pyridine-4-carboxylate-decorated organotin-lanthanide heterometallic antimotungstates. Inorg. Chem. 2020, 59, 11287–11297.
Zhou, Q. P.; Jiang, X. Y.; Zhang, X. C.; Wang, D. W.; Yang, G.; Zhou, H.; Wu, Y. C.; Guo, F.; Chen, M.; Diao, G. W. et al. Polyoxomolybdate-based metal-organic framework-derived Cu-embedded molybdenum dioxide hybrid nanoparticles as highly efficient electrocatalysts for Al–S batteries. ChemSusChem 2024, 17, e202400424.
Yang, H. K.; Yang, K. M.; Zhang, Z. Y. Self-assembly of polyoxometalate-based hybrid molecules into nanoparticles or vesicles regulated by simple experimental manipulation. Colloid Polym. Sci. 2019, 297, 957–965.
Fu, L.; Gao, H. Q.; Yan, M.; Li, S. Z.; Li, X. Y.; Dai, Z. F.; Liu, S. Q. Polyoxometalate-based organic-inorganic hybrids as antitumor drugs. Small 2015, 11, 2938–2945.
Hasenknopf, B.; Delmont, R.; Herson, P.; Gouzerh, P. Anderson-type heteropolymolybdates containing Tris(alkoxo) ligands: Synthesis and structural characterization. Eur. J. Inorg. Chem. 2002, 2002, 1081–1087.
Marcoux, P. R.; Hasenknopf, B.; Vaissermann, J.; Gouzerh, P. Developing remote metal binding sites in heteropolymolybdates. Eur. J. Inorg. Chem. 2003, 2003, 2406–2412.
Ling, L. B.; Yao, C.; Du, Y. W.; Ismail, M.; He, R. Y.; Hou, Y. P.; Zhang, Y.; Li, X. S. Assembled liposomes of dual podophyllotoxin phospholipid: Preparation, characterization and in vivo anticancer activity. Nanomedicine 2017, 12, 657–672.
Zhao, W.; Cong, Y.; Li, H. M.; Li, S. Y.; Shen, Y. M.; Qi, Q. S.; Zhang, Y. M.; Li, Y. Z.; Tang, Y. J. Challenges and potential for improving the druggability of podophyllotoxin-derived drugs in cancer chemotherapy. Nat. Prod. Rep. 2021, 38, 470–488.
Ramezani Aliakbari, M.; Varshosaz, J.; Sadeghi-Aliabadi, H.; Hassanzadeh, F.; Rostami, M. Biotin-targeted nanomicellar formulation of an anderson-type polyoxomolybdate: Synthesis and in vitro cytotoxicity evaluations. Langmuir 2021, 37, 6475–6489.
Blazevic, A.; Rompel, A. The Anderson-Evans polyoxometalate: From inorganic building blocks via hybrid organic-inorganic structures to tomorrows “Bio-POM”. Coord. Chem. Rev. 2016, 307, 42–64.
Zhang, Q. Y.; Lei, D. D.; Luo, Q. Z.; Wang, J. L.; Deng, T. L.; Zhang, Y. T.; Ma, P. H. Efficient biodiesel production from oleic acid using metal-organic framework encapsulated Zr-doped polyoxometalate nano-hybrids. RSC Adv. 2020, 10, 8766–8772.
Martin, C.; Lamonier, C.; Fournier, M.; Mentré, O.; Harlé, V.; Guillaume, D.; Payen, E. Preparation and characterization of 6-molybdocobaltate and 6-molybdoaluminate cobalt salts. Evidence of a new heteropolymolybdate structure. Inorg. Chem. 2004, 43, 4636–4644.
Narayan Yadav, S.; Rai, S.; Shah, P.; Roy, N.; Bhattarai, A. Spectrophotometric and conductometric studies on the interaction of surfactant with polyelectrolyte in the presence of dye in aqueous medium. J. Mol. Liq. 2022, 355, 118949.
Dai, L. X.; Wang, T.; Liu, Y. T.; Lan, Y. J.; Ji, L.; Jiang, J. X.; Li, P. F. Fluorescence probe technique for determining the hydrophobic interactions and critical aggregation concentrations of Gleditsia microphylla gum, circular Gleditsia sinensis gum, and tara gum. Int. J. Biol. Macromol. 2023, 247, 125707.
Schmid, P.; Buchecker, T.; Khoshsima, A.; Touraud, D.; Diat, O.; Kunz, W.; Pfitzner, A.; Bauduin, P. Self-assembly of a short amphiphile in water controlled by superchaotropic polyoxometalates: H4SiW12O40 vs. H3PW12O40. J. Colloid Interface Sci. 2021, 587, 347–357.
Tiwari, S.; Mall, C.; Solanki, P. P. CMC studies of CTAB, SLS & tween 80 by spectral and conductivity methodology to explore its potential in photogalvanic cell. Surf. Interfaces 2020, 18, 100427.
Niraula, T. P.; Shah, R.; Kumar, D.; Dominguez, H.; Ríos-López, M.; Salazar-Arriaga, A. B.; De, R.; Bhattarai, A. Influence of solvent permittivity and divalent salt on micellization behavior of sodium dodecyl sulfate: Conductivity measurements and simulation study. J. Mol. Liq. 2022, 349, 118186.
Wu, R. L. G.; Tian, M. C.; Shu, C.; Zhou, C. C.; Guan, W. J. Determination of the critical micelle concentration of surfactants using fluorescence strategies. Soft Matter. 2022, 18, 8920–8930.
Wang, P.; Wang, Z. T.; Wang, P. S.; Chishti, A. N.; Zhang, H. X.; Shi, J. H.; Ni, L. B.; Jamil, S.; Wei, Y. G. Supramolecular self-assembly of polyoxometalates and cyclodextrin: Progress and perspectives. Polyoxometalates 2024, 3, 9140047.
Chu, Y.; Saad, A.; Yin, P. C.; Wu, J. Y. Z.; Oms, O.; Dolbecq, A.; Mialane, P.; Liu, T. B. Light-and solvent-controlled self-assembly behavior of spiropyran-polyoxometalate-alkyl hybrid molecules. Chem.—Eur. J. 2016, 22, 11756–11762.
Zhang, Y. W.; Wang, J. Q.; Chen, Z.; Xie, Y. P.; Wu, J. Q.; Wang, X. J.; Zang, D. J.; Liu, T. Polyoxometalates-based vesicles for application in biological systems. Mater. Today Commun. 2022, 33, 104991.
Fang, D. X.; Pi, M. H.; Pan, Z. C.; Song, N. J.; He, X. L.; Li, J. H.; Luo, F.; Tan, H.; Li, Z. Stable, bioresponsive, and macrophage-evading polyurethane micelles containing an anionic tripeptide chain extender. ACS Omega 2019, 4, 16551–16563.
Traldi, F.; Liu, P. F.; Albino, I.; Ferreira, L.; Zarbakhsh, A.; Resmini, M. Protein-nanoparticle interactions govern the interfacial behavior of polymeric nanogels: Study of protein corona formation at the air/water interface. Int. J. Mol. Sci. 2023, 24, 2810.
Zhao, L. S.; Ckurshumova, W.; Fefer, M.; Liu, J.; Hoare, T. Fabrication, characterization and in planta uptake of engineered surfactant nanovesicles for the delivery of the biostimulant sodium copper chlorophyllin. J. Agric. Food Chem. 2022, 70, 15028–15037.
Moataz El-Dahmy, R.; Hassen Elshafeey, A.; Ahmed El-Feky, Y. Fabrication, optimization, and evaluation of lyophilized lacidipine-loaded fatty-based nanovesicles as orally fast disintegrating sponge delivery system. Int. J. Pharm. 2024, 655, 124035.
Zhang, T. Y.; Zheng, X. X.; Lin, R. Y.; Sun, H.; Wu, H. H.; Zhang, J. S.; Chen, S. H.; Li, Y. S.; Xu, D. H.; Gao, J. Q. Lyophilizable stem cell-hybrid liposome with long-term stability and high targeting capacity. Adv. Healthc. Mater. 2024, 13, 2400704.
Meulewaeter, S.; Nuytten, G.; Cheng, M. H. Y.; De Smedt, S. C.; Cullis, P. R.; De Beer, T.; Lentacker, I.; Verbeke, R. Continuous freeze-drying of messenger RNA lipid nanoparticles enables storage at higher temperatures. J. Control. Release 2023, 357, 149–160.
Fan, X. F.; Pang, W.; Feng, H.; Zhang, R. Y.; Zhu, W. T.; Wang, Q. S.; Miao, J.; Li, Y. W.; Liu, Y. J.; Xu, X. Q. Light-guided tumor diagnosis and therapeutics: From nanoclusters to polyoxometalates. Chin. Chem. Lett. 2022, 33, 2783–2798.
Bijelic, A.; Aureliano, M.; Rompel, A. Polyoxometalates as potential next-generation metallodrugs in the combat against cancer. Angew. Chem., Int. Ed. 2019, 58, 2980–2999.
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