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RGDS- and doxorubicin-modified poly[N-(2-hydroxypropyl)methacrylamide]-coated γ-Fe2O3 nanoparticles for treatment of glioblastoma

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Abstract

Block copolymer comprising of hydrophilic poly[N-(2-hydroxypropyl)methacrylamide] (PHP) and reactive poly[N-(2-hydrazinyl-2-oxoethyl)methacrylamide] (PMAH) was synthesized by a reversible addition-fragmentation chain transfer (RAFT) polymerization and conjugated with doxorubicin (Dox) and/or RGDS targeting peptide via one-step reaction using N-γ-maleimidobutyryl-oxysuccinimide ester. The resulting copolymer served as a coating of magnetic γ-Fe2O3 nanoparticles that were tested in cell proliferation and in vivo experiments on a mice model with inoculated rat C6 glioblastoma tumor. The nanoparticles conjugated with RGDS peptide and doxorubicin easily engulfed both C6 tumor cell line, primary glioblastoma (GB) cells, and human mesenchymal stem cells (hMSC) used as a control; the particles decreased the GB cell growth by 45% compared to control cells without any treatment. Moreover, the γ-Fe2O3@P(HP-MAH)-RGDS-Dox nanoparticles injected into C6 glioblastoma cell-derived tumors grown in the posterior flank of mice decreased the tumor size and more apoptotic cells were spread compared to that treated with free Dox.

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References

  1. Hassanpour SH, Dehghani M (2017) Review of cancer from perspective of molecular. J Cancer Res Pract 4:127–129. https://doi.org/10.1016/j.jcrpr.2017.07.001

    Article  Google Scholar 

  2. Rosenblum D, Joshi N, Tao W, Karp JM, Peer D (2018) Progress and challenges towards targeted delivery of cancer therapeutics. Nat Commun 9:1410. https://doi.org/10.1038/s41467-018-03705-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yao VJ, D’Angelo S, Butler KS, Theron C, Smith TL, Marchiò S, Gelovani JG, Sidman RL, Dobroff AS, Brinker CJ, Bradbury ARM, Arap W, Pasqualini R (2016) Ligand-targeted theranostic nanomedicines against cancer. J Control Release 240:267–286. https://doi.org/10.1016/j.jconrel.2016.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Antonov AS, Antonova GN, Munn DH, Mivechi N, Lucas R, Catravas JD, Verin AD (2011) αVβ3 integrin regulates macrophage inflammatory responses via PI3 kinase/Akt-dependent NF-κB activation. J Cell Physiol 226:469–476. https://doi.org/10.1002/jcp.22356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Brake DA, Debouck C, Biesecker G (1990) Identification of an Arg-Gly-Asp (RGD) cell adhesion site in human immunodeficiency virus type I transactivation protein, tat. J Cell Biol 111:1275–1281. https://doi.org/10.1083/jcb.111.3.1275

    Article  CAS  PubMed  Google Scholar 

  6. Lo WL, Lo SW, Chen SJ, Chen MW, Huang YR, Chen LC, Chang CH, Li MH (2021) Molecular imaging and preclinical studies of radiolabeled long-term RGD peptides in U-87 MG tumor-bearing mice. Int J Mol Sci 22:5459. https://doi.org/10.3390/ijms22115459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ramezanizadeh M, Masterifarahani A, Sadeghzadeh N, Abediankenari S, Mardanshahi A, Maleki F (2020) 99mTc-D(RGD): molecular imaging probe for diagnosis of αvβ3-positive tumors. Nucl Med Commun 41:104–109. https://doi.org/10.1097/MNM.0000000000001121

    Article  CAS  PubMed  Google Scholar 

  8. Wang L, Wang X, Shen L, Alrobaian M, Panda SK, Almasmoum HA, Ghaith MM, Almaimani RA, Ibrahim IAA, Singh T, Baothman AA, Choudhry H, Beg S (2021) Paclitaxel and naringenin-loaded solid lipid nanoparticles surface modified with cyclic peptides with improved tumor targeting ability in glioblastoma multiforme. Biomed Pharmacother 138:111461. https://doi.org/10.1016/j.biopha.2021.111461

    Article  CAS  PubMed  Google Scholar 

  9. Ullah I, Chung K, Bae S, Li Y, Kim C, Choi B, Nam HY, Kim SH, Yun CO, Lee KY, Kumar P, Lee SK (2020) Nose-to-brain delivery of cancer-targeting paclitaxel-loaded nanoparticles potentiates antitumor effects in malignant glioblastoma. Mol Pharm 17:1193–1204. https://doi.org/10.1021/acs.molpharmaceut.9b01215

    Article  CAS  PubMed  Google Scholar 

  10. Chung K, Ullah I, Kim N, Lim J, Shin J, Lee SC, Jeon S, Kim SH, Kumar P, Lee SK (2020) Intranasal delivery of cancer-targeting doxorubicin-loaded PLGA nanoparticles arrests glioblastoma growth. J Drug Target 28:617–626. https://doi.org/10.1080/1061186X.2019.1706095

    Article  CAS  PubMed  Google Scholar 

  11. Zhang J, Xiao X, Zhu J, Gao Z, Lai X, Zhu X, Mao G (2018) Lactoferrin- and RGD-comodified, temozolomide and vincristine-coloaded nanostructured lipid carriers for gliomatosis cerebri combination therapy. Int J Nanomed 13:3039–3051. https://doi.org/10.2147/IJN.S161163

    Article  CAS  Google Scholar 

  12. Garanti T, Alhnan MA, Wan KW (2020) RGD-decorated solid lipid nanoparticles enhance tumor targeting, penetration and anticancer effect of asiatic acid. Nanomedicine (Lond) 15:1567–1583. https://doi.org/10.2217/nnm-2020-0035

    Article  CAS  Google Scholar 

  13. Shi X, Ma R, Lu Y, Cheng Y, Fan X, Zou J, Zheng H, Li F, Piao JG (2020) iRGD and TGN co-modified PAMAM for multi-targeted delivery of ATO to gliomas. Biochem Biophys Res Commun 527:117–123. https://doi.org/10.1016/j.bbrc.2020.04.064

    Article  CAS  PubMed  Google Scholar 

  14. Liu YL, Chen D, Shang P, Yin DC (2019) A review of magnet systems for targeted drug delivery. J Control Release 302:90–104. https://doi.org/10.1016/j.jconrel.2019.03.031

    Article  CAS  PubMed  Google Scholar 

  15. Xiao Y, Du J (2020) Superparamagnetic nanoparticles for biomedical applications. J Mater Chem B 8:354–367. https://doi.org/10.1039/C9TB01955C

    Article  CAS  PubMed  Google Scholar 

  16. Vallabani NVS, Singh S (2018) Recent advances and future prospects of iron oxide nanoparticles in biomedicine and diagnostics. Biotech 8:279. https://doi.org/10.1007/s13205-018-1286-z

    Article  Google Scholar 

  17. Coyne DW (2009) Ferumoxytol for treatment of iron deficiency anemia in patients with chronic kidney disease. Expert Opin Pharmacother 10:2563–2568. https://doi.org/10.1517/14656560903224998

    Article  CAS  PubMed  Google Scholar 

  18. Molday RS, Mackenzie D (1982) Immunospecific ferromagnetic iron-dextran reagents for the labeling and magnetic separation of cells. J Immunol Methods 52:353–367. https://doi.org/10.1016/0022-1759(82)90007-2

    Article  CAS  PubMed  Google Scholar 

  19. Robinson MR, Abdelmoula M, Mallet M, Coustel R (2019) Starch functionalized magnetite nanoparticles: new insight into the structural and magnetic properties. J Solid State Chem 277:587–593. https://doi.org/10.1016/j.jssc.2019.06.033

    Article  CAS  Google Scholar 

  20. Khmara I, Strbak O, Zavisova V, Koneracka M, Kubovcikova M, Antal I, Kavecansky V, Lucanska D, Dobrota D, Kopcansky P (2019) Chitosan-stabilized iron oxide nanoparticles for magnetic resonance imaging. J Magn Magn Mater 474:319–325. https://doi.org/10.1016/j.jmmm.2018.11.026

    Article  CAS  Google Scholar 

  21. Sanchez LM, Martin DA, Alvarez VA, Gonzalez JS (2018) Polyacrylic acid-coated iron oxide magnetic nanoparticles: the polymer molecular weight influence. Colloids Surf A 543:28–37. https://doi.org/10.1016/j.colsurfa.2018.01.050

    Article  CAS  Google Scholar 

  22. Khoee S, Kavand A (2014) A new procedure for preparation of polyethylene glycol-grafted magnetic iron oxide nanoparticles. J Nanostruct Chem 4:111. https://doi.org/10.1007/s40097-014-0111-4

    Article  Google Scholar 

  23. Lal M, Verma SR (2017) Synthesis and characterization of polyvinyl alcohol functionalized iron oxide nanoparticles. Macromol Symp 376:1700017. https://doi.org/10.1002/masy.201700017

    Article  CAS  Google Scholar 

  24. Zasońska BA, Boiko N, Klyuchivska O, Trchová M, Petrovský E, Stoika R, Horák D (2013) Silica-coated γ-Fe2O3 nanoparticles: Preparation and engulfment by mammalian macrophages. J Nanopharm Drug Deliv 1:182–192. https://doi.org/10.1166/jnd.2013.1020

    Article  Google Scholar 

  25. Tucker BS, Sumerlin BS (2014) Poly(N-(2-hydroxypropyl) methacrylamide)-based nanotherapeutics. Polym Chem 5:1566–1572. https://doi.org/10.1039/C3PY01279D

    Article  CAS  Google Scholar 

  26. Kopeček J, Kopečková P (2010) HPMA copolymers: Origins, early developments, present, and future. Adv Drug Deliv Rev 62:122–149. https://doi.org/10.1016/j.addr.2009.10.004

    Article  CAS  PubMed  Google Scholar 

  27. Chen L, Wu Y, Wu H, Li J, Xie J, Zang F, Ma M, Gu N, Zhang Y (2019) Magnetic targeting combined with active targeting of dual-ligand iron oxide nanoprobes to promote the penetration depth in tumors for effective magnetic resonance imaging and hyperthermia. Acta Biomater 96:491–504. https://doi.org/10.1016/j.actbio.2019.07.017

    Article  CAS  PubMed  Google Scholar 

  28. Plichta Z, Horák D, Mareková D, Turnovcová K, Kaiser R, Jendelová P (2020) Poly[N-(2-hydroxypropyl)methacrylamide]-modified magnetic γ-F2O3 nanoparticles conjugated with doxorubicin for glioblastoma treatment. ChemMedChem 15:96–104. https://doi.org/10.1002/cmdc.201900564

    Article  CAS  PubMed  Google Scholar 

  29. Plichta Z, Kozak Y, Panchuk R, Sokolova V, Epple M, Kobylinska L, Jendelová P, Horák D (2018) Cytotoxicity of doxorubicin-conjugated poly[N-(2-hydroxypropyl)methacrylamide]-modified γ-Fe2O3 nanoparticles towards human tumor cells. Beilstein J Nanotechnol 9:2533–2545. https://doi.org/10.3762/bjnano.9.236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ulbrich K, Šubr V, Strohalm J, Plocová D, Jelínková M, Říhová B (2000) Polymeric drugs based on conjugates of synthetic and natural macromolecules. I. Synthesis and physico-chemical characterization. J Control Release 64:63–79. https://doi.org/10.1016/S0168-3659(99)00141-8

    Article  CAS  PubMed  Google Scholar 

  31. Babič M, Horák D, Trchová M, Jendelová P, Glogarová K, Lesný P, Herynek V, Hájek M, Syková E (2008) Poly(L-lysine)-modified iron oxide nanoparticles for stem cell labeling. Bioconjug Chem 19:740–750. https://doi.org/10.1021/bc700410z

    Article  CAS  PubMed  Google Scholar 

  32. Golunova A, Velychkivska N, Mikšovská Z, Chochola V, Jaroš J, Hampl A, Pop-Georgievski O, Proks V (2021) Direct and indirect biomimetic peptide modification of alginate: Efficiency, side reactions, and cell response. Int J Mol Sci 22:5731. https://doi.org/10.3390/ijms22115731

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zasonska BA, Bober P, Jošt P, Petrovský E, Boštík P, Horák D (2016) Magnetoconductive maghemite core/polyaniline shell nanoparticles as promising tools for biomedical applications. Colloids Surf B 141:382–389. https://doi.org/10.1016/j.colsurfb.2016.01.059

    Article  CAS  Google Scholar 

  34. Etrych T, Jelínková M, Říhová B, Ulbrich K (2001) New HPMA copolymers containing doxorubicin bound via pH-sensitive linkage: synthesis and preliminary in vitro and in vivo biological properties. J Control Release 73:89–102. https://doi.org/10.1016/S0168-3659(01)00281-4

    Article  CAS  PubMed  Google Scholar 

  35. Kostiv U, Kotelnikov I, Proks V, Šlouf M, Kučka J, Engstová H, Ježek P, Horák D (2016) RGDS- and TAT-conjugated upconversion of NaYF4:Yb3+/Er3+&SiO2 nanoparticles: In vitro human epithelioid cervix carcinoma cellular uptake, imaging, and targeting. ACS Appl Mater Interfaces 8:20422–20431. https://doi.org/10.1021/acsami.6b07291

    Article  CAS  PubMed  Google Scholar 

  36. Antonow MB, Franco C, Prado W, Beckenkamp A, Silveira GP, Buffon A, Guterres SS, Pohlmann AR (2017) Arginylglycylaspartic acid-surface-functionalized doxorubicin-loaded lipid-core nanocapsules as a strategy to target alpha(V) beta(3) integrin expressed on tumor cells. Nanomaterials (Basel) 8:2. https://doi.org/10.3390/nano8010002

    Article  CAS  Google Scholar 

  37. Rizvi SFA, Mu S, Wang Y, Li S, Zhang H (2020) Fluorescent RGD-based pro-apoptotic peptide conjugates as mitochondria-targeting probes for enhanced anticancer activities. Biomed Pharmacother 127:110179. https://doi.org/10.1016/j.biopha.2020.110179

    Article  CAS  PubMed  Google Scholar 

  38. Ganipineni LP, Ucakar B, Joudiou N, Riva R, Jérôme C, Gallez B, Danhier F, Préat V (2019) Paclitaxel-loaded multifunctional nanoparticles for the targeted treatment of glioblastoma. J Drug Target 27:614–623. https://doi.org/10.1080/1061186X.2019.1567738

    Article  CAS  PubMed  Google Scholar 

  39. Zhou P, Zhao H, Wang Q, Zhou Z, Wang J, Deng G, Wang X, Liu Q, Yang H, Yang S (2018) Photoacoustic-enabled self-guidance in magnetic-hyperthermia Fe@Fe3O4 nanoparticles for theranostics in vivo. Adv Healthcare Mater 7:1701201. https://doi.org/10.1002/adhm.201701201

    Article  CAS  Google Scholar 

  40. Fang Y, Jiang Y, Zou Y, Meng F, Zhang J, Deng C, Sun H, Zhong Z (2017) Targeted glioma chemotherapy by cyclic RGD peptide-functionalized reversibly core-crosslinked multifunctional poly(ethylene glycol)-b-poly(ε-caprolactone) micelles. Acta Biomater 50:396–406. https://doi.org/10.1016/j.actbio.2017.01.007

    Article  CAS  PubMed  Google Scholar 

  41. Mo J, He L, Ma B, Chen T (2016) Tailoring particle size of mesoporous silica nanosystem to antagonize glioblastoma and overcome blood-brain barrier. ACS Appl Mater Interfaces 8:6811–6825. https://doi.org/10.1021/acsami.5b11730

    Article  CAS  PubMed  Google Scholar 

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Funding

Financial support of the Czech Science Foundation (No. 20-02177J) and the Operational Programme Research, Development and Education in the framework of the project Center of Reconstructive Neuroscience (No. CZ.02.1.01/0.0./0.0/15_003/0000419) is gratefully acknowledged.

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Authors and Affiliations

  1. Institute of Macromolecular Chemistry, Czech Academy of Sciences, Heyrovského nám. 2, 162 06, Prague 6, Czech Republic

    Daniel Horák, Zdeněk Plichta & Vladimír Proks

  2. Institute of Experimental Medicine, Czech Academy of Sciences, Vídeňská 1083, 142 20, Prague 4, Czech Republic

    Karolína Turnovcová, Dana Mareková & Pavla Jendelová

  3. Second Faculty of Medicine, Charles University, V úvalu 84, 150 06, Prague 5, Czech Republic

    Dana Mareková & Pavla Jendelová

  4. Department of Neurosurgery and Neurooncology, First Faculty of Medicine, Charles University and Military University Hospital, U Vojenské nemocnice 1, 162 00, Prague 6, Czech Republic

    Radek Kaiser & David Netuka

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  1. Daniel Horák
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Correspondence to Daniel Horák.

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The guidelines and approval of the Institutional Review Board (IRB) with signed informed consent was obtained for tumor glioblastoma cell sample. All animal experiments were performed in accordance with the European Communities Council Directive of 22 September 2010 (2010/63/EU) regarding the use of animals in research and were approved by the Ethics Committee of the Institute of Experimental Medicine and Committee of the Czech Academy of Sciences under Project No 78/2020.

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Horák, D., Turnovcová, K., Plichta, Z. et al. RGDS- and doxorubicin-modified poly[N-(2-hydroxypropyl)methacrylamide]-coated γ-Fe2O3 nanoparticles for treatment of glioblastoma. Colloid Polym Sci 300, 267–277 (2022). https://doi.org/10.1007/s00396-021-04895-6

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