Hyperthermia Efficacy of PEGylated-PLGA Coated Monodisperse Iron Oxide Nanoparticles

Abstract

Magnetic nano hyperthermia (MNH) is a promising technique for the treatment of a variety of malignancies. This non-invasive technique employs magnetic nanoparticles and alternating magnetic fields to generate local heat at the tumor location, which activates cell death pathways. However, the efficacy of MNH is dependent on the physicochemical properties of the magnetic nanoparticles, such as size, size distribution, magnetic properties, biocompatibility, and dispersibility in the medium. In this study, it is aimed to evaluate the heating capacity of poly (lactic-co-glycolic acid)-poly (ethylene glycol) di-block copolymer (PLGA-b-PEG) coated monodisperse iron oxide nanoparticles (IONs) as an effective mediator for MNH application. For this purpose, monodisperse IONs with a narrow size distribution and a mean particle size of 8.6 nm have been synthesized via the thermal decomposition method. The resulting IONs were then coated with the PEGylated-PLGA polymer and homogeneously dispersed in the polymeric matrix, which had a clearly defined spherical shape. Additionally, the specific absorption rate (SAR), reflecting the amount of heat dissipation from the NPs to the surrounding medium, was calculated for different concentrations (10, 5, 2.5, and 1.25 mg/mL) of PEGylated-PLGA-IONs. At 5 mg/mL PEGylated-PLGA-IONs (125 μgFe/mL) were found to have a maximum SAR value of 313 W/g. In conclusion, the homogenous dispersion of IONs in PEGylated-PLGA matrix may be one of the critical parameters to enhance the SAR value for MNH-based cancer therapy.

Keywords

• Magnetic nano hyperthermia
• Iron oxide nanoparticles
• Induction heating
• SAR
• PLGA
• PEG
• PEGylated-PLGA

Thanks

The author is sincerely grateful for the assistance of the Cell and Tissue Engineering Research Group at Hacettepe University. The author is also thankful to Dr. Mehmet Burak Kaynar for the hyperthermia measurements, as well as Dr. Soner Cakmak for all of the support

References

1. 1. Albarqi HA, Wong LH, Schumann C, Sabei FY, Korzun T, Li X, Hansen MN, Dhagat P, Moses AS, Taratula O, Taratula O. Biocompatible nanoclusters with high heating efficiency for systemically delivered magnetic hyperthermia. ACS Nano. 2019;13(6):6383-6395. doi:10.1021/acsnano.8b06542.
2. 2. Senturk F, Çakmak S, Ozturk GG. Synthesis and characterization of oleic acid coated magnetic nanoparticles for hyperthermia applications. Natural and Applied Sciences Journal. 2019;2(2):16-29. doi:10.38061/idunas.657975.
3. 3. Beik J, Abed Z, Ghoreishi FS, Hosseini-Nami S, Mehrzadi S, Shakeri-Zadeh A, Kamrava SK. Nanotechnology in hyperthermia cancer therapy: From fundamental principles to advanced applications. J Control Release. 2016;235:205-221. doi:10.1016/j. jconrel.2016.05.062.
4. 4. Senturk F, Kocum IC, Guler Ozturk G. Stepwise implementation of a low-cost and portable radiofrequency hyperthermia system for in vitro/in vivo cancer studies. Instrumentation Science & Technology. 2021:1-13. doi:10.1080/10739149.2021.1927075.
5. 5. El-Boubbou K. Magnetic iron oxide nanoparticles as drug carriers: Preparation, conjugation and delivery. Nanomedicine. 2018;13(8):929-952. doi:10.2217/nnm-2017-0320.
6. 6. Deatsch AE, Evans BA. Heating efficiency in magnetic nanoparticle hyperthermia. Journal of Magnetism and Magnetic Materials. 2014;354:163-172. doi:10.1016/j.jmmm.2013.11.006.
7. 7. Senturk F. Current advances in glioblastoma therapy, in: N. Duran (Ed.), Medical and health research theory, method and practice. Livre De Lyon, Lyon. 2021;81:35-50.
8. 8. Senturk F, Cakmak S. Fabrication of curcumin-loaded magnetic PEGylated-PLGA nanocarriers tagged with GRGDS peptide for improving anticancer activity. MethodsX. 2023:102229. doi:10.1016/j.mex.2023.102229.

9. 9. Senturk F, Cakmak S, Kocum IC, Gumusderelioglu M, Ozturk GG. Effects of radiofrequency exposure on in vitro blood-brain barrier permeability in the presence of magnetic nanoparticles. Biochem Biophys Res Commun. 2022;597:91-97. doi: 10.1016/j. bbrc.2022.01.112.
10. 10. Senturk F, Cakmak S, Kocum IC, Gumusderelioglu M, Ozturk GG. GRGDS-conjugated and curcumin-loaded magnetic polymeric nanoparticles for the hyperthermia treatment of glioblastoma cells. Colloids and Surfaces A: Physicochemical and Engineering Aspects. 2021:126648. doi: 10.1016/j.colsurfa.2021.126648.
11. 11. Shubitidze F, Kekalo K, Stigliano R, Baker I. Magnetic nanoparticles with high specific absorption rate of electromagnetic energy at low field strength for hyperthermia therapy. J Appl Phys. 2015;117(9):094302. doi:10.1063/1.4907915.
12. 12. Xie L, Jin W, Chen H, Zhang Q. Superparamagnetic Iron Oxide Nanoparticles for Cancer Diagnosis and Therapy. J Biomed Nanotechnol. 2019;15(2):215-416. doi:10.1166/jbn.2019.2678
13. 13. Dadfar SM, Roemhild K, Drude NI, von Stillfried S, Knuchel R, Kiessling F, Lammers T. Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications. Adv Drug Deliv Rev. 2019;138:302-325. doi:10.1016/j.addr.2019.01.005.
14. 14. Cai J, Miao YQ, Yu BZ, Ma P, Li L, Fan HM. Large-Scale, Facile Transfer of Oleic Acid-Stabilized Iron Oxide Nanoparticles to the Aqueous Phase for Biological Applications. Langmuir. 2017;33(7):1662-1669. doi:10.1021/acs.langmuir.6b03360.
15. 15. Aguilar AA, Ho MC, Chang E, Carlson KW, Natarajan A, Marciano T, Bomzon Ze, Patel CB. Permeabilizing cell membranes with electric fields. Cancers (Basel). 2021;13(9):2283. doi:10.3390/ cancers13092283.
16. 16. Senturk F, Bahadir A. Potential effects of electromagnetic fields used in cancer therapy on SARS-COV-2 infection. in A. Urfalıoglu and H. Kamalak (Eds.). The clinical implications and evaluations of pandemic disease (COVID-19) in Turkey. Livre De Lyon, Lyon 2021;78:1-18.
17. 17. Szasz A. Thermal and nonthermal effects of radiofrequency on living state and applications as an adjuvant with radiation therapy. Journal of Radiation and Cancer Research. 2019;10(1):1. doi:10.4103/jrcr.jrcr_25_18.
18. 18. Park J, An K, Hwang Y, Park JG, Noh HJ, Kim JY, Park JH, Hwang NM, Hyeon T. Ultra-large-scale syntheses of monodisperse nanocrystals. Nat Mater. 2004;3(12):891-895. doi: 10.1038/nmat1251.
19. 19. Prabhu S, Goda JS, Mutalik S, Mohanty BS, Chaudhari P, Rai S, Udupa N, Rao BSS. A polymeric temozolomide nanocomposite against orthotopic glioblastoma xenograft: tumor-specific homing directed by nestin. Nanoscale. 2017;9(30):10919-10932. doi:10.1039/ c7nr00305f.
20. 20. Chun SH, Shin SW, Amornkitbamrung L, Ahn SY, Yuk JS, Sim SJ, Luo D, Um SH. Polymeric Nanocomplex Encapsulating Iron Oxide Nanoparticles in Constant Size for Controllable Magnetic Field Reactivity. Langmuir. 2018;34(43):12827-33.
21. 21. Raval N, Maheshwari R, Kalyane D, Youngren-Ortiz SR, Chougule MB, Tekade RK. Importance of physicochemical characterization of nanoparticles in pharmaceutical product development. Basic fundamentals of drug delivery. 2019:369-400. doi:10.1016/B978-0- 12-817909-3.00010-8.
22. 22. Ghosh R, Pradhan L, Devi YP, Meena SS, Tewari R, Kumar A, Sharma S, Gajbhiye NS, Vatsa RK, Pandey BN, Ningthoujam RS. Induction heating studies of Fe3O4 magnetic nanoparticles capped with oleic acid and polyethylene glycol for hyperthermia. J Mater Chem. 2011;21(35). doi:10.1039/c1jm10092k.
23. 23. Wildeboer R, Southern P, Pankhurst Q. On the reliable measurement of specific absorption rates and intrinsic loss parameters in magnetic hyperthermia materials. Journal of Physics D: Applied Physics. 2014;47(49):495003. doi:10.1088/0022-3727/47/49/495003.
24. 24. Ruggiero MR, Geninatti Crich S, Sieni E, Sgarbossa P, Cavallari E, Stefania R, Dughiero F, Aime S. Iron oxide/PLGA nanoparticles for magnetically controlled drug release. International Journal of Applied Electromagnetics and Mechanics. 2017;53(S1):S53-S60. doi:10.3233/JAE-162246.
25. 25. Eivazzadeh-Keihan R, Asgharnasl S, Aliabadi HAM, Tahmasebi B, Radinekiyan F, Maleki A, Bahreinizad H, Mahdavi M, Alavijeh MS, Saber R. Magnetic graphene oxide–lignin nanobiocomposite: a novel, eco-friendly and stable nanostructure suitable for hyperthermia in cancer therapy. RSC advances. 2022;12(6):3593- 3601. doi:10.1039/D1RA08640E.
26. 26. Kossatz S, Ludwig R, Dähring H, Ettelt V, Rimkus G, Marciello M, Salas G, Patel V, Teran FJ, Hilger I. High therapeutic efficiency of magnetic hyperthermia in xenograft models achieved with moderate temperature dosages in the tumor area. Pharm Res. 2014;31(12):3274-88. doi:10.1007/s11095-014-1417-0
27. 27. Unni M, Uhl AM, Savliwala S, Savitzky BH, Dhavalikar R, Garraud N, Arnold DP, Kourkoutis LF, Andrew JS, Rinaldi C. Thermal Decomposition Synthesis of Iron Oxide Nanoparticles with Diminished Magnetic Dead Layer by Controlled Addition of Oxygen. ACS Nano. 2017;11(2):2284-303. doi:10.1021/ acsnano.7b00609.
28. 28. Dallet L, Stanicki D, Voisin P, Miraux S, Ribot EJ. Micron-sized iron oxide particles for both MRI cell tracking and magnetic fluid hyperthermia treatment. Sci Rep. 2021;11(1):1-13. doi:10.1038/ s41598-021-82095-6.
29. 29. Senturk F, Cakmak S, Gumusderelioglu M, Ozturk GG. Hydrolytic instability and low-loading levels of temozolomide to magnetic PLGA nanoparticles remain challenging against glioblastoma therapy. Journal of Drug Delivery Science and Technology. 2022;68:103101. doi:10.1016/j.jddst.2022.103101.
30. 30. Spivakov A, Lin C-R, Chang Y-C, Wang C-C, Sarychev D. Magnetic and Magneto-Optical Oroperties of Iron Oxides Nanoparticles Synthesized under Atmospheric Pressure. Nanomaterials. 2020;10(9):1888. doi:10.3390/nano10091888
31. 31. Smolensky ED, Park H-YE, Zhou Y, Rolla GA, Marjańska M, Botta M, Pierre VC. Scaling laws at the nanosize: the effect of particle size and shape on the magnetism and relaxivity of iron oxide nanoparticle contrast agents. Journal of Materials Chemistry B. 2013;1(22):2818-28. doi:10.1039/C3TB00369H.
32. 32. Wu K, Su D, Liu J, Saha R, Wang J-P. Magnetic nanoparticles in nanomedicine: A review of recent advances. Nanotechnology. 2019;30(50):502003. doi:10.1088/1361-6528/ab4241.
33. 33. Ramírez-Morales MA, Goldt AE, Kalachikova PM, Ramirez B JA, Suzuki M, Zhigach AN, Ben Salah A, Shurygina LI, Shandakov SD, Zatsepin T. Albumin stabilized Fe@ C core–shell nanoparticles as candidates for magnetic hyperthermia therapy. Nanomaterials. 2022;12(16):2869. doi:10.3390/nano12162869.
34. 34. Liu X, Zhang Y, Wang Y, Zhu W, Li G, Ma X, Zhang Y, Chen S, Tiwari S, Shi K. Comprehensive understanding of magnetic hyperthermia for improving antitumor therapeutic efficacy. Theranostics. 2020;10(8):3793. doi:10.7150/thno.40805.
35. 35. Kim J-w, Wang J, Kim H, Bae S. Concentration-dependent oscillation of specific loss power in magnetic nanofluid hyperthermia. Sci Rep. 2021;11(1):1-10. doi:10.1038/s41598-020-79871-1.