In vitro и in vivo photodynamic therapy of solid tumors with a combination of riboflavin and upconversion nanoparticles

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Abstract

Rationale: Riboflavin (vitamin B2) is one of the most promising agents for photodynamic therapy (PDT). However, its use is limited by the excitation in the ultraviolet (UV) and visible spectral ranges and, as a result, by a small penetration into biological tissue not exceeding a few millimeters. This problem could be solved by approaches ensuring excitation of riboflavin molecules within tumor tissues by infrared (IR) light. Upconversion nanoparticles (UCNPs) can be potentially considered as mediators able to effectively convert the exciting radiation of the near IR range, penetrating into biological tissue to a 3 cm depth, into the photoluminescence in the UV and visible spectral ranges.

Aim: To evaluate the efficacy of UCNPs for IR-mediated riboflavin activation in the depth of tumor tissue during PDT.
Materials and methods: The water-soluble riboflavin flavin mononucleotide (FMN, Pharmstandard-UfaVITA, Russia) was used as a photosensitizer in in vitro and in vivo experiments. The in vitro experiments were performed on human breast adenocarcinoma SK-BR-3, human glioblastoma U-87 MG, and rat glioma C6 cell lines. Lewis lung carcinoma (LLC) inoculated to hybrid BDF1 mice was used as a model to demonstrate the delivery of FMN to the tumor. UCNPs with a core/shell structure [NaYF4:Yb3+, Tm3+/NaYF4] were used for photoactivation of FMN in vivo. PDT based on FMN, UCNPs and laser radiation 975 nm (IR) was performed on mouse xenografts of human breast adenocarcinoma SKBR-3.

Results: We were able to show that FMN could act as an effective in vitro photosensitizer for SK-BR-3, U-87 MG, and C6 cell lines. FMN IC50 values for glioma cells were ~30 μM, and for SK-BR-3 cell line ~50 μM (24 h incubation, irradiation 4.2 J/cm2). In the LLC model, the appropriate concentration of FMN (30 μM and above) can be achieved in the tumor as a result of systemic administration of FMN (at 2 and 24 hours after injection). The effect of PDT using near IR light for UCNP-mediated excitation of FMN was demonstrated in mouse xenografts SKBR-3, with the tumor growth inhibition of 90±5%.

Conclusion: The study has demonstrated the possibility to use riboflavin (vitamin B2) as a photosensitizer for PDT. The photoexcitation of FMN via the anti-Stokes photoluminescence of UCNPs allows for implementation of the PDT technique with the near IR spectral range.

About the authors

N. V. Sholina

N.N. Blokhin National Medical Research Centre of Oncology; I.M. Sechenov First Moscow State Medical University; Federal Scientific Research Centre Crystallography and Photonics, Russian Academy of Sciences

Author for correspondence.
Email: SholinaNV@gmail.com
ORCID iD: 0000-0001-9866-2878

Natal'ya V. Sholina - Postgraduate Student, Junior Research Fellow, Laboratory of Biomarkers and Mechanisms of Tumor Angiogenesis N.N. Blokhin NMRCO; Laboratory of Photon Bioengineering, Institute of Molecular Medicine I.M. Sechenov FMSMU; Laboratory of Laser Biomedicine FSRC"Crystallography and Photonic, RAS.

24 Kashirskoe shosse, Moscow, 115478; 8/2 Trubetskaya ul., Moscow, 119991; 59 Leninsky prospekt, Moscow, 119333, tel.: + 7 (926) 957 96 63

Russian Federation

R. A. Akasov

I.M. Sechenov First Moscow State Medical University; Federal Scientific Research Centre Crystallography and Photonics, Russian Academy of Sciences

Email: fake@neicon.ru
ORCID iD: 0000-0001-6486-8114

Roman A. Akasov - PhD, Research Fellow, Laboratory of Photon Bioengineering, Institute of Molecular Medicine I.M. Sechenov FMSMU; Laboratory of Laser Biomedicine FSRCCrystallography and Photonic, RAS.

8/2 Trubetskaya ul., Moscow, 119991; 59 Leninsky prospekt, Moscow, 119333

Russian Federation

D. A. Khochenkov

N.N. Blokhin National Medical Research Centre of Oncology

Email: fake@neicon.ru
ORCID iD: 0000-0002-5694-3492

Dmitry A. Khochenkov - PhD (in Biol.), Head of the Laboratory of Biomarkers and Mechanisms of Tumor Angiogenesis N.N. Blokhin NMRCO.

24 Kashirskoe shosse, Moscow, 115478

Russian Federation

A. N. Generalova

Federal Scientific Research Centre Crystallography and Photonics, Russian Academy of Sciences; M.M. Shemyakin – Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences

Email: fake@neicon.ru
ORCID iD: 0000-0001-9646-1693

Alla N. Generalova - PhD (in Chem.), Senior Research Fellow, Laboratory of Laser Biomedicine FSRCCrystallography and Photonic, RAS; Laboratory "Polymers for Biology" M.M. Shemyakin - Yu.A. Ovchinnikov IBC, RAS.

59 Leninsky prospekt, Moscow, 119333; 16/10 Miklukho-Maklaya ul., Moscow, 117997

Russian Federation

V. A. Semchishen

Federal Scientific Research Centre Crystallography and Photonics, Russian Academy of Sciences

Email: fake@neicon.ru
ORCID iD: 0000-0003-1035-3013

Vladimir A. Semchishen – PhD (in Phys. and Math.), Leading Research Fellow, Laboratory of Laser Biomedicine.

59 Leninsky prospekt, Moscow, 119333

Russian Federation

E. V. Khaydukov

I.M. Sechenov First Moscow State Medical University; Federal Scientific Research Centre Crystallography and Photonics, Russian Academy of Sciences

Email: fake@neicon.ru
ORCID iD: 0000-0002-3900-2949

Evgeny V. Khaydukov - PhD (in Phys. and Math.), Head of the Laboratory of Photon Bioengineering, Institute of Molecular Medicine I.M. Sechenov FMSMU; Head of the Laboratory of Laser Biomedicine FSRC"Crystallography and Photonic, RAS.

8/2 Trubetskaya ul., Moscow, 119991; 59 Leninsky prospekt, Moscow, 119333

Russian Federation

References

  1. Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, Hahn SM, Hamblin MR, Juzeniene A, Kessel D, Korbelik M, Moan J, Mroz P, Nowis D, Piette J, Wilson BC, Golab J. Photodynamic therapy of cancer: an update. CA Cancer J Clin. 2011;61(4):250–81. doi: 10.3322/caac.20114.
  2. Dysart JS, Patterson MS. Characterization of Photofrin photobleaching for singlet oxygen dose estimation during photodynamic therapy of MLL cells in vitro. Phys Med Biol. 2005;50(11): 2597–616. doi: 10.1088/0031-9155/50/11/011.
  3. Allison RR, Sibata CH. Oncologic photodynamic therapy photosensitizers: a clinical review. Photodiagnosis Photodyn Ther. 2010;7(2):61–75. doi: 10.1016/j.pdpdt.2010.02.001.
  4. Cardoso DR, Libardi SH, Skibsted LH. Riboflavin as a photosensitizer. Effects on human health and food quality. Food Funct. 2012;3(5):487–502. doi: 10.1039/c2fo10246c.
  5. Baier J, Maisch T, Maier M, Engel E, Landthaler M, Bäumler W. Singlet oxygen generation by UVA light exposure of endogenous photosensitizers. Biophys J. 2006;91(4):1452–9. doi: 10.1529/biophysj.106.082388.
  6. Yang MY, Chang CJ, Chen LY. Blue light induced reactive oxygen species from flavin mononucleotide and flavin adenine dinucleotide on lethality of HeLa cells. J Photochem Photobiol B. 2017;173:325–32. doi: 10.1016/j.jphotobiol.2017.06.014.
  7. Ohara M, Fujikura T, Fujiwara H. Augmentation of the inhibitory effect of blue light on the growth of B16 melanoma cells by riboflavin. Int J Oncol. 2003;22(6):1291–5. doi: 10.3892/ijo.22.6.1291.
  8. Pass HI. Photodynamic therapy in oncology: mechanisms and clinical use. J Natl Cancer Inst. 1993;85(6):443–56. doi: 10.1093/jnci/85.6.443.
  9. Nadort A, Sreenivasan VK, Song Z, Grebenik EA, Nechaev AV, Semchishen VA, Panchenko VY, Zvyagin AV. Quantitative imaging of single upconversion nanoparticles in biological tissue. PLoS One. 2013;8(5):e63292. doi: 10.1371/journal.pone.0063292.
  10. Wang M, Abbineni G, Clevenger A, Mao C, Xu S. Upconversion nanoparticles: synthesis, surface modification and biological applications. Nanomedicine. 2011;7(6):710–29. doi: 10.1016/j.nano.2011.02.013.
  11. Generalova AN, Rocheva VV, Nechaev AV, Khochenkov DA, Sholina NV, Semchishen VA, Zubov VP, Koroleva AV, Chichkova BN, Khaydukova EV. PEG-modified upconversion nanoparticles for in vivo optical imaging of tumors. RSC Adv. 2016;(36):30089–97. doi: 10.1039/C5RA25304G.
  12. Guller AE, Generalova AN, Petersen EV, Nechaev AV, Trusova IA, Landyshev NN, Nadort A, Grebenik EA, Deyev SM, Shekhter AB, Zvyagin AV. Cytotoxicity and non-specific cellular uptake of bare and surface-modified upconversion nanoparticles in human skin cells. Nano Res. 2015;8(5):1546–62. doi: 10.1007/s12274-014-0641-6.
  13. Bareford LM, Avaritt BR, Ghandehari H, Nan A, Swaan PW. Riboflavin-targeted polymer conjugates for breast tumor delivery. Pharm Res. 2013;30(7):1799–812. doi: 10.1007/s11095-013-1024-5.
  14. Thomas TP, Choi SK, Li MH, Kotlyar A, Baker JR Jr. Design of riboflavin-presenting PAMAM dendrimers as a new nanoplatform for cancer-targeted delivery. Bioorg Med Chem Lett. 2010;20(17):5191–4. doi: 10.1016/j.bmcl.2010.07.005.
  15. Sau A, Sanyal S, Bera K, Sen S, Mitra AK, Pal U, Chakraborty PK, Ganguly S, Satpati B, Das C, Basu S. DNA Damage and apoptosis induction in cancer cells by chemically engineered thiolated riboflavin gold nanoassembly. ACS Appl Mater Interfaces. 2018;10(5):4582–9. doi: 10.1021/acsami.7b18837.
  16. Jayapaul J, Arns S, Bunker M, Weiler M, Rutherford S, Comba P, Kiessling F. In vivo evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts. Nano Res. 2016;9(5):1319–33. doi: 10.1007/s12274-016-1028-7.
  17. Rao PN, Levine E, Myers MO, Prakash V, Watson J, Stolier A, Kopicko JJ, Kissinger P, Raj SG, Raj MH. Elevation of serum riboflavin carrier protein in breast cancer. Cancer Epidemiol Biomarkers Prev. 1999;8(11):985–90.
  18. Makdoumi K, Goodrich R, Bäckman A. Photochemical eradication of methicillin-resistant Staphylococcus aureus by blue light activation of riboflavin. Acta Ophthalmol. 2017;95(5):498–502. doi: 10.1111/aos.13409.
  19. Meinhardt M, Krebs R, Anders A, Heinrich U, Tronnier H. Wavelength-dependent penetration depths of ultraviolet radiation in human skin. J Biomed Opt. 2008;13(4):044030. doi: 10.1117/1.2957970.
  20. Рочева ВВ, Шолина НВ, Деревяшкин СП, Генералова АН, Нечаев АВ, Хоченков ДА, Семчишен ВА, Хайдуков ЕВ, Степанова ЕВ, Панченко ВЯ. Люминесцентная диагностика опухолей с применением апконвертирующих наночастиц. Альманах клинической медицины. 2016;44(2):227–33. doi: 10.18786/2072-0505-2016-44-2-227-233.

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Copyright (c) 2019 Sholina N.V., Akasov R.A., Khochenkov D.A., Generalova A.N., Semchishen V.A., Khaydukov E.V.

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