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4EFFECT OF THE INJECTION OF UPCONVERSION NANOPARTICLES ON THE OPTICAL PARAMETERS OF BIOLOGICAL TISSUES IN THE AREA OF TUMOR DEVELOPMENT
E. N. LAZAREVA,1,2* D. K. TUCHINA,1,2,3 A. A. DORONKINA,1 A. M. MYLNIKOV,4 N. A. NAVOLOKIN,4,5,6 V.
I. KOCHUBEY,1,2 AND I. YU. YANINA1,2
'Institute of Physics, Saratov State University, 83 Astrakhanskaya str., Saratov 410012, Russia 2Laboratory of Laser Molecular Imaging and Machine Learning, Tomsk State University, 36 Lenin's av., Tomsk 634050,
Russia
3A.N. Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, Moscow,
33Leninsky Prospect, building 2, Moscow 119071, Russia 4Department of Pathological Anatomy, Saratov State Medical University, 112 B Kazachaya str., Saratov 410012, Russia 5Center for Collective Use of Experimental Oncology, Experimental Department, Saratov State Medical University, 112
B Kazachaya str., Saratov 410012, Russia 6Pathological Department, State Healthcare Institution "Saratov City Clinical Hospital No. 1 named after Yu. Ya.
Gordeev", 19 Kholzunova st., Saratov 410017, Russia
lazarevaen@ list.ru
ABSTRACT
An urgent task of biophotonics at present is the development of fast and minimally invasive diagnostic methods that make it possible to detect pathological changes in tissues at an early stage. For this purpose, various methods have already been developed that are used without classical labels, based on both inelastic (spectroscopic) and elastic (scattering) interactions of light and tissues [1, 2].
One of the promising methods of clinical oncology is photodynamic therapy (PDT), a non-surgical method of cancer treatment, which is currently being intensively used with high efficiency. The necessary components of PDT are a photosensitizer (PS), localized in the focus of the disease, and a radiation source of the appropriate wavelength. PS include such dyes as methylene blue, Bengal rose, organic molecules - chlorin e6, porphyrin and phthalocyanine derivatives, various inorganic compounds. The radiation range of the source is limited by the PS absorption spectrum (<600 nm), which, as a rule, does not intersect in the spectrum with the "transparency window of biological tissue", covering the region of 750-1000 nm. This determines the shallow depth of therapeutic action. However, there are some problems with the use of PS, such as their non-specific distribution in the body and the hydrophobicity of some drugs. For example, during PDT with preparations based on chlorin e6 and photosens after intravenous administration, the same PS content is observed in tumor structures and in the wall of unchanged vessels 3-4 and 1-2 hours after administration, respectively. As a result, there is a need to use FS carriers. In particular, such carriers can be particles whose surface is functionalized by the addition of PS, ligands that ensure compatibility with water. In addition, targeting agents can be attached to the surface of the nanoparticles, allowing them to be selectively targeted to specific cells. The creation of functionalized nanoparticles with FS makes it possible to increase the effectiveness of the therapeutic effect. The results of an experimental study of the absorption and reflection spectra of biological tissues and the determination of their optical characteristics (absorption, scattering, anisotropy) in normal conditions and their changes after the introduction of nanoparticles are presented [1-4].
Among nanoparticles, special mention should be made of upconversion nanoparticles (UCNPs) that are promising in bioapplications (for example, photodynamic therapy) [3, 4]. Similar energy levels of trivalent lanthanide ions embedded in the corresponding inorganic host lattice to produce higher energy anti-Stokes luminescence [5,6]. Thus, it converts two or more low energy excitation photons, which are usually NIR radiation, into shorter wavelength/ (eg NIR, visible and UV). It has been shown that dye nanoparticles are used in photodynamic therapy to slow down the growth of tumor tissue [7, 8]. However, it is important to know the optical properties of tissues in the area of photodynamic exposure for both functionalized and UCNPs, since this makes it possible to evaluate the effect of nanoparticles on the optical properties of tissues in the irradiation area, which must be taken into account when calculating the amount of dye associated with nanoparticles. This study shows the change in optical parameters, such as absorption coefficient, transport scattering coefficient, anisotropy coefficient, of biological tissues before and after the introduction of UCNPs taken from the tumor development area. An experimental study was performed on white outbred mature male rats, according to the method described in the article. [9]. Animal experiments were performed in accordance with international ethical standards [10]. The development of alveolar liver cancer (cholangiocarcinoma, PC1) was modeled by introducing 0.5 ml of a 25% tumor suspension in Hanks solution subcutaneously into the area of the scapula. Animals were withdrawn from the experiment on day 28 after tumor implantation.
Total and collimated transmission spectra, as well as diffuse reflection spectra of rat biological tissues in the area of tumor grafting were measured in the spectral range 380-2000 nm using a spectrophotometer LAMBDA 950 (PerkinElmer, USA). The inverse Monte Carlo method was used to process the experimental results and determine the optical parameters [11]. Samples of biological tissues for measuring the spectra of total and collimated transmission, as well as diffuse reflection, were placed between two glass slides in a spacer, which made it possible to fix a thickness of 1 mm between them.
Figure 1 shows the spectra of the absorption coefficient, transport scattering coefficient, and anisotropy factor of ex vivo rat tumor samples with different types of UCNPs.
Tumor
Tumor with NaYF4
Tumor with heating NaYF4 and SiO.
Tumor with heating NaYF4
-Tumor
-Tumor with NaYF4
Tumor with heating NaYF4 and SiO;, -Tumor with heating (MaYF4
400 600 800 1000 1200 1400 1600 1800 2000 Wavelength, nm
(a)
1.0-j
400 800 800 1000 1200 1400 1800 1800 2000 Wavelength, nm
(b)
-Tumor
- Tumor wilh NaYF, Tumor with heating NaYF, and SiO, Tumor Willi heating NaYF4
400 600 800 1000120014001600 1800 2000 Wavelength, nm
(C)
Figure 1: Spectra of the absorption coefficient (a), transport scattering coefficient (b), anisotropy factor (c) ex vivo of rat tumor samples after the introduction of various types of UCNPs.
Most notable in the near IR region, changes in the optical characteristics of the tumor tissue, associated with a decrease in absorption and an increase in scattering, can confirm the accumulation of injected UCNPs. In the visible spectral region, the greatest changes were observed upon the introduction of the heating NaYF4 complex with SiO2. Also, the results of histological analysis of biopsy specimens of organs and tumors of laboratory animals were obtained, which showed a weak complex toxicity, which showed that changes in the liver and lungs were reversible, and myocardial edema developed in the heart of the animals. Our result is in good agreement with the data of other researchers and can serve as a basis for further study of the effect of various types of particles on the optical characteristics of tissues, which will help in the development of new and improvement of existing methods of photodynamic therapy.
The study was supported by RSF grant no. 21-72-10057, https://rscf.ru/project/21 -72-10057/. REFERENCES
[1] V.V. Tuchin, J. Popp, V. Zakharov (Eds.), Multimodal Optical Diagnostics of Cancer, Springer International Publishing, 1605, 2020.
[2] V.V. Tuchin, Tissue Optics: Light Scattering Methods and Instruments for Medical Diagnostics, 3rd ed., (PIE Press, Bellingham, WA) (2015).
[3] M. R. Hamblin, "Upconversion in photodynamic therapy: plumbing the depths," Dalton Trans. Vol. 47, pp.8571-8580 (2018).
[4] F. Auzel, "Upconversion and anti-stokes processes with f and d ions in solids," Chem. Rev. Vol. 104, pp. 139-174 (2004).
[5] F. Wang, and X. Liu, "Recent advances in the chemistry of lanthanide-doped upconversion nanocrystals," Chem.Soc. Rev. vol. 38 (4), pp. 976-989 (2009).
[6] J. Xie, Y. Wang, W. Choi, P. Jangili, Y. Ge, Y. Xu, J.Kang, L.Liu, B.Zhang, Z Xie, J.He, N.Xie, G. Nie, H.Zhang and J. S. Kim, "Overcoming barriers in photodynamic therapy harnessing nano-formulation strategies," Chem. Soc. Rev., vol. 50, pp. 9152-9201 (2021).
[7] M.H. Abdel-Kader, Photodynamic therapy (Springer-Verlag Berlin An), (2016).
[8] H.S. Qian, H.C. Guo, P.C. Ho, R. Mahendran, Y. Zhang, "Mesoporous-silica-coated upconversion fluorescent nanoparticles for photodynamic therapy", Small, vol. 5 (20), pp. 2285-90, (2009).
[9] A.B. Bucharskaya, N.I. Dikht, G.A. Afanas'eva, G.S. Terentyuk, N.B. Zakharova, G.N. Maslyakova, B.N. Khlebtsov, and N. G. Khlebtsov, Saratov. Nauch.-Med. Zh. vol. 11, p. 1072015, (2015).
[10] International Guiding Principles for Biomedical Research Involving Animals. CIOMS and ICLAS. http://www.cioms.ch/index.php/12-newsflash/227-cioms-and-iclas-release-the-newinternational-guiding-principles-for-biomedical-researchinvolving-animals, (2012).
[11] A.N. Bashkatov, E.A. Genina, V.I. Kochubey, E.A. Kolesnikova, V.V. Tuchin., V.S. Rubtsov, "Optical properties of human colon tissues in the 350-2500 nm spectral range", Quantum Electronics vol. 44 (8) 2014, pp. 779-784, (2014).
