CC BY
16B-I-9
Complementary fluorescence and optoacoustic monitoring of treatment with novel photoactivatable agents for combined photodynamic and chemotherapy
I. Turchin1, M. Kirillin1, A. Orlova1, V. Perekatova1, V. Plekhanov1, E. Sergeeva1, D. Kurakina1, A. Khilov1, A. Kurnikov1, P. Subochev1, M. Shirmanova2, A. Komarova2, D. Yuzhakova2, A. Gavrina2, S. Bano3, S. Mallidi34, T. Hasan3
1 - Institute of Applied Physics RAS, 46 Uljanov Street, 603950, Nizhny Novgorod, Russia 2 - Privolzhsky Research Medical University, 10/1 Minin Square, 603005, Nizhny Novgorod, Russia 3 - Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA 4 - Department of Biomedical Engineering, Tufts University, Medford, MA 02155, USA
Photodynamic therapy (PDT) is a therapeutic approach gaining wide recognition in clinical practice. It is based on irradiation of photoactive photosensitizers (PS) with light of a certain wavelength in the presence of oxygen in a tissue resulting in formation of cytotoxic reactive oxygen species [1]. Most of the modern studies aimed at improving the PDT efficiency are directed at development of novel photosensitizers, validation of new protocols of tumor irradiation, combination of PDT with other methods of anticancer treatment, and development of new methods of monitoring of tumor response to PDT. In this study we investigate the efficiency of complementary fluorescence (FL) and optoacoustic (OA) imaging monitoring approach to analyze in vivo both drug accumulation and its preservation in the blood flow and vascular response to treatment. The system for combined FL and OA imaging is described in general in [2]. It contains the raster-scan optoacoustic microscope at 532 nm wavelength with imaging depth up to 2 mm, axial/transverse resolution of 38/50 ^m, and acquisition speed of 2000 A-scans per second. It enables to visualize the tumor vascular system development during natural growth, as well as under therapeutic effects. A newly developed approach has been applied to describe vasculature changes numerically by a specific vesselness index, associated with vessel density [3]. Wide-field FL imaging at 690 nm excitation wavelength was applied to control PS accumulation after drug administration, photobleaching during laser irradiation, and PS circulation after the procedure. For PDT combined cancer treatment we have engineered photoactivatable multi-inhibitor liposomes (PMILs) carrying a lipid-anchored derivative of the photosensitizer benzoporphyrin derivative (BPD) served as a PS in the bilayer (PALs) and topoisomerase I inhibitor (Irinotecan: IRI) served as a chemotherapy agent entrapped in the inner core of nanoliposomes L-[IRI]. This nanoconstructs are proposed for a cooperative enhancement of photodynamic and chemotherapeutic regimens. Our in vivo results on mice with CT26 tumor show that the PMILs demonstrate the best inhibitory effect on tumor growth compared to the treatment with monotherapies. When monitored by the complementary FL and OA imaging system, it appears that the largest increase in the vesselness index in tumors employing PMILs is in good agreement with the histological data. This shows that the strongest therapeutic effect manifested by the largest number of hemorrhage is in the PMILs treated mice as compared to PALs or L-[IRI] treated mice. We can conclude that the newly developed multimodal imaging system combining optoacoustic angiography and fluorescence emission of the photosensitizer allows for immediate response evaluation of post-treatment, suggesting that combined photodynamic and chemotherapy of tumors, employing PMILs is an efficient way to improve cancer therapeutic efficiency.
The study is supported by the RFBR project 17-54-33043 onko-a and the Center of Excellence «Center of Photonics» funded by The Ministry of Science and Higher Education of the Russian Federation, contract № 075-15-2020-906
[1] P. Agostinis, K. Berg, K. A. Cengel, T. H. Foster, A. W. Girotti, S. O. Gollnick, S. M. Hahn, M. R. Hamblin, A. Juzeniene, and D. Kessel, "Photodynamic therapy of cancer: an update," CA: a cancer journal for clinicians 61, 250-281 (2011).
[2] D. Kurakina, M. Kirillin, V. Perekatova, V. Plekhanov, A. Orlova, E. Sergeeva, A. Khilov, A. Nerush, P. Subochev, and S. Mallidi, "Towards Bimodal Optical Monitoring of Photodynamic Therapy with Targeted Nanoconstructs: A Phantom Study," Applied Sciences 9, 1918(2019)
[3] V. Perekatova, M. Kirillin, P. Subochev, A. Kurnikov, A. Khilov, A. Orlova, D. Yuzhakova, and I. Turchin, "Quantification of microvasculature parameters based on optoacoustic angiography data," Laser Physics Letters (2021).
