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

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.

Люминесцентные Наноматериалы, Допированные Редкоземельными Ионами, И Перспективы Их Биомедицинского Применения (Обзор)

“…Например, наночастицы могут одновременно являться контрастирующими агентами в клиническом методе МРТ и быть использованы для фототерапии. К методам фототерапии относятся фототермическая абляция (ФТА) и фотодинамическая терапия (ФДТ), в которых свет используется для лечения различных заболеваний, в том числе онкологических [210,211,217,218].…”

Photoinduced Reduction of Novel Dual-Action Riboplatin Pt(IV) Prodrug

“…Because an increased uptake of RF was reported for various cancers, − drug functionalization with RF moieties is widely used for targeting cancer cells. − Additionally, RF was proposed as an adjuvant in cisplatin-based chemoradiotherapy . RF is an efficient photosensitizer capable of ROS formation under UV- and blue-light irradiation that results in its antitumor, antibacterial, antiviral properties, and its perspectives as a PDT agent. − Salassa et al. reported a bioorthogonal catalytic reduction of Pt­(IV) prodrugs by RF derivatives and flavoproteins in mixed solutions under irradiation with blue light. − In view of excellent photochemical properties of RF, its cancer-cell affinity, and the ability to catalyze Pt­(IV) prodrug reduction, Riboplatin prodrug is expected to be a controllably activated anticancer prodrug capable of both blue light-induced ROS generation and release of Pt­(II) species.…”