Riboflavin for COVID-19 Adjuvant Treatment in Patients With Mental Health Disorders: Observational Study.

Background: COVID-19 treatment remains a challenge for medicine because of the extremely short time for clinical studies of drug candidates, so the drug repurposing strategy, which implies the use of well-known and safe substances, is a promising approach. Objective: We present the results of an observational clinical study that focused on the influence of riboflavin (vitamin B2) supplementation on the immune markers of COVID-19 severity in patients with mental health disorders. Results: We have found that 10 mg of flavin mononucleotide (a soluble form of riboflavin) intramuscularly twice a day within 7 days correlated with the normalization of clinically relevant immune markers (neutrophils and lymphocytes counts, as well as their ratio) in COVID-19 patients. Additionally, we demonstrated that total leucocytes, neutrophils, and lymphocytes counts, as well as the neutrophils to leucocytes ratio (NLR), correlated with the severity of the disease. We also found that patients with organic disorders (F0 in ICD-10) demonstrated higher inflammation then patients with schizophrenia (F2 in ICD-10). Conclusion: We suggest that riboflavin supplementation could be promising for decreasing inflammation in COVID-19, and further evaluation is required. This observational clinical trial has been registered by the Sverzhevsky Research Institute of Clinical Otorhinolaryngology (Moscow, Russia), Protocol No. 4 dated 05/27/2020.

Upconversion Nanoparticles Decorated with Polysialic Acid for Solid Tumors Visualization In Vivo.

Upconversion nanoparticles (UCNPs) are a promising nanoplatform for bioreagent formation for in vivo imaging, which emit UV and blue light under the action of near-infrared radiation, providing deep tissue penetration and maintaining a high signal-to-noise ratio. In the case of solid tumor visualization, the UCNP surface functionalization is required to ensure a long circulation time, biocompatibility, and non-toxicity. The effective UCNP accumulation in the solid tumors is determined by the disturbed architecture of the vascular network and lymphatic drainage. This work demonstrates an approach to the UCNP biofunctionalization with endogenous polysialic acid for in vivo bioreagent formation. Bioreagents possess a low level of nonspecific protein adsorption and macrophage uptake, which allow the prolongation of the circulation time in the bloodstream up to 3 h. This leads to an intense photoluminescent signal in the tumor.

Nanosized Anti-Stokes Phosphors for Antitumor Drug Delivery and Solid Tumor Theranostics.

Abstract-Theranostics is the direction in modern biomedicine aimed at developing drugs that combine the capabilities of diagnosis and therapy of tumors in one agent. Upconversion nanophosphors (UCNPs) are inorganic crystalline materials that can be used to create a nanoplatform providing diagnostic and therapeutic modalities. They have been proposed as luminescent markers for optical imaging of biological tissue due to their anti-Stokes luminescence, lack of photodegradation and low toxicity. In this article, UCNPs as a theranostic agent for both optical imaging and delivery of anticancer drugs have been offered. To obtain biocompatible nanocomplexes, UCNP surface with a core/shell structure of NaYF4:Yb3+Tm3+/NaYF4 was modified with polylactic acid in the presence of various stabilizers (dextran, polyvinyl alcohol, and poly-N-vinylpyrrolidone). To give the therapeutic modality to the nanocomplex, the antitumor antibiotic doxorubicin was loaded into the polymer shell. The loading efficiency was up to 0.1 mg per 1 mg UCNPs. The toxicity and the intracellular accumulation of nanocomplexes were evaluated in vitro. It was concluded that the modification of UCNPs with polylactic acid provides the transport of doxorubicin, allowing the combination of diagnostic and therapeutic modalities in one agent.

Photodynamic therapy of melanoma by blue-light photoactivation of flavin mononucleotide.

Melanoma is one of the most aggressive and lethal form of cancer. Photodynamic therapy (PDT) is a clinically approved technique for cancer treatment, including non-melanoma skin cancer. However, the most of conventional photosensitizers are of low efficacy against melanoma due to the possible dark toxicity at high drug concentrations, melanin pigmentation, and induction of anti-oxidant defense mechanisms. In the current research we propose non-toxic flavin mononucleotide (FMN), which is a water-soluble form of riboflavin (vitamin B2) as a promising agent for photodynamic therapy of melanoma. We demonstrated selective accumulation of FMN in melanoma cells in vivo and in vitro in comparison with keratinocytes and fibroblasts. Blue light irradiation with dose 5 J/cm2 of melanoma cells pre-incubated with FMN led to cell death through apoptosis. Thus, the IC50 values of human melanoma A375, Mel IL, and Mel Z cells were in a range of FMN concentration 10-30 µM that can be achieved in tumor tissue under systemic administration. The efficiency of reactive oxygen species (ROS) generation under FMN blue light irradiation was measured in single melanoma cells by a label-free technique using an electrochemical nanoprobe in a real-time control manner. Melanoma xenograft regression in mice was observed as a result of intravenous injection of FMN followed by blue-light irradiation of tumor site. The inhibition of tumor growth was 85-90% within 50 days after PDT treatment.

Ultraviolet phototoxicity of upconversion nanoparticles illuminated with near-infrared light.

Recently introduced upconversion nanoparticles (UCNPs) have pushed the depth of photodynamic therapy (PDT) treatment to the centimetre range by converting deeply-penetrating near-infrared (NIR) radiation to visible radiation for photoexcitation of PDT drugs. Here we demonstrate that the direct exposure of the cancer tissue to phototoxic ultraviolet radiation generated by NIR-photoexcited UCNPs enabled successful PDT. To this aim, core/shell UCNPs of the formula NaYF4:Yb3+Tm3+/NaYF4 featuring an enhanced band in the ultraviolet UV-A and UV-B spectral bands were rationally designed and synthesised. Coupling UCNPs to the recombinant modules of the Designed Ankyrin Repeat Protein (DARPin) fused to a fluorescent protein mCherry allowed the target delivery of DARPin-mCherry/UCNP to human breast adenocarcinoma SK-BR-3 cells overexpressing HER2/neu receptors, as confirmed by fluorescence microscopy. DARPin-mCherry/UCNPs were demonstrated to be phototoxic to SK-BR-3 cells under 975 nm laser irradiation at a dose of 900 J cm-2 due to the UV photoexcitation of endogenous photosensitizers and concomitant generation of reactive oxygen species. The Lewis lung cancer mouse model was employed to demonstrate the feasibility of PDT using UCNP-mediated UV excitation of endogenous photosensitizers in the tumor tissue at a NIR dose of 1200 J cm-2. This study paves the way for exploring and harnessing UV photoexcitation processes in deep tissues in vivo.