Системы доставки лекарств
и биоактивных веществ

Multidrug resistance (MDR) remains one of the principal challenges in cancer chemotherapy, necessitating new strategies to restore drug efficacy. In this study we developed and characterize a redox-responsive nanoplatform based on trithiocyanuric acid and polyethylene glycol (TTCA-PEG NPs) as a potential tool to overcome MDR and provide a biocompatible delivery system for conventional antitumor drugs. The platform was evaluated using doxorubicin (DOX), bleomycin (Bleo), or cisplatin (Cis) each pre-loaded into TTCA-PEG NPs and tested across three pairs of drug-sensitive and resistant cancer cell lines. TTCA-PEG NPs reduced drug resistance from 2- to 5 fold compared with free drug, consistent with the recovery of intracellular drug accumulation and cytotoxic activity. The nanoplatform was synthesized through a one-step process completed within one hour, offering substantial simplification compared with conventional redox-responsive systems. Mechanistic studies revealed that treatment induced G2 /M cell cycle arrest and apoptosis, confirming the restoration of the drugs' cytotoxic pathways in resistant cells. In vivo evaluation demonstrated a biocompatible profile, with no detectable hematopoietic, hepatic, renal, neurological, or cardiac toxicity at therapeutic doses. Pharmacokinetic studies showed that TTCA-PEG NPs modulated the rapid burst release of free Cis into a controlled, sustained-release profile, resulting in prolonged circulation and reduced systemic exposure. These findings present TTCA-PEG NPs as a biocompatible and adaptable redox-responsive platform. While in vivo efficacy studies are required to fully establish therapeutic utility, the current data regarding safety, pharmacokinetics, and in vitro MDR reversal suggest the platform is a promising candidate for further development.

Industrial phosphatides (lecithins) are mixtures of phospholipids and other lipids (steroids, free fatty acids, etc.). Therefore, the properties of lecithins represent the average properties of the mixture’s components, which can manifest as synergies or antagonisms. Differences in the compositions of lecithins significantly affect the properties of liposomal systems, creating difficulties in reproducing characteristics and limiting the use of natural lecithins in pharmaceuticals, but opening up prospects for the food and cosmetic industries. The aim of this study was to comparatively evaluate the physicochemical properties of liposomal systems obtained from soybean and sunflower lecithins produced in India and China, with an emphasis on the influence of their composition on the encapsulation efficiency of the hydrophobic antioxidant resveratrol. The novelty of this study lies in identifying the dependence of liposome parameters on their origin, which has practical implications for the development of stable carriers in the pharmaceutical, food, and cosmetic industries. Liposomes were obtained by ultrasonic homogenization, and their characteristics were determined by dynamic light scattering. Encapsulation efficiency was determined spectrophotometrically after centrifugation. The hydrodynamic radius of the liposomes was found to vary from 39,94 to 51,93 nm, with the exception of one sample based on sunflower lecithin from a Chinese manufacturer, which exhibited pronounced heterogeneity (average size of 386,93 nm). The polydispersity index of most samples did not exceed 0.3, indicating the formation of homogeneous nanoparticles. The zeta potential ranged from –37,81 to –28,9 mV and ensured colloidal stability. The encapsulation efficiency of resveratrol ranged from 53,26 to 64,94%. High values were characteristic of both larger and smaller liposomes. This indicates differences in the encapsulation mechanisms. The study results confirm the significant impact of lipid composition variability and impurities on the structure and properties of liposomal systems. Further in-depth analysis of the phospholipid composition and associated fractions of the studied lecithins is necessary to improve the predictability and efficacy of liposomal systems.

Application of fluorescent redox-sensitive nanoparticles in current biomedicine ensures high sensitivity and accuracy of biovisualization. Nanoparticles are potent as they can long circulate in the blood, where the level of glutathione is relatively low, and are destroyed in tumor cells, releasing loaded dyes or drugs. The aim of the study was to develop new nanoparticles based on trithiocyanuric acid for biovisualization of malignant tumors and study capabilities of the developed nanoparticles. Materials and Methods. Nanoparticles were obtained by polycondensation of trithiocyanuric acid using iodine. Scanning and transmission electron microscopy was used for their characterization, the loading of fluorescent dyes was assessed by means of spectrophotometry. Confocal laser scanning microscopy was applied to study the impact of nanoparticles on the viability of the 4T1 and A549 cell lines as well as their interaction with cells. The distribution of nanoparticles in tissues and organs of BALB/c model mice with grafted tumors was performed using fluorescence visualization. Results. According to scanning microscopy, the size of the synthesized particles reached 100±20 nm. The adsorption isotherm demonstrated that adsorption of 0.27 mg of the RhB fluorescent dye per 1 mg of nanoparticles could be achieved. Enhanced release of the packed fluorescent dye was seen in the presence of glutathione and acetylcysteine. The particles did not significantly affect the viability of 4T1 and A549 cells. After intratumoral administration, they ensured a more intense fluorescent signal in the tumor area compared to a regular fluorescent dye solution. Conclusion. The developed system of trithiocyanuric-acid-based nanoparticles demonstrated high efficiency in biovisualization of malignant tumors and has a potential for targeted delivery of treatment agents.

Microbubbles have numerous applications in fields such as drug delivery, diagnostic imaging, and localized therapies. In this study, we propose a method for generating microbubbles with controlled size, confined by the dimensions of a hollow shell. The hollow capsules were fabricated from trithiocyanuric acid and further modified with gold nanoparticles to enhance their photothermal properties. We demonstrate that irradiation with a near-infrared laser can induce the formation of microbubbles within these capsules. The bubbles remain spatially confined by the shell and stable for the duration of the laser operation. This approach offers a versatile platform for applications requiring targeted control of microbubble formation and heat generation in biomedical and microfluidic systems.

Vitamin K derivatives such as menadione (MD) have been recognized as promising redox-modulating and chemosensitizing agents for anticancer therapy, however, their cellular activities in peptide-targeted nanocarriers have not been elucidated to date. This study provides the guidelines for developing MD-loaded solid lipid nanoparticle (SLN) modified with extracellular matrix (ECM)-derived peptides. Relationships between RGD peptide concentration and changes in DLS characteristics as well as accumulation of SLN in cancer cells were revealed to adjust the peptide-lipid ratio. SLN maintained their nanoparticle concentration and low dispersity after introduction of MD and MD/RGD, whereas formulated MD was protected from immediate conjugation with reduced glutathione (GSH). RGD-modified MD-containing SLN showed enhanced prooxidant, GSH-depleting and cytotoxic activities toward prostate cancer cells PC-3 attributed to improved cellular pharmacokinetics of the targeted formulation. Furthermore, this formulation effectively sensitized PC-3 and ovarian cancer cells OVCAR-4 to free doxorubicin and cisplatin so that cell growth was inhibited by MD-drug composition at non-toxic concentrations of the ingredients. These results provide an important background for further improving chemotherapeutic methods based on combination of conventional cytostatics with peptide-targeted SLN formulations of MD.

Redox-responsive drug delivery systems present a promising avenue for drug delivery due to their ability to leverage the unique redox environment within tumor cells. In this work, we describe a facile and cost-effective one-pot synthesis method for a redox-responsive delivery system based on novel trithiocyanuric acid (TTCA) nanoparticles (NPs). We conduct a thorough investigation of the impact of various synthesis parameters on the morphology, stability, and loading capacity of these NPs. The great drug delivery potential of the system is further demonstrated in vitro and in vivo by using doxorubicin as a model drug. The developed TTCA-PEG NPs show great drug delivery efficiency with minimal toxicity on their own both in vivo and in vitro. The simplicity of this synthesis, along with the promising characteristics of TTCA-PEG NPs, paves the way for new opportunities in the further development of redox-responsive drug delivery systems based on TTCA.