Improving the Antitumor Effect of Doxorubicin in the Treatment of Eyeball and Orbital Tumors

Abstract

Malignant tumors of the orbit are the main cause for 41–45.9% of orbital tumor, and they will threaten both the organ of vision and the life of the patient. In our opinion, improving the effectiveness of treatment of malignant tumors can be implemented in the following areas: a) immobilization of doxorubicin in synthetic polymeric materials, which will fill the tissue structures that were resected and reduce the percentage of tumor recurrence. b) the use of nanomaterials for the delivery of doxorubicin to tumor cells. To develop a hydrogel implant and nanoparticles, to study the diffusion kinetics of doxorubicin in a hydrogel implant and the ability of nanoparticles to transport doxorubicin. The developed gels based on acrylic acid (AAc) were obtained by radical polymerization of an aqueous solution of monomers (AAc and N, N-methylenebisacrylamide (MBA)) at a temperature of 70°C. Matrices based on polyvinyl formal (PVF) were obtained by treatment of polyvinyl alcohol (PVA) with formaldehyde in the presence of a strong acid. Experimental studies were performed on rabbits of the Chinchilla breed, weighing 2–3 kg, aged 5–6 months, which during the study were in the same conditions. We implanted the hybrid gel in the scleral sac; orbital tissue and in the ear tissue of rabbits: Evaluation of the response of soft tissues and bone structures to implant materials was carried out on the basis of analysis of changes in clinical and pathomorphological parameters was performed after 10, 30 and 60 days. Diffusion of doxorubicin was examined by using UV spectroscopy [spectrophotometer-fluorimeter DS-11 FX + (DeNovix, USA)], analyzing samples at regular intervals during the day at a temperature of 25° C. The concentration of active substances was determined by the normalized peak absorption of doxorubicin at 480 nm. The release kinetics of the antitumor drug doxorubicin were investigated by using a UV spectrometer “Specord M 40” (maximum absorption 480 nm). The developed hydrogel implant has good biocompatibility and germination of surrounding tissues in the structure of the implant, as well as the formation of a massive fibrous capsule around it. An important advantage of the implant is also the lack of its tendency to resorption. Moreover, the results showed that the diffusion kinetics of doxorubicin from a liquid-crosslinked hydrogel reaches a minimum therapeutic level within a few minutes, while in the case of a tightly crosslinked - after a few hours. It was also found that the liquid-crosslinked hydrogel adsorbs twice as much as the cytostatic - doxorubicin. The analysis of the research results approved that the size of the nanoparticles is the main factor for improving drug delevary and penetration. Thus, nanoparticles with a diameter of less than 200 nm can penetrate into cells and are not removed from the circulatory system by macrophages, thereby prolonging their circulation in the body. About 10 nm. The developed hybrid hydrogel compositions have high mechanical strength, porosity, which provides 100% penetration of doxorubicin into experimental animal tissues. It was found that the kinetics of diffusion of drugs from liquid-crosslinked hydrogel reaches a minimum therapeutic level within a few minutes, whereas in the case of densely crosslinked hydrogel diffusion begins with a delay of several hours and the amount of drug released at equilibrium reaches much lower values (20–25%). The obtained preliminary experimental results allow us to conclude that our developed pathways for the delivery of drugs, in particular, doxorubicin to tumor cells will increase the effectiveness of antitumor therapy.