항암 치료를 위한 고분자화된 페닐보론산 기반의 이중 약물 전달 시스템 개발

Abstract

Even with rapid advances in technology, cancer is one of the challengeable diseases showing a high mortality rate even today. Since various therapeutic agents are used as anticancer drugs, drug delivery systems for carrying therapeutic agents also have been developed, and various theories and techniques have been proposed to conquer cancer. Polymer-based drug delivery systems have various advantages and are widely used in the anticancer field, still some refractory cancers are difficult to treat. To overcome the problem, dual drugs showing a synergistic effect can be delivered simultaneously to maximize the therapeutic effect, but the synthesis of the delivery system may get complicated. Therefore, it is necessary to develop a dual drug delivery system that is manufactured through simple synthesis and can maximize the therapeutic effect. In this study, the possibility of solving the aforementioned problems was suggested with a dual drug delivery system based on polymerized phenyl boronic acid. In Chapter I, the advantages of polymer-based drug delivery systems and the possibility of polymerized phenylboronic acid (pPBA) as drug delivery systems were discussed. Subsequently, the problem of the current drug delivery system and the possibility of solving the problem through polymerized phenylboronic acid were described. In Chapter II, TiO2 nanoparticles (TNP), a sonodynamic agent, and doxorubicin (DOX), a chemotherapeutic agent, were simultaneously delivered using pPBA. Only one chemotherapeutic agent is used, it can cause much harmful side effects if the cure fails. The possibility of increase of multi drug resistant (MDR) cancer cells and heterogeneity of cancer is the reason of the side effects. Therefore, the combination therapy can be expected to demonstrate high therapeutic effects on both MDR cancer cells and heterogenetic cancer cells. The delivered TNP generates reactive oxygen species (ROS) by external ultrasonic stimulation, and DOX is released in response to ROS generated in the carrier. The high anticancer effect by the combination therapy of generated ROS and released DOX was confirmed through in vitro and in vivo experiments. In Chapter III, pPBA was used to simultaneously deliver tumor antigen and mannan, which acts as an adjuvant, forming in situ hydrogel with mannan. Mannan, a polysaccharide, was combined with phenylboronic acid to assemble a hydrogel, and tumor lysate was loaded therein. As mannan was sustainably released from the hydrogel. APCs (Antigen presenting cell) were matured by the released mannan and increased the tumor antigen cross presentation. Anti-cancer immunotherapy was confirmed through a hydrogel composed of pPBA and mannan. In conclusion, polymerized phenylboronic acid based dual delivery system was successfully developed, and indicated significant anti-cancer effects in both the combination therapy of Chapter II and immunotherapy of Chapter III. This suggested the possibility of anti-cancer therapy through a polymerized phenylboronic acid based dual drug delivery system.