아데노바이러스를 젤라틴젤로 캡슐화함으로써 감소되는 항바이러스 면역반응 및 향상된 항종양 효과 평가

Abstract

Oncolytic adenovirus, an adenovirus (Ad) with cancer-specific cytotoxicity, selectively replicates in and lyses cancer cells while being innocuous to normal cells. Clinical efficacy of oncolytic Ad is limited due to host-immune cells in the blood, triggering antiviral immune response and production of neutralizing antibodies which nullifies efficacy of the virus. Accumulated oncolytic Ad in tumor site has limited replication activity and can only be sustained for 4-5 days. In order to overcome such limitations, virus is repeatedly administered in high doses which can also lead to significant side-effects such as hepatotoxicity, accumulation of virus in host tissues, and life-threatening immune response. Therefore in this study, we have utilized gelatin hydrogel with remarkable biocompatibility and biodegradability to encapsulate oncolytic Ad which can be administered to localized target site in a single dose. Gel-encapsulated oncolytic Ad can overcome limitations of conventional Ad as it can be gradually released in therapeutic dose over prolonged period of time while also evading antiviral immune response. Gelatin gel-encapsulated oncolytic Ad’ prolonged release of the virus was confirmed by experiments in vitro and in vivo, and augmented antitumor efficacy of the virus in comparison to administration of naked virus. Furthermore, more viral particles were detected in tumor tissues from gelatin gel-encapsulated adenovirus than naked Ad and we observed almost degradation of gelatin gel 14 days from administration. Statistically significant difference in antitumor efficacy and tumor growth inhibition between naked Ad and gel-encapsulated Ad was observed in Syrian golden hamster Hap-T1 pancreatic cancer model. Lastly, we noticed significantly reduced innate and adaptive immune response from gel-encapsulated Ad in comparison with naked Ad. These results indicate that oncolytic Ad’ therapeutic efficacy can be greatly enhanced by encapsulation with gelatin hydrogel as encapsulation maintains therapeutic dose over prolonged period of time with single administration while also inducing significantly less immune response, and thus gel-encapsulation should be considered as delivery strategy of Ad in future clinical studies.