한빛사논문
- 조회159
경희대학교 약학대학, 큐리진
Dae Hoon Lee1,2,3, Jung Ki Yoo1,2,3, Ki Hwan Um1,2,3,4, Wootae Ha3, Soo Min Lee1,4, Junseong Park5, Min Jeong Kye3, Jungyo Suh6 and Jin Woo Choi1,2,3,4*
1Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
2Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
3R&D Center of Curigin Ltd., Curigin, Seoul 04778, Republic of Korea.
4Department of Regulatory Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea.
5Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea.
6Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
*Correspondence: Jin Woo Choi
Abstract
Background: Recent intravesical administration of adenoviral vectors, either as a single injection or in combination with immune checkpoint inhibitors, exemplified by cretostimogene grenadenorepvec and nadofaragene firadenovec, has demonstrated remarkable efficacy in clinical trials for non-muscle invasive bladder cancer. Despite their ability to induce an enhanced immune reaction within the lesion, the intracellular survival signaling of cancer cells has not been thoroughly addressed.
Methods: An analysis of the prognostic data revealed a high probability of therapeutic efficacy with simultaneous inhibition of mTOR and STAT3. Considering the challenges of limited pharmaco-accessibility to the bladder due to its pathophysiological structure and the partially undruggable nature of target molecules, we designed a dual siRNA system targeting both mRNAs. Subsequently, this dual siRNA system was encoded into the adenovirus 5/3 (Ad 5/3) to enhance in vivo delivery efficiency.
Results: Gene-targeting efficacy was assessed using cells isolated from xenografted tumors using a single-cell analysis system. Our strategy demonstrated a balanced downregulation of mTOR and STAT3 at the single-cell resolution, both in vitro and in vivo. This approach reduced tumor growth in bladder cancer xenograft and orthotopic animal experiments. In addition, increased infiltration of CD8+ T cells was observed in a humanized mouse model. We provided helpful and safe tissue distribution data for intravesical therapy of siRNAs coding adenoviruses.
Conclusions: The bi-specific siRNA strategy, encapsulated in an adenovirus, could be a promising tool to augment cancer treatment efficacy and overcome conventional therapy limitations associated with "undruggability." Hence, we propose that dual targeting of mTOR and STAT3 is an advantageous strategy for intravesical therapy using adenoviruses.
논문정보
- Research article
- 2024년 06월 (BRIC 등록일 2024-07-04)
- 국내 연구진
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