한빛사논문
Ha Rin Kim a,b,c, Seong Jin Park a, Young Seok Cho d, Yoon Gun Ko e, Sang Yoon Kim e, Youngro Byun a
aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
bSchool of Medicine, Stanford University, CA 94305, United States
cSchool of Applied Chemistry, Kookmin University, Seoul 02707, Republic of Korea
dCollege of Pharmacy, University of Michigan, Ann Arbor, MI 48109, United States
ePharosgen Co.Ltd, Seoul 05852, Republic of Korea
Corresponding author : Youngro Byun
Abstract
Despite significant progress in combining cancer immunotherapy with chemotherapy to treat triple negative breast cancer (TNBC), challenges persist due to target depletion and tumor heterogeneity, especially in metastasis. Chemotherapy lacks precise targeting abilities, and targeted therapy is inadequate in addressing the diverse heterogeneity of tumors. To address these challenges, we introduce RGDEVD-DOX as a tumor-specific immunogenic agent, namely TPD1, which targets integrin αvβ3 and gets continuously activated by apoptosis. TPD1 facilitates the caspase-3-mediated in situ amplification that results in tumor-specific accumulation of doxorubicin. This local concentration of doxorubicin induces immunogenic cell death and promotes the recruitment of immune cells to the tumor site. Notably, the tumor-targeting capabilities of TPD1 help bypass the systemic immunotoxicity of doxorubicin. Consequently, this alters the tumor microenvironment, converting it into a ‘hot’ tumor that is more susceptible to immune checkpoint inhibition. We demonstrated the anti-metastatic and anti-cancer efficacy of this treatment using various xenograft and metastatic models. This study underscores the high potential of caspase-3 cleavable peptide-drug conjugates to be used in conjunction with anti-cancer immunotherapies.
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