Abstract 3122: A novel solid tumor-tissue-penetrating platform technology: Overcoming tumor microenvironment barriers for an effective targeted delivery of therapeutic agents into solid tumors
Authors: Serry Koh, Ji-young Lee, Young Pil Jung, Won-seok Choi, Min Gyu Soung
Journal: Cancer Research (2025)

Abstract The tumor microenvironment (TME)—comprising tumor vasculature, stromal cells, immune cells, and extracellular matrix (ECM)—presents significant challenges for effective anticancer therapy delivery. To address these challenges, we developed a novel solid tumor-tissue penetrating (STTP) platform featuring DST-516, a tumor-penetrating peptide designed to enhance tumor-specific delivery and deep penetration of therapeutic agents into solid tumors. Preclinical studies demonstrated that DST-516 outperformed the iRGD control in terms of tumor penetration. Confocal laser scanning microscopy (CLSM) revealed that co-administration of DST-516 with fluorescently labeled doxorubicin (10 mg/kg) and 70 kDa albumin (10 mg/kg) resulted in profound and extensive tissue penetration. Enhanced distribution was observed over a period of 1 to 24 hours in AsPC-1 xenograft mouse models. The efficacy of fluorescently labeled doxorubicin penetration was further validated in both 3D PANC-1 and 3D AsPC-1 spheroids. Co-administration of DST-516 with gemcitabine and paclitaxel resulted in a significantly greater reduction in pancreatic tumor volume compared to either drugs alone or in combination with iRGD, demonstrating enhanced therapeutic efficacy in vivo. The efficient delivery of 70 kDa albumin to pancreatic tumors via co-administration with DST-516 highlights its potential for transporting large molecules, laying a strong foundation for future applications in antibody-drug conjugates (ADCs) and other advanced cancer therapies through the STTP platform. Mechanistic studies demonstrated that DST-516 preferentially binds to neuropilin-1 (NRP-1) and integrins αvβ3/αvβ5 in AsPC-1 cells, with minimal binding in siNRP-1-transfected AsPC-1 cells, emphasizing DST-516's tumor specificity. This specificity suggests that DST-516 could minimize off-target toxicity while maximizing therapeutic efficacy. Comprehensive safety evaluations, including nine preclinical toxicology studies, confirmed DST-516’s tolerability, with no significant adverse effects observed in single- or repeated-dose intravenous toxicity or genetic toxicity assessments. These results support its translational feasibility and clinical development potential. In conclusion, our findings establish DST-516 and the STTP platform as a promising strategy to overcome TME-mediated resistance, enabling safe and efficient delivery of therapeutic agents to solid tumors. Future studies will expand its applications across various solid tumor types and further refine its mechanism of action. This platform represents a pivotal step toward advancing precision oncology and improving outcomes for patients with hard-to-treat cancers. Citation Format: Serry Koh, Ji-young Lee, Young Pil Jung, Won-seok Choi, Min Gyu Soung. A novel solid tumor-tissue-penetrating platform technology: Overcoming tumor microenvironment barriers for an effective targeted delivery of therapeutic agents into solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3122.