Abstract LB026: A metabolism-responsive self-assembling SMDC for dual-targeting therapy of refractory solid tumors

Abstract Refractory solid malignancies such as pancreatic cancer and glioblastoma remain clinically challenging due to aggressive behavior, metabolic heterogeneity, and poor prognosis. Spatial metabolomics analysis of clinical samples from pancreatic cancer, glioblastoma, and lung cancer patients revealed significant dysregulation in choline metabolism, consistent with the upregulated expression of the choline transporter SLC44A1 confirmed at both transcriptional and protein levels. Based on this finding, a tumor metabolism-responsive small-molecule drug conjugate (SMDC), PTX-SA-R, was designed to target the choline transporter SLC44A1, which is highly expressed in these tumors. PTX-SA-R integrates choline covalently linked to paclitaxel (PTX) via a spacer, enabling SLC44A1-mediated active cellular uptake while conferring amphiphilicity for spontaneous self-assembly into micelles. The conjugate thus functions as both a cytotoxic payload and a self-delivering nanocarrier, leveraging both passive accumulation via the EPR effect and active cellular targeting. To optimize intravenous delivery, PTXSAR was coassembled with Solutol HS15, yielding PTX-SA-R@HS15 micelles with reduced surface charge. This coassembly system features an organic solvent-free, simple, low-cost, and nonimmunogenic preparation and demonstrates excellent longterm stability (>3 months). The micelles exhibit pHsensitive drug release within the acidic tumor microenvironment, promoting selective toxicity. In vivo, PTX-SA-R@HS15 showed superior tumor accumulation, reduced thymic injury, and enhanced blood-brain barrier penetration compared to nab-paclitaxel and PTX polymeric micelles. It exerted potent, broad-spectrum antitumor activity, achieving tumor growth inhibition of 95.46% in pancreatic cancer, 94.26% in Lewis lung carcinoma, and 98.75% in an orthotopic glioblastoma patient-derived xenograft model. Collectively, this work establishes a generalizable SMDC design paradigm that synergizes passive EPR-driven delivery with active metabolism-responsive targeting, offering a translatable and stable nanotherapeutic strategy for refractory solid tumors. Citation Format: Yan Li, Kaijing Guo, Yuhan An, Xing Xiang, Yuhan Zhang, Yulin Wang, Zheng Qu, Ting Lei, Fangjun Liu, Penghui Yang, Zeper Abliz, Jiuming He. A metabolism-responsive self-assembling SMDC for dual-targeting therapy of refractory solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB026.