Abstract A123: Dual-Drug Micellar Approach to Overcome Stromal Barriers in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of less than 13% and remains a leading cause of cancer death in the United States. PDAC dense stroma hinders drug delivery and reduces treatment efficacy. Calcipotriol (Cal), a known stromal modulator, may enhance drug delivery. This study evaluated the combination of Cal and paclitaxel (PTX) in a polymeric micelle formulation (M-Cal/PTX) to improve drug distribution and efficacy in a PDAC mouse model. Methods: Cal and PTX were encapsulated in a 1: 3 ratio in a polymeric micelle (Size: 40-50 nm, Polydispersity index: ⁓0. 2). In vitro: Nile Red incorporated into the polymeric micelle was used to image the cellular uptake in Kras* Cells on confocal microscopy. In vivo: Using an orthotopic Kras* PDAC mouse model, we assessed the antitumor effect of M-Cal/PTX. Mice were divided and randomized into three groups: M-Cal/PTX (1. 8 mg/kg-5. 5 mg/kg) (n=7), Abraxane (8 mg/kg) (n=6), and vehicle (sham polymeric micelle) (n=6). Doses were administered intravenously (11 doses) /intraperitoneally (4 doses), five days per week for three weeks, and all surviving animals were sacrificed after the fourth week. Tumors were harvested at the end of the study, weighed, and compared. Results: Sectional imaging from confocal microscopy showed a cytoplasmic uptake of the micelles in Kras* cells within 5 minutes of incubation. Kaplan-Meier analysis showed median survival times of ∼14–15 days for vehicle, ∼21. 5 days for Abraxane, and 28 days for M-Cal/PTX. Final survival rates were 0%, ∼33%, and ∼60%, respectively. Mice in the vehicle group exhibited large tumors (mean weight ∼3. 1–3. 6 g). Abraxane moderately reduced tumor burden, with variable weights ranging from 1. 2 to 5. 3 g. In contrast, the M-Cal/PTX group showed a marked reduction in tumor size, with several tumors under 0. 2 g. Conclusion: The M-Cal/PTX group demonstrates the greatest survival benefit, indicating improved therapeutic efficacy of the combination treatment. These results demonstrate that M-Cal/PTX suppresses tumor growth more effectively than Abraxane or control, supporting the enhanced efficacy of stromal modulation in combination therapy. Ongoing work is to confirm the significance of these findings with a larger sample size, longer survival monitoring period, and bioluminescence imaging. Citation Format: Fatima Dagher, Guodong Zhang, Mikayla Skillman, Muhammad Hamza. Malik, Sundus Jabeen Amina, Amir Mohammad Gholizadeh, Chun Li, Diana S-L. Chow. Dual-Drug Micellar Approach to Overcome Stromal Barriers in Pancreatic Cancer abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A123.