Abstract 3125: Stroma-penetrating nanocomplex enhances drug delivery and regulates tumor innervation to improve therapeutic outcomes in pancreatic cancer

Abstract Objective: Dense fibrous tumor stroma creates a drug delivery barrier and cultivates aggressive tumor biology and immunosuppression in pancreatic cancer. A well-recognized hallmark of pancreatic cancer is nerve infiltration into tumors (neural invasion) and cancer cell-invaded neurons (perineural invasion), which often correlate with local recurrence, metastasis, resistance to therapy, and poor survival. The goal of this study is to develop tumor stroma-penetrating and cancer nerve-modulating hyaluronic acid nanoparticles (HANPs) carrying a chemotherapy drug and a peptidic immune checkpoint blockade for targeted therapy of pancreatic cancer, activation of the immune response, and mitigation of cancer-induced neuropathic pain. Methods: A tumor-targeting and tumor stroma-penetrating ligand was developed by fusing the amino-terminal fragment (ATF) of uPA with the MMP14 catalytic domain. The resulting ATFmmp14 protein and a PD-L1 binding and inhibiting peptide (PD1Y) were then covalently conjugated onto HANPs carrying SN38, an active metabolite of irinotecan, at a ratio of five ATFmmp14 and 129 PD1Y molecules per HANP/SN38. The drug delivery efficacy of ATFmmp14-HANP/SN38 in tumors was quantified by analyzing SN38 levels in tumor tissue using HPLC in two pancreatic cancer patient-derived xenografts (PDXs). For therapeutic studies, ATFmmp14(PD1Y)-HANP/SN38 was intravenously (i.v.) injected into orthotopic pancreatic cancer PDX and mouse KPC tumor models at 10 mg/kg of the equivalent amount of SN38 or PD1Y for 5 weekly treatments. Results: The results showed that 22-33% of the total delivered SN38 in ATFmmp14-HANP/SN38 accumulated in pancreatic cancer PDX tumors, which was 22-fold higher than free SN38 and 4-fold higher than ATF-HANP/SN38 at 24 hours post-injection. Tumor growth inhibition of 78-98% was achieved in pancreatic PDX models compared to the untreated control group. A significant decrease in both PDX tumor sensory and sympathetic nerves was observed after ATFmmp14-HANP/SN38 treatment. In KPC mouse tumor models, the addition of PD1Y to ATFmmp14-HANP/SN38 led to increased infiltration of activated CD8+/CD107a T cells and dendritic cells with upregulated MHCII, further enhancing the therapeutic effect and activating immune responses in tumors. Conclusion: ATFmmp14(/PD1Y)-HANP/SN38 is a promising nanomedicine that can penetrate dense tumor stroma to deliver more drugs into tumors, modulate the tumor microenvironment, and regulate cancer-associated nerves to enhance pancreatic cancer treatment efficacy and relieve cancer-related pain. Citation Format: Songyu Wu, Lei Zhu, Lily Yang. Stroma-penetrating nanocomplex enhances drug delivery and regulates tumor innervation to improve therapeutic outcomes in pancreatic cancer [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 3125.