Abstract 2762: Development of a novel peptide-formed nanoparticle for pancreatic cancer treatment

Abstract

Abstract Background and objective: Pancreatic ductal adenocarcinoma (PDAC) is the most common malignant tumor of pancreas with an overall 5-year survival rate of less than 5%. Surgical operation is an curable treatment, however, only 10-20% of patients with PDAC are respectable at diagnosis. Taking advantage of the progression in nanoparticle study, we developed a novel peptide-formed nanoparticle (PF-Nano) and investigate its therapeutic effect in PDAC treatment. Methods: Phage display peptide library was used to screen a high-affinity tumor-homing peptide (THP) for pancreatic cancer (PC) cells. Ligation of THP with cell penetrating peptide was used to prepare a tandem peptide, which automatically formed a nanoparticle. We used this PF-Nano as a vehicle to load and deliver siRNA.Dynamic light scattering (DLS) was employed to define nanoparticle size; and fluorescence imaging was applied to assess PF-Nano siRNA delivery efficiency. In vitro, we used MTT assay and colony formation to evaluate cell growth; wound healing assay to detect cell migration, and flow cytometry to evaluate cell cycle and apoptosis. Therapeutic effect was evaluated by measuring final tumor weight in the mice receiving different treatments. qPCR and Western Blot (WB) were used to detect gene expression in mRNA and protein level. Immunoprecipitation in combination with mass spectrometry and immunofluorescence were used to identify THP’s ligands. Results: The screened peptide has a high-affinity with PC cells. DLS identified evenly distributed PF-Nano with a diameter of approximately 230nm. Detection of fluorescence signal from labeled siRNAs in PC cells and tumor tissue suggested that PF-Nano owned the capacity to successfully deliver siRNA in vitro and in vivo. In vitro treatment with PF-Nano significantly suppressed PC cell proliferation, colony formation, and cell migration. Also it caused cycle arrest in S phase (DNA synthesis) and increase in cell apoptosis. Treatment of tumor-bearing mice with PF-Nano by intraperitoneal injection markedly suppressed tumor growth, evidenced by the reduction of tumor weight to 25% relevant to that in control mice without treatment. Immunoprecipitation and mass spectrometry revealed that protein phosphatase 1 catalytic subunit gamma (PP1C) was a potential binding target of the specific THP. Mechanistically, PF-Nano treatment strongly suppressed RAC-alpha serine/threonine-protein kinase (AKT) phosphorylation, suggesting PP1-AKT signal pathway may be responsible for peptide effect in pancreatic tumor. Conclusion: The established PF-Nano is able to specifically deliver siRNAs to PC tumors and therapeutically suppresses PC tumor growth. Citation Format: Qiongling Wang, Kevin F. Staveley-O’Carroll, Guangfu Li. Development of a novel peptide-formed nanoparticle for pancreatic cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2762.