Abstract 1481: Development of theranostic mesoporous silica nanoparticles for pancreatic cancer

Abstract

Abstract Purpose: Modern methods of pancreatic cancer diagnosis and treatment are severely lacking and have failed to provide effectual treatment options for patients. The root cause of this inadequacy stems from the hypovascularized nature of pancreatic cancer, making traditional chemotherapeutics and cancer detecting contrast agents nearly obsolete. A potential solution for tumor-targeting difficulties is through the implementation of nanotechnology, specifically targeting ligand capped, theranostic nanoparticles. We hypothesize that silica based, mesoporous nanoparticles capped with the targeting ligand, urokinase plasminogen activator (UPA) will serve as theranostic agents for treatment and diagnosis of pancreatic cancer. Methods: Mesoporous, silica nanoparticles (MSNs) were synthesized through the covering of acetyl trimethylammonium bromide (CTAB) scaffolding with tetraethyl orthosilicate (TEOS) in an aqueous environment. Refluxing was later used to remove the CTAB scaffolding and construct the desired mesoporous structure of the nanoparticles. MSNs were chemically engineered to be sensitive to acidic pH, contain fluorescent dye, and utilize a protein targeting ligand UPA. Multiple characterization techniques were employed to analyze the synthesized MSNs including UV-Vis spectroscopy, Zeta Potential, and Transmission Electron Microscopy (TEM). Pancreatic cancer tumor cells, S2CP9 and S2VP10, were treated with UPA-targeted or no-ligand encapsulated MSNs at pH 7.4 and 6.5. Following treatment, cells were washed to remove unbound particles followed by particle visualization based upon fluorescent dyes rhodamine or indocyanine green. Alternatively, cells treated with indocyanine green (ICG) loaded MSNs were placed into a tissue phantom and viewed using the Multispectral Optoacoustic Tomography system (MSOT). Mice with S2CP9 orthotopic pancreatic tumors were i.v. injected with 100 μL of UPA-ICG loaded MSNs. Particle localization was conducted using MSOT after 4h post injection. Results: Zeta potential and UV-Vis analysis confirmed the MSNs chemical conjugation, attributing the MSNs properties of pH sensitivity and fluorescence. pH sensitivity tests on the MSNs displayed drug release quantities at pH 6.5 to be ∼x2 the quantities of pH 6.8 and 7.4. Fluorescence microscopy showed the MSN uptake into S2VP10 and S2CP9 cell lines, while NIH3T3 cells (negative control) showed less binding. Use of UPAR antibody on S2VP10 and S2CP9 cell lines (positive control) blocked cellular binding. In tissue phantoms, UPA-ICG loaded MSNs at pH 6.5 demonstrated 20X and 7X more cell signal than without ligand or at pH 7.4, respectively. In-vivo, UPA-ICG loaded MSNs were detected within the orthotopic pancreatic tumor. Conclusion: UPA targeted, pH sensitive MSNs were found to possess substantial tumor cell binding against multiple cell lines and demonstrate potential as a theranostic nanoparticle for pancreatic cancer. Citation Format: Dillon S. Pender, Anil Khanal, Michael E. Egger, Lacey R. McNally. Development of theranostic mesoporous silica nanoparticles for pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1481. doi:10.1158/1538-7445.AM2015-1481