Abstract 1953: Co-delivery of doxorubicin and siRNA using octreotide-conjugated gold nanorods for targeted neuroendocrine cancer therapy
Authors: Renata Jaskula-Sztul, Yuling Xiao, Alireza Javadi, Jacob Eide, Wenjin Xu, Muthusamy Kunnimalaiyaan, Sarah Gong, Herbert Chen
Journal: Cancer Research (2012)

Abstract Introduction: Gastrointestinal (GI) carcinoids are neuroendocrine (NE) tumors that secrete hormones causing carcinoid syndrome. Metastatic carcinoids are not amenable to curative surgery. Therefore, siRNA-mediated gene silencing, in combination with targeted chemotherapy, may be a potential therapeutic strategy for patients with carcinoid neoplasms. We have developed and assessed antitumor effects of a gold nanorod (Au NR)-based nanocarrier conjugated with an anticancer drug (doxorubicin (DOX)) and small interfering RNA (siRNA against carcinoid tumor marker ASCL1, a protein required for NE cancer cell proliferation) specifically targeting the NE cancer cells with overexpressed somatostatin receptors (SSTRs) using octreotide (Oct) as an active - tumor targeting ligand. Methods: Au NR-based nanoparticles (NPs) were synthesized via a multiple step reaction. DOX was conjugated onto the Au NR via hydrazone bonds. siRNA was complexed onto the cationic poly(L-arginine) polymer. Oct targeting ligand was selectively conjugated onto the distal end of PEG arms. A human GI carcinoid cell line (BON) was treated with either non-targeted (Au-DOX) or targeted (Au-DOX-Oct) NPs with or without siRNA, at a concentration of 1 μg/ml for 30′ and 120′ or 24, 48, 72 hours. Based on the doxorubicin fluorescent intensity, the cellular uptake of NPs was analyzed by flow cytometry and confocal laser scanning microscope (CLSM). MTT assay and Western blot were used to determine cell proliferation and assess ASCL1 expression, respectively. Results: DOX release profiles from NPs were dependent on the environmental pH values, which can minimize systemic spread of toxic drugs during circulation. BON cells incubated with Au-DOX-Oct exhibited higher cellular uptake than Au-DOX (14% and 44% increase after 30 min and 120 min, respectively) measured by flow cytometry. The CLSM observations confirmed that the intracellular transport of Au-DOX-Oct is faster than Au-DOX. MTT assay showed that Au-DOX-Oct-ASCL1siRNA has the strongest inhibitory effect on carcinoid cell proliferation (more than 50% of growth reduction). Immunoblot analysis demonstrated that Au-DOX-Oct-ASCL1siRNA reduced the expression of ASCL1 much more than other NPs. Conclusions: We have developed a multifunctional, pH-responsive and tumor-targeting Au NR-based nanoplatform for anticancer drug therapy. We showed that the presence of the surface ligand Oct increased the cellular uptake of the NPs (Au-DOX-Oct) substantially in a BON cell line compared to the non-targeted NPs (Au-DOX). Targeted NPs with ASCL1siRNA were the most efficient in altering the neuroendocrine phenotype of BON cells demonstrating the strongest anti-proliferative effect. Thus, targeted delivery of anticancer drug (DOX) and genetic material (ASCL1siRNA) specifically to the tumor tissue could achieve therapeutic outcomes in treating carcinoid disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1953. doi:1538-7445.AM2012-1953