%0 Journal Article
%T Systemic siRNA Delivery via Peptide-Tagged Polymeric Nanoparticles, Targeting PLK1 Gene in a Mouse Xenograft Model of Colorectal Cancer
%A Meenakshi Malhotra
%A Catherine Tomaro-Duchesneau
%A Shyamali Saha
%A Satya Prakash
%J International Journal of Biomaterials
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/252531
%X Polymeric nanoparticles were developed from a series of chemical reactions using chitosan, polyethylene glycol, and a cell-targeting peptide (CP15). The nanoparticles were complexed with PLK1-siRNA. The optimal siRNA loading was achieved at an N£¿:£¿P ratio of 129.2 yielding a nanoparticle size of >200£¿nm. These nanoparticles were delivered intraperitoneally and tested for efficient delivery, cytotoxicity, and biodistribution in a mouse xenograft model of colorectal cancer. Both unmodified and modified chitosan nanoparticles showed enhanced accumulation at the tumor site. However, the modified chitosan nanoparticles showed considerably, less distribution in other organs. The relative gene expression as evaluated showed efficient delivery of PLK1-siRNA (0.5£¿mg/kg) with % knockdown ( ) of PLK1 gene. The in vivo data reveals no systemic toxicity in the animals, when tested for systemic inflammation and liver toxicity. These results indicate a potential of using peptide-tagged nanoparticles for systemic delivery of siRNA at the targeted tumor site. 1. Introduction Cancer is characterized by the uncontrolled growth of a group of cells that infest adjacent tissues and often metastasize to other organs via the lymphatic or circulatory system. It is primarily caused by environmental factors (90¨C95%), but also by genetic factors (5¨C10%) [1]. Typically the alteration in cell growth promoting oncogenes and cell division inhibiting tumor suppressive genes leads to the formation of cancer cells [2]. Depending on the stage of the cancer, the treatment options available include surgical removal, chemotherapy with anticancer drugs, such as 5-fluorouracil, oxaliplatin, and leucovorin [3], radiation therapy, immunotherapy [4], and hormone therapy with drugs like cetuximab and panitumumab [5]. However, it has been shown that cancers with genetic origin do not benefit from these chemotherapies [5]. Moreover, the toxicity and side-effects have severely limited the safety and effectiveness of these methods. One of the target proteins in cancer therapy is serine/threonine-protein kinase (PLK1), a key regulator of mitosis in mammalian cells. PLK1 is a protooncogene overexpressed in a variety of human cancers [6, 7]. It is directly associated with p53, a tumor suppressor protein, and on interaction with p53, it inhibits the latter¡¯s transactivation and proapoptotic activity [8], leading to uncontrolled cell proliferation. Recently, the inhibition of PLK1 with antibodies, antisense oligonucleotides (ASOs), small interfering RNA (siRNA), or dominant negative mutants that suppress
%U http://www.hindawi.com/journals/ijbm/2013/252531/