Abstract
Abstract RNAi technology has brought a new category of treatments for cancer. NFκB is a transcription factor which can inhibit apoptosis and promote cell proliferation. Activation of NFκB is linked to the progression of various cancers. Inhibition of NFκB and its downstream targets using NFκB-siRNA (NS) for cancer therapy has been investigated. However, for successful siRNA delivery, it has to be delivered into the cytoplasm of cancer cells. Naked siRNA is prone to degradation and has a plasma half-life of less than five minutes. In addition, the relatively small size of the siRNA leads to rapid renal clearance. These facts, together with the negatively charged siRNA which limits permeability across cell membrane, mean that successful delivery of naked siRNA is unlikely. Cationic lipid based systems have emerged as the most attractive siRNA delivery, however the use is limited due to poor transfection efficiency and toxicity. The use of polymers (polyethyleneimines and polyesteramines) has been hampered due to substantial toxicity. Natural polymer based delivery systems (chitosan, gelatin, albumin) are biocompatible and biodegradable with high physiological tolerance and low immunogenicity. The purpose of this study was to develop NS loaded into gelatin nanocarriers (NS-GNCs) that enables effective delivery in a targeted fashion to tumors. The NS-GNCs were prepared using cationic gelatin by desolvation method. The NS-GNCs were characterized for size, charge, entrapment, release and in vitro efficacy against lung and breast cancer cells. The size and zeta potential was found to be 180 ± 4 nm and 16 ± 2 mV respectively. Entrapment efficiency was found to be 81 ± 1.4 % and the release of siRNA was in a controlled manner up to 48 h. The dose dependent in vitro efficacy of NS-GNCs was studied using A549 lung cancer and MDA-MB-231 breast cancer cells compared to naked NS using untreated cells as a control. NS-GNCs showed significantly (p<0.05) higher cytotoxicity against lung and breast cancer cells in a dose dependant manner compared to naked NS. At 30ng/ml, NS-GNCs treated A549 cells showed 46% cytotoxicity compared to 16% in naked NS treated A549 cells. At 60ng/ml, NS-GNCs treated MDA-MB-231 cells showed 54% cytotoxicity compared to 21% in naked NS treated cells. The increased cytotoxicity with NS-GNCs can be attributed to the tumor specific accumulation of positively charged GNCs by uptake through electrochemical diffusion. Moreover, NS-GNCs showed comparable cytotoxicity as compared to lipofectamine (tranfecting agent) in both the cancer cells. The developed targeted NS-GNCs showed enhanced activity compared to naked NS against cancer cells. This innovative delivery approach will help to overcome the limitations and adverse side effects associated with current delivery approaches. We are currently investigating NS-GNC conjugation with RGD peptide to enhance the tumor specific delivery via receptor mediated endocytosis. 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 5644. doi:1538-7445.AM2012-5644
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