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Author  |
Chou, S.-T.; Leng, Q.; Scaria, P.; Kahn, J.D.; Tricoli, L.J.; Woodle, M.; Mixson, A.J. |
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Surface modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition |
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Journal Article |
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2013 |
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Biomacromolecules |
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Biomacromolecules |
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We characterized in this study the pharmacokinetics and antitumor efficacy of histidine-lysine (HK):siRNA nanoplexes modified with PEG and a cyclic RGD (cRGD) ligand targeting alphavbeta3 and alphavbeta5 integrins. With non-invasive imaging, systemically administered surface modified HK:siRNA nanoplexes showed nearly 4-fold greater blood levels, 40% higher accumulation in tumor tissue, and 60% lower luciferase activity than unmodified HK:siRNA nanoplexes. We then determined whether the surface modified HK:siRNA nanoplex carrier was more effective in reducing MDA-MB-435 tumor growth with an siRNA targeting Raf-1. Repeated systemic administration of the selected surface modified HK:siRNA nanoplexes targeting Raf-1 showed 35% greater inhibition of tumor growth than unmodified HK:siRNA nanoplexes and 60% greater inhibition of tumor growth than untreated mice. The improved blood pharmacokinetic results and tumor localization observed with the integrin-targeting surface modification of HK:siRNA nanoplexes correlated with greater tumor growth inhibition. This investigation reveals that through control of targeting ligand surface display in association with a steric PEG layer, modified HK: siRNA nanoplexes show promise to advance RNAi therapeutics in oncology and potentially other critical diseases. |
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English |
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1525-7797 |
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PMID:23360232 |
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37525 |
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