Surface-Modified HK:siRNA
Nanoplexes with Enhanced
Pharmacokinetics and Tumor Growth Inhibition
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Abstract
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 αvβ3 and αvβ5
integrins. With noninvasive 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