Surface-modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition.

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 αvß3 and αvß5 integrins. With noninvasive imaging, systemically administered surface-modified HKsiRNA nanoplexes showed nearly 4-fold greater blood levels, 40% higher accumulation in tumor tissue, and 60% lower luciferase activity than unmodified HKsiRNA nanoplexes. We then determined whether the surface-modified HKsiRNA 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 HKsiRNA nanoplexes targeting Raf-1 showed 35% greater inhibition of tumor growth than unmodified HKsiRNA 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 HKsiRNA 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.