Surface-modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition.
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.
Department of Pathology, University of Maryland Baltimore, MSTF Building, 10 South Pine Street, Baltimore, MD 21201, USA.
Szu-Ting
ST
Chou
Qixin
Q
Leng
Puthupparampil
P
Scaria
Jason D
JD
Kahn
Lucas J
LJ
Tricoli
Martin
M
Woodle
A James
AJ
Mixson
D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D006639:Histidine / Q000737:chemistry*; D006801:Humans; D008239:Lysine / Q000737:chemistry*; D051379:Mice; D049329:Nanostructures / Q000737:chemistry*; D009369:Neoplasms / Q000188:drug therapy*; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000493:pharmacokinetics* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D006639:Histidine; D019908:Proto-Oncogene Proteins c-raf; D008239:Lysine