Surface-modified HK:siRNA nanoplexes with enhanced pharmacokinetics and tumor growth inhibition.
Biomacromolecules
; 14(3): 752-60, 2013 Mar 11.
Article
em En
| MEDLINE
| ID: mdl-23360232
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
RNA Interferente Pequeno
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Nanoestruturas
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Histidina
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Lisina
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Neoplasias
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article