Journal
BIOMATERIALS
Volume 33, Issue 2, Pages 583-591Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2011.09.061
Keywords
PLGA; Nanoparticle; Gene delivery; RNA interference
Funding
- Chicago Institute of Neurosurgery and Neuroresearch (CINN) Foundation
- Voices Against Brain Cancer (VABC) Foundation
- Yale Institute for Nanoscience and Quantum Engineering (YINQE)
- NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING [R01EB000487] Funding Source: NIH RePORTER
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Therapies based on RNA interference, using agents such as siRNA, are limited by the absence of safe. efficient vehicles for targeted delivery in vivo. The barriers to siRNA delivery are well known and can be individually overcome by addition of functional modules, such as conjugation of moieties for cell penetration or targeting. But, so far, it has been impossible to engineer multiple modules into a single unit. Here, we describe the synthesis of degradable nanoparticles that carry eight synergistic functions: 1) polymer matrix for stabilization/controlled release; 2) siRNA for gene knockdown; 3) agent to enhance endosomal escape; 4) agent to enhance siRNA potency; 5) surface-bound PEG for enhancing circulatory time; and surface-bound peptides for 6) cell penetration; 7) endosomal escape; and 8) tumor targeting. Further, we demonstrate that this approach can provide prolonged knockdown of PLK1 and control of tumor growth in vivo. Importantly, all elements in these octa-functional nanoparticles are known to be safe for human use and each function can be individually controlled, giving this approach to synthetic RNA-loaded nanoparticles potential in a variety of clinical applications. (C) 2011 Elsevier Ltd. All rights reserved.
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