Journal
BIOMATERIALS
Volume 29, Issue 6, Pages 709-723Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2007.09.039
Keywords
non-viral vector; gene delivery; nuclear delivery; sugar; envelope-type nano device
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Efficient nuclear gene delivery is essential for successful gene therapy. This study developed a novel system that mimics the mechanism of nuclear entry of adenovirus (Ad) by means of a Multifunctional Envelope-type Nano Device (MEND). In this system, plasmid DNA (pDNA) was condensed with polycation, followed by encapsulation in a lipid membrane. To target MEND to the nuclear pore complex (NPC), sugar served as a NPC-mediated nuclear targeting device was modified on the surface of the lipid envelope. This was accomplished via synthesis of a sugar-cholesterol conjugate. After binding of the MEND to the NPC, the pDNA core was transferred into the nucleus in conjunction with a breakdown of the lipid envelope. Sugar-modified MEND showed higher transfection efficiency compared with unmodified MEND, in non-dividing and dividing cells. Confocal microscopy confirmed that nuclear transfer of pDNA was improved by sugar modification of MEND. Furthermore, destabilization of the lipid envelope significantly enhanced transfection activity: therefore, nuclear-delivery efficiency was closely related to lipid envelope stability. Moreover, quantitative evaluation of cellular uptake and nuclear transfer processes by real-time PCR confirmed that the surface sugars affected nuclear transfer, but not cellular uptake. In summary, a novel system for the nuclear delivery of pDNA was successfully developed by using a sugar-modified MEND and by optimizing the lipid envelope stability. (c) 2007 Elsevier Ltd. All rights reserved.
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