MMP-9 gene silencing by a quantum dot-siRNA nanoplex delivery to maintain the integrity of the blood brain barrier.
The matrix-degrading metalloproteinases (MMPs), particularly MMP-9, are involved in the neuroinflammation processes leading to disrupting of the blood brain barrier (BBB), thereby exacerbating neurological diseases such as HIV-1 AIDS dementia and cerebral ischemia. Nanoparticles have been proposed to act as non-viral gene delivery vectors and have great potential for therapeutic applications in several disease states. In this study, we evaluated the specificity and efficiency of quantum dot (QD) complexed with MMP-9-siRNA (nanoplex) in downregulating the expression of MMP-9 gene in brain microvascular endothelial cells (BMVEC) that constitute the BBB. We hypothesize that silencing MMP-9 gene expression in BMVECs and other cells such as leukocytes may help prevent breakdown of the BBB and inhibit subsequent invasion of the central nervous system (CNS) by infected and inflammatory cells. Our results show that silencing of MMP-9 gene expression resulted in the up-regulation of extracellular matrix (ECM) proteins like collagen I, IV, V and a decrease in endothelial permeability, as reflected by reduction of transendothelial resistance across the BBB in a well validated in-vitro BBB model. MMP-9 gene silencing also resulted in an increase in expression of the gene tissue inhibitor of metalloproteinase-1 (TIMP-1). This indicates the importance of a balance between the levels of MMP-9 and its natural inhibitor TIMP-1 in maintaining the basement membrane integrity. These studies promise the application of a novel nanoparticle based siRNA delivery system in modulating the MMP-9 activity in BMVECs and other MMP-9 producing cells. This will prevent neuroinflammation and maintain the integrity of the BBB.
Bonoiu
Adela
A
Institute for Lasers, Photonics and Biophotonics, University at Buffalo, The State University of New York, Buffalo, New York, 14260-3000, USA.
Mahajan
Supriya D
SD
Ye
Ling
L
Kumar
Rajiv
R
Ding
Hong
H
Yong
Ken-Tye
KT
Roy
Indrajit
I
Aalinkeel
Ravikumar
R
Nair
Bindukumar
B
Reynolds
Jessica L
JL
Sykes
Donald E
DE
Imperiale
Marco A
MA
Bergey
Earl J
EJ
Schwartz
Stanley A
SA
Prasad
Paras N
PN
D001485:Basement Membrane / Q000187:drug effects / Q000201:enzymology; D001812:Blood-Brain Barrier / Q000201:enzymology; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004660:Encephalitis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D016326:Extracellular Matrix Proteins / Q000187:drug effects / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics; D061965:Matrix Metalloproteinase Inhibitors; D053758:Nanoparticles / Q000627:therapeutic use; D045663:Quantum Dots; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000235:genetics; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000187:drug effects / Q000378:metabolism
D016326:Extracellular Matrix Proteins; D061965:Matrix Metalloproteinase Inhibitors; D034741:RNA, Small Interfering; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9