Synthetic Viruslike Particles for Targeted Gene Delivery to αvβ3 Integrin-Presenting Endothelial Cells

To achieve efficient systemic gene delivery to the lung with minimal toxicity, a vector was developed by chemically conjugating a cationic polymer, polyethylenimine (PEI), with anti-platelet endothelial cell adhesion molecule (PECAM) antibody (Ab). Transfection of mouse lung endothelial cells with a plasmid expression vector with cDNA to luciferase (pCMVL) complexed with anti-PECAM Ab-PEI conjugate was more efficient than that with PEI-pCMVL complexes. Furthermore, the anti-PECAM Ab-PEI conjugate mediated efficient transfection at lower charge plus-to-minus ratios. Conjugation of PEI with a control IgG (hamster IgG) did not enhance transfection of mouse lung endothelial cells, suggesting that the cellular uptake of anti-PECAM Ab-PEI-DNA complexes and subsequent gene expression were governed by a receptor-mediated process rather than by a nonspecific charge interaction. Conjugation of PEI with anti-PECAM Ab also led to significant improvement in lung gene transfer to intact mice after intravenous administration. The increase in lung transfection was associated with a decrease compared with PEI-pCMVL with respect to circulating proinflammatory cytokine (tumor necrosis factor-α) levels. These results indicate that targeted gene delivery to the lung endothelium is an effective strategy to enhance gene delivery to the pulmonary circulation while simultaneously reducing toxicity.

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Use of N-terminal modified poly(L-lysine)-antibody conjugate as a carrier for targeted gene delivery in mouse lung endothelial cells

Bioconjugate Chemistry ◽

10.1021/bc00016a011 ◽

1992 ◽

Vol 3 (4) ◽

pp. 323-327 ◽

Cited By ~ 97

Author(s):

Vladimir S. Trubetskoy ◽

Vladimir P. Torchilin ◽

Stephen J. Kennel ◽

Leaf Huang

Keyword(s):

Endothelial Cells ◽

Gene Delivery ◽

Mouse Lung ◽

Targeted Gene Delivery ◽

Antibody Conjugate ◽

Lung Endothelial Cells

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Targeted gene delivery of polyethyleneimine-grafted chitosan with RGD dendrimer peptide in αvβ3 integrin-overexpressing tumor cells

Carbohydrate Polymers ◽

10.1016/j.carbpol.2017.07.035 ◽

2017 ◽

Vol 174 ◽

pp. 1059-1068 ◽

Cited By ~ 22

Author(s):

Young-Min Kim ◽

Seong-Cheol Park ◽

Mi-Kyeong Jang

Keyword(s):

Gene Delivery ◽

Tumor Cells ◽

Αvβ3 Integrin ◽

Targeted Gene Delivery

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Optimization of ultrasound and microbubbles targeted gene delivery to cultured primary endothelial cells

Journal of Drug Targeting ◽

10.1080/10611860701605088 ◽

2007 ◽

Vol 15 (10) ◽

pp. 664-671 ◽

Cited By ~ 50

Author(s):

Bernadet D. M. Meijering ◽

Robert H. Henning ◽

Wiek H. Van Gilst ◽

Ivana Gavrilović ◽

Annemieke Van Wamel ◽

...

Keyword(s):

Endothelial Cells ◽

Gene Delivery ◽

Targeted Gene Delivery

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Targeted gene delivery to the cardiac tissue by adenovirus conjugated magnetic nanobeads

The Thoracic and Cardiovascular Surgeon ◽

10.1055/s-0030-1269121 ◽

2011 ◽

Vol 59 (S 01) ◽

Author(s):

Y Zhang ◽

W Li ◽

W Wang ◽

L Ou ◽

A Liebold ◽

...

Keyword(s):

Gene Delivery ◽

Cardiac Tissue ◽

Targeted Gene Delivery ◽

Magnetic Nanobeads

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Tropism-Modification Strategies for Targeted Gene Delivery Using Adenoviral Vectors

Viruses ◽

10.3390/v2102290 ◽

2010 ◽

Vol 2 (10) ◽

pp. 2290-2355 ◽

Cited By ~ 81

Author(s):

Lynda Coughlan ◽

Raul Alba ◽

Alan L. Parker ◽

Angela C. Bradshaw ◽

Iain A. McNeish ◽

...

Keyword(s):

Gene Delivery ◽

Adenoviral Vectors ◽

Targeted Gene Delivery

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Maternal Anti-HPA-1a Antibodies Increase Endothelial Cell Apoptosis and Permeability

Journal of Vascular Research ◽

10.1159/000515703 ◽

2021 ◽

pp. 1-9

Author(s):

Rima Dardik ◽

Ophira Salomon

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Intracranial Hemorrhage ◽

Cell Apoptosis ◽

Endothelial Damage ◽

Αvβ3 Integrin ◽

Endothelial Cell Apoptosis ◽

Vascular Beds ◽

Alloimmune Thrombocytopenia

Intracranial hemorrhage (ICH) associated with fetal/neonatal alloimmune thrombocytopenia (FNAIT) is attributed mainly to endothelial damage caused by binding of maternal anti-HPA-1a antibodies to the αvβ3 integrin on endothelial cells (ECs). We examined the effect of anti-HPA-1a antibodies on EC function using 2 EC lines from different vascular beds, HMVEC of dermal origin and hCMEC/D3 of cerebral origin. Anti-HPA-1a sera significantly increased apoptosis in both HMVEC and hCMEC/D3 cells and permeability in hCMEC/D3 cells only. This increase in both apoptosis and permeability was significantly inhibited by a monoclonal anti-β3 antibody (SZ21) binding to the HPA-1a epitope. Our results indicate that (1) maternal anti-HPA-1a antibodies impair EC function by increasing apoptosis and permeability and (2) ECs from different vascular beds vary in their susceptibility to pathological effects elicited by maternal anti-HPA-1a antibodies on EC permeability. Examination of maternal anti-HPA-1a antibodies for their effect on EC permeability may predict potential ICH associated with FNAIT.

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Structure and Function of a Vimentin-associated Matrix Adhesion in Endothelial Cells

Molecular Biology of the Cell ◽

10.1091/mbc.12.1.85 ◽

2001 ◽

Vol 12 (1) ◽

pp. 85-100 ◽

Cited By ~ 111

Author(s):

Meredith Gonzales ◽

Babette Weksler ◽

Daisuke Tsuruta ◽

Robert D. Goldman ◽

Kristine J. Yoon ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factors ◽

Endothelial Cell ◽

Branching Morphogenesis ◽

Basement Membranes ◽

Αvβ3 Integrin ◽

Dependent Manner ◽

Matrix Adhesion ◽

Focal Contacts

The α4 laminin subunit is a component of endothelial cell basement membranes. An antibody (2A3) against the α4 laminin G domain stains focal contact-like structures in transformed and primary microvascular endothelial cells (TrHBMECs and HMVECs, respectively), provided the latter cells are activated with growth factors. The 2A3 antibody staining colocalizes with that generated by αv and β3 integrin antibodies and, consistent with this localization, TrHBMECs and HMVECs adhere to the α4 laminin subunit G domain in an αvβ3-integrin–dependent manner. The αvβ3 integrin/2A3 antibody positively stained focal contacts are recognized by vinculin antibodies as well as by antibodies against plectin. Unusually, vimentin intermediate filaments, in addition to microfilament bundles, interact with many of the αvβ3 integrin-positive focal contacts. We have investigated the function of α4-laminin and αvβ3-integrin, which are at the core of these focal contacts, in cultured endothelial cells. Antibodies against these proteins inhibit branching morphogenesis of TrHBMECs and HMVECs in vitro, as well as their ability to repopulate in vitro wounds. Thus, we have characterized an endothelial cell matrix adhesion, which shows complex cytoskeletal interactions and whose assembly is regulated by growth factors. Our data indicate that this adhesion structure may play a role in angiogenesis.

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