Targeted SAINT-O-Somes for improved intracellular delivery of siRNA and cytotoxic drugs into endothelial cells

Adrian, Joanna E.; Morselt, Henriëtte W. M.; Süss, Regine; Barnert, Sabine; Ásgeirsdóttir, Sigrídur A.; Ruiters, Marcel H. J.; Molema, Grietje; Kamps, Jan A. A. M.

doi:10.1016/j.jconrel.2010.03.003

Cited by 33 publications

(37 citation statements)

References 30 publications

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“…Peptide-targeted liposomes loaded with doxorubicin or cisplatin together with oligonucleotides against the molecules involved in two main drug resistance mechanisms, B cell lymphoma 2 (BCL-2) and MDR1 (multidrug-resistance protein 1), had high efficacy in human ovarian cancer xenografts 155 . Moreover, a combination of the colorectal cancer drug irinotecan and 5-fluoroorotic acid in pegylated liposomes (at a 5:1 ratio) had synergistic effects and had higher therapeutic efficacy than did the free drug mixtures in animal models, including KB-tumour-bearing mice 156,157 . For example, in a Phase I clinical trial, liposomes loaded with irinotecan and floxuridine liposomes (in a 1:1 molar ratio) were well tolerated and had antitumour activity in patients with advanced colorectal cancer, whereby 13 out of 15 patients responded to therapy 158 .…”

Section: Nddss For Combination Therapymentioning

confidence: 99%

Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Torchilin

2014

Nat Rev Drug Discov

1,323

953

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The use of nanoparticulate pharmaceutical drug delivery systems (NDDSs) to enhance the in vivo effectiveness of drugs is now well established. The development of multifunctional and stimulus-sensitive NDDSs is an active area of current research. Such NDDSs can have long circulation times, target the site of the disease and enhance the intracellular delivery of a drug. This type of NDDS can also respond to local stimuli that are characteristic of the pathological site by, for example, releasing an entrapped drug or shedding a protective coating, thus facilitating the interaction between drug-loaded nanocarriers and target cells or tissues. In addition, imaging contrast moieties can be attached to these carriers to track their real-time biodistribution and accumulation in target cells or tissues. Here, I highlight recent developments with multifunctional and stimuli-sensitive NDDSs and their therapeutic potential for diseases including cancer, cardiovascular diseases and infectious diseases.

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Section: Nddss For Combination Therapymentioning

confidence: 99%

Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Torchilin

2014

Nat Rev Drug Discov

1,323

953

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“…To deliver antioxidants to these sites, we and others have devised a means of vascular immunotargeting of protein conjugates and nanocarriers [16-20]. In particular, conjugating antioxidants or their carriers to ligands of the endothelial cell surface determinant Platelet Endothelial Cell Adhesion Molecule, PECAM-1, represents an attractive strategy [16, 17].…”

Section: Introductionmentioning

confidence: 99%

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

Howard

Greineder

Hood

et al. 2014

Journal of Controlled Release

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Production of excessive levels of reactive oxygen species (ROS) in the vascular endothelium is a common pathogenic pathway in many dangerous conditions, including acute lung injury, ischemia-reperfusion, and inflammation. Ineffective delivery of antioxidants to the endothelium limits their utility for management of these conditions. In this study, we devised a novel translational antioxidant intervention targeted to the vascular endothelium using PEG-liposomes loaded with EUK-134 (EUK), a potent superoxide dismutase/catalase mimetic. EUK loaded into antibody-coated liposomes (size 197.8±4.5 nm diameter, PDI 0.179±0.066) exerted partial activity in the intact carrier, while full activity was recovered upon liposome disruption. For targeting we used antibodies (Abs) to platelet-endothelial cell adhesion molecule (PECAM-1). Both streptavidin-biotin and SATA/SMCC conjugation chemistries provided binding of 125-150 Ab molecules per liposome. Ab/EUK/liposomes, but not IgG/EUK/liposomes: i) bound to endothelial cells and inhibited cytokine-induced inflammatory activation in vitro; and, ii) accumulated in lungs after intravascular injection, providing >60% protection against pulmonary edema in endotoxin-challenged mice (vs <6% protection afforded by IgG/liposome/EUK counterpart). Since the design elements of this drug delivery system are already in clinical use (PEG-liposomes, antibodies, SATA/SMCC conjugation), it is an attractive candidate for translational interventions using antioxidant molecules such as EUK and other clinically acceptable drugs.

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“…We have shown that E-selectin targeted, lipid-based, conventional liposomes are extensively taken up by TNF-a activated HUVEC but also that they are degraded to a minor extent inside the endocytic vesicles of the endothelial cells (65). Regardless of the entry pathway, a lack of endosomal escape generally leads to poor siRNA efficacy, thus carriers have to be able to release their siRNA before entering lysosomes and enable escape of intact siRNA from the endosomal compartment into the cytoplasm (Fig.…”

Section: Intracellular Fate Of Endothelium Targeted Delivery Systems mentioning

confidence: 99%

“…These liposomes harnessed with anti-Eselectin antibody showed specific uptake by activated endothelial cells, and displayed good size stability (100 nm in diameter) in the presence of serum, but were destabilized at lower pH as occurs in the endosomes of endothelial cells, thereby showing superior intracellular release of their content. We were able to efficiently encapsulate low molecular weight compounds such as doxorubicin and siRNA in these carrier systems, rendering this formulation an interesting candidate for systemic application (65).…”

Section: Endothelial Cell Targeted Sirna Delivery Systemsmentioning

confidence: 99%

Targeted siRNA delivery to diseased microvascular endothelial cells—Cellular and molecular concepts

et al. 2011

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SummaryIncreased insight in the role of endothelial cells in the pathophysiology of cancer, inflammatory and cardiovascular diseases, has drawn great interest in pharmacological interventions aiming at the endothelium in diseased sites. Their location in the body makes them suitable targets for therapeutic approaches based on targeted drug delivery. Functional heterogeneity of the microvascular bed in normal organ homeostasis has been appreciated for a long time, and more recent studies have revealed heterogeneity in endothelial reactivity to inflammatory stimuli as well. Upon stimulation, each organ displays a vascular bed specific pattern of cell adhesion molecules providing challenging opportunities to deliver drugs or small RNAs to organ specific (micro)vascular endothelial subsets. In this review we introduce general concepts of endothelial heterogeneity in relation to disease state and its consequences for targeted therapeutic interventions. Furthermore, we will describe novel approaches to interfere with endothelial cell engagement in disease with a main focus on siRNA therapeutics and currently used nonviral lipid and polymer-based siRNA delivery systems. The last part of this review addresses some technical issues that are essential in proving the concept of target mRNA knock down in a vascular bed specific manner, and the further development of effective endothelial cell specific drug delivery devices.

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Targeted SAINT-O-Somes for improved intracellular delivery of siRNA and cytotoxic drugs into endothelial cells

Cited by 33 publications

References 30 publications

Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Multifunctional, stimuli-sensitive nanoparticulate systems for drug delivery

Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation

Targeted siRNA delivery to diseased microvascular endothelial cells—Cellular and molecular concepts

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