Heteromultivalent liposomal nanoconstructs for enhanced targeting and shear-stable binding to active platelets for site-selective vascular drug delivery

Modery, Christa L.; Ravikumar, Madhumitha; Wong, Timothy L.; Dzuricky, Michael; Durongkaveroj, Nat; Gupta, Anirban Sen

doi:10.1016/j.biomaterials.2011.08.067

Cited by 62 publications

(66 citation statements)

References 37 publications

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“…Additionally, systemic direct delivery of such serine protease agents can lead to indiscriminate off-target action, leading to major side effects including hemorrhage. The Sen Gupta lab has engineered platelet-inspired nanoparticle-based synthetic delivery vehicles that can bind to clot-associated activated platelets and proteins under hemodynamic shear flow 25–27 . We thus examined whether these nanoparticles can bind to the actively forming thrombi in an artery.…”

Section: Representative Resultsmentioning

confidence: 99%

Ferric Chloride-induced Murine Thrombosis Models

Nieman

Gupta

2016

JoVE

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Arterial thrombosis (blood clot) is a common complication of many systemic diseases associated with chronic inflammation, including atherosclerosis, diabetes, obesity, cancer and chronic autoimmune rheumatologic disorders. Thrombi are the cause of most heart attacks, strokes and extremity loss, making thrombosis an extremely important public health problem. Since these thrombi stem from inappropriate platelet activation and subsequent coagulation, targeting these systems therapeutically has important clinical significance for developing safer treatments. Due to the complexities of the hemostatic system, in vitro experiments cannot replicate the blood-to-vessel wall interactions; therefore, in vivo studies are critical to understand pathological mechanisms of thrombus formation. To this end, various thrombosis models have been developed in mice. Among them, ferric chloride (FeCl3) induced vascular injury is a widely used model of occlusive thrombosis that reports platelet activation and aggregation in the context of an aseptic closed vascular system. This model is based on redox-induced endothelial cell injury, which is simple and sensitive to both anticoagulant and anti-platelets drugs. The time required for the development of a thrombus that occludes blood flow gives a quantitative measure of vascular injury, platelet activation and aggregation that is relevant to thrombotic diseases. We have significantly refined this FeCl3-induced vascular thrombosis model, which makes the data highly reproducible with minimal variation. Here we describe the model and present representative data from several experimental set-ups that demonstrate the utility of this model in thrombosis research.

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Section: Representative Resultsmentioning

confidence: 99%

Ferric Chloride-induced Murine Thrombosis Models

Nieman

Gupta

2016

JoVE

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“…1–3 Factors that influence targeting efficacy include ligand-receptor affinities 4 , heteromultivalent ligand targeting strategies 5 , ligand presentation (linkers) 6–8 , as well as targeting ligand density. Studies to determine optimal surface ligand densities have demonstrated unique challenges specific to each material, ligand and application combination.…”

Section: Introductionmentioning

confidence: 99%

Tuning Ligand Density on Intravenous Hemostatic Nanoparticles Dramatically Increases Survival Following Blunt Trauma

et al. 2013

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Targeted nanoparticles are being pursued for a range of medical applications. Here, we utilized targeted nanoparticles (synthetic platelets) to halt bleeding in acute trauma. One of the major questions that arises in the field is the role of surface ligand density on targeted nanoparticles’ performance. We developed intravenous hemostatic nanoparticles (GRGDS-NP1), and previously demonstrated their ability to reduce bleeding following femoral artery injury and increase survival after lethal liver trauma in the rat. These nanoparticles are made from block copolymers, poly(lactic-co-glycolic acid)-b- poly-ι-lysine-b-poly(ethylene glycol). Surface-conjugated targeting ligand density can be tightly controlled with this system, and here we investigated the effect of varying density on hemostasis and biodistribution. We increased the targeting peptide (GRGDS) concentration 100-fold (GRGDS-NP100) and undertook an in vitro dose-response study using rotational thromboelastometry (ROTEM), finding GRGDS-NP100 hemostatic nanoparticles were efficacious at doses at least 10-fold lower than the GRGDS-NP1. These results were recapitulated in vivo, demonstrating efficacy at 8-fold lower concentration after lethal liver trauma. 1-hour survival increased to 92%, compared to a scrambled peptide control, 45% (OR=14.4, 95% CI=[1.36, 143]), a saline control, 47% (OR=13.5, 95% CI=[1.42, 125]), and GRGDS-NP1, 80% (OR=1.30, n.s.). This work demonstrates the impact of changing synthetic platelet ligand density on hemostasis, and lays the foundation for methods to determine optimal ligand concentration parameters.

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“…The novel DDS for thromboprophylaxis includes flow sensitive nanoparticles which are coated with tissue plasminogen activator (tPA) which release it at the site of clot. [5960616263]…”

Section: Targeted Drug Deliverymentioning

confidence: 99%