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Mechanically-Activated Drug Targeting Nanotechnology

A nanotherapeutic concentrates thrombolytics at blood clot sites based on high shear stress or chemotherapeutics at cancer sites using ultrasound activation

The Wyss team has developed a novel drug targeting nanotechnology that is activated locally by mechanical forces, either endogenous high shear stresses in blood created by vascular occlusion or mechanical energy applied locally using low-energy ultrasound radiation.

Today, vascular blockage is the leading cause of death and disability in United States and Europe. Current therapies have a major problem – their side effects put patients at significant risk of adverse events, including brain hemorrhage and death.

In this animation, learn how the Wyss Institute clot-busting nanotherapeutic is activated by fluid high shear force – which occurs where blood flows through vessels narrowed by obstruction – to specifically target clots and dissolve them away. By pairing this drug with an intra-arterial device that restores blood flow to complete obstructions, the drug-device combination could one day be used to treat stroke. Credit: Wyss Institute at Harvard University

Mechanical drug targeting – used in the Wyss Institute’s clot-busting nanotherapeutic – is a unique approach to concentrate drugs at the site of high shear forces, which are elevated in regions where blood clots produce partial obstruction of blood vessels. By targeting and concentrating thrombolytic drugs at sites where clots obstruct blood vessels in patients with major life-threatening diseases, such as pulmonary embolism, stroke and myocardial infarction, this shear stress-targeted clot-busting nanotherapeutic significantly reduces the amount of drug required, thereby decreasing the likelihood of potentially complicating bleeding side effects.  Reducing the required dose of anti-cancer agents while increasing their local concentration at the tumor site with directed ultrasound could have similar positive impact on treatment of cancer patients as well.

The vascular nanotherapeutic becomes activated in regions of high shear stress, at the exact places where it needs to do its job.

Donald E. Ingber

The Wyss Institute clot-busting nanotherapeutic is composed of an aggregate of biodegradable nanoparticles (180 nm diameter) created with commercial spray-drying manufacturing and coated with a clot-busting drug, such as tissue plasminogen activator (tPA), urokinase or other thrombolytic drug, which mimics the way blood platelets behave inside our own bodies. The nanoparticles are composed of poly(lactic-co-glycolic acid) (PLGA) which is used in many FDA-approved medical devices. When blood vessels narrow, the shear force of blood flow increases at that location to produce a physical cue that causes platelets to stick to the vessel wall. Similarly, the nanotherapeutic is activated by high levels of fluid shear stress, releasing tPA-coated nanoparticles in these narrowed regions where vessels are partially occluded, binding to the blood clot and dissolving it away. When loaded with imaging agents, this technology also provides a way to visualize sites of vascular obstruction, or when combined with drug loading, to create theranostic clot-busting nanodevices.

The anti-cancer nanotherapeutic uses the same nanoparticle aggregates, except that chemotherapeutic agents are pre-loaded within the individual PLGA nanoparticles to create multiple sustained-drug release nanovehicles before the aggregate is created. When the mechanically-activated anti-cancer nanotherapeutics are injected intravenously and low-energy ultrasound energy is applied to the tumor site, the circulating aggregates deploy their drug-loaded nanoparticles, which concentrate within the cancer microenviroment and deliver sustained drug doses over time that produce enhanced anti-cancer effects with reduced systemic side effects.

This technology is available for licensing.

Faculty Lead Donald E. Ingber describes the clot-busting nanotherapeutic. Credit: Wyss Institute at Harvard University.

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