Draft:Shear-Stress Triggered Drug Delivery

Introduction

Shear stress-triggered drug release is a drug delivery system (DDS) that utilizes natural or synthetic shear stress as a mechanical stimulus to induce drug release. Cells experience shear stress naturally within areas that undergo fluid flow such as the vasculature and kidneys, however shear stress within the body can also be produced via external ultrasound. As a result, it is possible to make drug delivery systems that respond to elevated levels of shear stress, oftentimes targeting instances of thrombosis, kidney disease, and solid tumors. Because there are no specific chemical biomarkers for many of these cardiovascular diseases, mechano-sensitive drug delivery systems have been studied as a viable alternative for targeted drug delivery. Instances of research surrounding this DDS have grown significantly since early research in the 1990s and increased drastically in the early 2000s. Early research focused mainly on quantification and characterization of other drug delivery systems’ shear sensitivity., whereas current literature explores shear specific drug delivery systems.

Wall Shear Stress in the Body

Laminar shear of fluid between two plates. Friction between the fluid and the moving boundaries causes the fluid to shear (flow). The force required for this action per unit area is the stress. The relation between the stress (force) and the shear rate (flow velocity) determines the viscosity. (By Duk at the English-language Wikipedia, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=4168566)

Shear stress is a mechanical force and is defined as the parallel or tangential component of a force vector on a cross sectional area . However, shear stress in the body is usually a specific type of shear stress known as wall shear stress, and is defined as the force per unit area that a solid boundary exerts on a fluid in motion. The wall shear stress decreases as a function of distance from the solid boundary; the closer to the boundary, the higher the shear stress. Alternatively the relationship between fluid velocity and shear has also been studied and observed to be inversely proportional; the lower the shear stress the higher the fluid velocity.

Wall Shear Stress in Vasculature

The majority of wall shear stress is exerted by the vasculature on components of the blood, which are naturally very deformable to account for the shear. This shear stress is essential for maintaining endothelial homeostasis throughout the body and a healthy artery can usually generate a shear stress around one pascal. Deviations from a healthy shear stress, however, can dictate changes in vascular diameter and remodeling if maintained over time. In areas of low shear stress, the body will respond with a complex cascade of signaling which has been attributed to the formation of atherosclerotic plaque . In disorders that significantly affect the cardiovascular system such as atherosclerosis, diabetes, and hypertension this shear stress can become significantly elevated which further alters vascular pathology or trigger alternative shear stress-mediated cell signaling otherwise known as mechanotransduction.

Wall Shear Stress in Renal System

Another bodily system that undergoes and produces high shear stress conditions is the renal system. Renal tubular epithelial cells experience shear stress due to the constant flow of filtrate, and this mechanical stimulus has been attributed to various essential kidney functions such as protein uptake and barrier functions . Alterations in this flow, which can be attributed to various disorders, is thought to contribute to nephropathy or the deterioration of the kidneys eventually leading to kidney failure.

Carriers Used for Shear Stress Delivery

Shear-Sensitive Liposomes

Liposomes are composite structures made of phospholipids and may contain small amounts of other molecules. Though liposomes can vary in size from low micrometer range to tens of micrometers, unilamellar liposomes, as pictured here, are typically in the lower size range with various targeting ligands attached to their surface allowing for their surface-attachment and accumulation in pathological areas for treatment of disease.

Liposomes are a thoroughly studied method of drug delivery in which cholesterol and natural phospholipids are used to create artificial vesicles. The hydrophobicity and hydrophilicity of the components lends itself to relatively fast self-assembly, and these can be used to encapsulate drugs for delivery . Through various methods of formulation and materials used, the properties of the liposome such as charge, morphology, and mechanical properties can be altered to suit the required purpose. For instances of shear stress triggered drug delivery, the carriers often rely on changes in the morphology of the liposome inducing deformation to release the therapeutic within.

Liposomes that are not entirely isosymmetric, such as those of an elliptical or lenticular geometry, often release their payload preferably at high shear stress environments. These are considered clinically relevant mostly for acute treatment of myocardial infarction (heart attacks) or stroke. There are also isosymmetric, spherical liposome applications in instances of thrombosis.

Shear-Sensitive Nanoparticle Aggregates

Nanoparticle aggregates (NPAs) are collections of numerous nanoparticles that can be triggered to dissociate into individual nanoparticles and release their payload. The initial synthesis of nanoparticle aggregates, and aggregation in general, can depend on the size of the individual nanoparticles, the cross-linking, and the coating during formulation. In instances of elevated shear stress, shear stress as a mechanical stimulus can be used to provoke dissociation; sometimes this is natural shear stress, but it can also be induced via ultrasound application.

There are various nanoparticle aggregations that are being studied for applications in the body, the first of which is free NPAs. These aggregates are not bound by any larger vehicle and dissociate under high shear conditions. However, because of their size and lack of encapsulation, they are often cleared by the body very quickly, contributing to a decreased efficacy when compared with other aggregate technologies. Alternatively, there are nanoparticles bound and delivered using cells such as red blood cells (RBCs) or macrophages. The nanoparticles are bound via electrostatic interactions and aggregate on the cell surface instead of with each other. This allows for decreased systemic clearance while still allowing for shear activation. Cell carrier NPAs have been studied for both cardiovascular applications and cancer applications, specifically for lung metastasis. Finally, there are microsphere aggregates generally made out of peptide modified alginate and used for the purpose of accelerating tissue regeneration, specifically cartilage tissue. The use of microspheres allows for decreased clearance but does not require a supply of natural cells for synthesis.

Other Shear-Sensitive Drug Delivery Systems

Nanogels are a highly deformable, prominent drug delivery system composed of crosslinked nanoparticles and high water content. This relative deformability allows nanogels to reach places inaccessible to rigid nanoparticles and still release their payload upon deformation. There has not been much successful experimentation with these nanogels yet, but potential applications include targeting Plasmalemma Vesicle Associated Protein (PLVAP) in the lungs.

Micellar hydrogels are a type of shear-thinning and self-healing hydrogel that incorporate high quantities of drugs into their matrices. When placed in high shear environments, micellar hydrogels become less viscous and are able to flow more easily. Additionally, in the absence of any shear stress, these hydrogels are able to repair themselves and improve their overall strength. Applications of micellar hydrogels are generally related to thrombosis and limiting inflammation at the site of a clot.

Ultrasound in Shear Stress Applications

Principle of ultrasound (By Georg Wiora (Dr. Schorsch) - Self drawn with Inkscape, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=353362)

Ultrasound is closely linked to shear stress drug delivery as both a method of quantification and as a means to increase shear stress in a designated area. Quantification of shear stress in the body is species dependent, differs on an individual basis, and differs based on laminar versus turbulent flow. Thus, ultrasound has been used as a means of estimating shear stress levels under different conditions and for different species . Ultrasound is also known to alter endothelial shear stress due to its physical effects such as microbubbles or acoustic streaming. This is being studied due to the possible safety ramifications but also as a method for targeted drug delivery. Current applications of ultrasound generally last only minutes, and thus targeted drug delivery and safety considerations are generally focused on acute effects as opposed to chronic .

Applications for Cardiovascular Health

Applications for shear-sensitive drug delivery systems are most commonly involving cardiovascular applications, but can range anywhere from acute to chronic cardiovascular disorders. For many time-sensitive situations, such as an ischaemic stroke, the current technology is not adequate in providing the required therapeutic dose in a short time period. A targeted approach such as shear stress triggered drug delivery would aim to deliver the drug in a shorter time frame, as opposed to a systemic approach like intravenous injection.

Some potential cardiovascular disorders that could be treated by this method include: diabetes, hypertension, atherosclerosis, cerebrovascular disease, and deep vein thrombosis. All of these result in changes in shear stress within the vasculature which can be targets for this DDS.

Other Applications

Renal applications of this technology have also been explored, particularly how reabsorption and cellular uptake is affected by the constant fluid shear stress of urine in the renal tubule. Potential for a kidney-specific drug delivery system can help to combat toxicities associated with kidney disease treatments. Current research in this field has worked with microfluidics systems and in vivo models to better understand the effect of shear stress on renal epithelial cells, but at this time, no shear stress triggered drug delivery systems have been developed for the renal system.

Solid tumor cancer cells experience additional mechanical forces due to unregulated growth and the surrounding tumor microenvironment. Blood flow, pH, interstitial flow, and oxygenation are all irregular within a tumor and this can lead to differences in shear stresses within the tumor. Additionally, metastatic cells that break off from the tumor flow through the bloodstream and can undergo the same shear stress experienced by cells in the vasculature. Thus, there is research surrounding shear-sensitive nanoparticles in cancer treatment applications, and how an increase in shear stress can be attributed to an increase in cellular uptake of these nanoparticles