What’s up in nanomedicine for cardiovascular diseases?

Publications’ digest

Novel potent atherosclerosis nanotherapy

A disease caused by atherosclerosis is, for example, acute myocardial infarction. Risk factors are high lipid levels, smoking, high blood pressure and high serum glucose levels (1). Even when these risk factors are controlled after myocardial infarction and all treatment goals are met, the recurrence risk is high and another infarction occurs often within the first year (2). Dutta and coworkers explained that this is a systemic inflammatory response due to the reduced blood supply to the heart that aggravates the inflammation in atherosclerotic plaques at a distance as a result of the increased monocytes recruitment (3). After infiltration of these monocytes in the plaques, they differentiate into macrophages (inflammatory cells) that produce extracellular matrix digesting enzymes resulting in the rupture of plaques that may lead to athero-thrombotic events. Therefore, the inflammation of plaques is a therapeutic target (4). Statins [e.g., 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitor] are commonly used to upregulate the LDL receptor expression in hepatocytes. In general they also have immunomodulating effects of HMGR inhibition in inflammatory cells (5), which might be a possibility to inhibit the inflammation in plaques. To increase the oral dose of statins is not an option due to the side effects.

Duivenvoorden and coworkers developed high-density lipoprotein nanoparticles (rHDL) that can be used to deliver drugs to atherosclerotic plaques (6). The nanoparticles were constructed from human apolipoprotein A-1, 1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine and 1-myristoyl-2-hydroxy-sn-glycero-phospho-choline (phospholipids). As a target drug, simvastatin was encapsulated. The nanoparticles were 25–30 nm in diameter and have a discoid shape.

An in vitro study showed that the obtained anti-inflammatory effect is mediated by the inhibition of the mevalonate pathway, the metabolic pathway that is involved in multiple cellular processes such as cholesterol synthesis. The statin loaded nanoparticles were injected and studied in vivo in apolipoprotein E-knock-out mice (atherosclerosis model), in a high-dose and short-term study (1 week). It was shown that the inflammation in advanced plaques was decreased, while in a low-dose and long-term study (3 months) the inhibition of the plaque inflammation progression was achieved. With this study, Duivenvoorden et al. (6) showed that this novel nanotherapy enables the local treatment of atherosclerotic inflammation in mice.

The artificial pericardium

Even though the next discussed work does not reflect a core subject area of nanomedicine, it paves the way to a new direction of cardiac research and therapy studies within our field. In both clinical and basic cardiology, high-density multiparametric physiological mapping and stimulation are extremely important. Currently, this is done by the use of 2D sheets (7). The limitation here is that the full epicardial surface cannot be covered or, in case of chronic use, maintain reliable contact without the use of adhesives or sutures. Xu and coworkers developed a method to create 3D membranes that are elastic and shaped equivalent to the epicardium of a heart (8). To realize this, they used 3D printing to print a heart of interest, which was than used as a substrate. In all the experiments presented, explanted Langendorff-perfused rabbit hearts were used. On top of the 3D model, (opto-) electronic components (microscale inorganic light-emitting diodes for optical mapping), multifunctional sensors (pH sensors, temperature sensors/heaters, golden electrodes for electrical sensing/stimulation) and silicon nanomembranes for strain gauges, were assembled and a thin layer of silicone elastomer was casted and cured. When the substrate was removed, the remaining flexible 3D membrane was ready to be installed around a living heart that was used as a model. These membrane devices or artificial pericardia, completely envelope the heart while possessing inherent elasticity to provide a stable (a-)biotic interface during normal cardiac cycles. Xu et al. (8) demonstrated the capabilities of the developed membrane by high-precision mapping of, for example, epicardial electrical activity, mechanical analysis, multiparametric mapping during reperfusion or ischemia. With this work, it is shown that electrical, chemical and mechanical characteristics can be determined. These membranes are not limited to the heart but can be manufactured for other organs as well.

The endothelialized microfluidic chip

In the previous column, I emphasized the importance of micro/nanofluidic devices. Kim et al. (9) developed an endothelialized microfluidic device with controllable permeability. The microfluidic chip is made up of two-layer microfluidic channels that are compartmentalized. This enables the flow regulation in each channel independently. A porous membrane (3 μm pores) on which the endothelian cells are grown lies in between the two microfluidic channels. By the use of electrodes, placed at the inlets and outlets of the microfluidic channels, the permeability can be monitored by measuring the trans-endothelial electrical resistance.

Kim et al. (9) showed that the monolayer of human umbilical vein endothelian cells inside the microfluidic device becomes highly permeable when using TNF-α, but also when shear stress is applied. The intercellular junctional structures are then disrupted and the monolayer becomes permeable. Note, it is known that TNF-α is involved in the pathogenesis and progression of atherosclerosis, heart failure and ischemia/reperfusion injury (10).

To validate the microchip, Kim et al. studied the translocation of nanoparticles in vivo (New Zealand white rabbits) by using various (pre-) clinical imaging methods such as 3D dynamic contrast enhanced magnetic resonance imaging or near infrared fluorescent imaging. These results revealed that the translocation of these nanoparticles across the atherosclerotic endothelium depends on the vascular permeability. With this Kim and coworkers showed the potential utility of the microfluidic chip serving as a model system.

Upcoming events

The program of CLINAM 7/2014, the 7th European Summit for Clinical Nanomedicine and Targeted Medicine, is online (See also: http://www.clinam.org)

The summit runs from 23rd to 25th of June in Basel and is organized by the European Foundation for Clinical Nanomedicine (CLINAM) and the European Technology Platform on Nanomedicine (ETPN). This year’s focus topic is: Paving the Way to Personalized Diagnostics and Personalized Medicine. The conference is of interest to physicians, nanoscientist with a background in pharmacology, biology, physics, chemistry, biophysics, medicine materials science and engineering, developers of new tools and materials for nanomedicine but also to policymakers and experts from the industry in the life sciences. The summit includes clinical topics and sessions on technology, implications and on strategy, government and politics.

The European Society of Cardiology (ESC) Congress will be held from August 30th to 3rd of September in Barcelona, Spain. The aim of this year is to focus on “Innovation and the Heart” presenting the latest developments and innovations including the latest advances in cardiovascular medicine. This year, more than 11.000 abstracts from 100 countries have been submitted. It is the place to be for experts in the cardio-field like scientists, clinicians, epidemiologists, technicians, healthcare industry, policy makers and care opinion leaders.

October 16th–17th 2014, the 6th International Symposium on Neurocardiology; NEUROCARD and the 5th International Symposium on Noninvasive Electro-cardiology will be held in Belgrade, Serbia. The meeting will be of interest to medical specialists and researchers who are focused on the autonomic cardiovascular regulation in various fields, such as cardiology, genetics, engineering, nanomedicine, pharmacology and other expertises. The aim of this meeting is to enhance research in neurocardiology and related fields.