The application of nanotechnology to cardiovascular nanomedicine

(Nanowerk Spotlight) Ischemic cardiomyopathy (CM) is the most common type of dilated cardiomyopathy. In Ischemic CM, the heart's ability to pump blood is decreased because the heart's main pumping chamber, the left ventricle, is enlarged, dilated and weak. This is caused by ischemia – a lack of blood supply to the heart muscle caused by coronary artery disease and heart attacks.

Treatment of ischemic CM is aimed at treating coronary artery disease, improving cardiac function and reducing heart failure symptoms. Patients usually take several medications to treat CM. Doctors also recommend lifestyle changes to decrease symptoms and hospitalizations and improve quality of life. In addition, devices and surgery may be advised.

"Nanostructured systems have the potential to revolutionize both preventive and therapeutic approaches for treating cardiovascular disease," says Morteza Mahmoudi, Director of and Principal Investigator at the NanoBio Interactions Laboratory at Tehran University of Medical Sciences. "Given the unique physical and chemical properties of nanostructured systems, nanoscience and nanotechnology have recently demonstrated the potential to overcome many of the limitations of cardiovascular medicine through the development of new pharmaceuticals, imaging reagents and modalities, and biomedical devices."

Mahmoudi is first author of a review paper in Nature Nanotechnology ("Multiscale technologies for treatment of ischemic cardiomyopathy"), that covers the current state of the art in employing nanoparticulate systems either to inhibit or treat ischemic heart injuries caused by the stenosis or occlusion of coronary arteries.

The review provides a brief overview of recent advances in the use of nano platforms for early detection and treatment of coronary atherosclerosis to inhibit myocardial infarction (MI; heart attack). The authors also introduce new therapeutic opportunities in the regeneration/repair of ischemic myocardium using both nanoparticles and nanostructured biomaterials that can deliver therapeutic molecules and/or (stem) cells into hibernating myocardium.

The paper further provides an overview of recent advances in precise in vivo imaging of transplanted cells using bacterially developed nanoparticles and explain how these findings address crucial issues in in vivo cell monitoring and facilitate the clinical translation of cell therapies.

Finally, the authors examine the strengths and limitations of current approaches and discuss likely future trends in the application of nanotechnology to cardiovascular nanomedicine.

Applications of various nano platforms in the prevention and treatment of cardiovascular disease. Nano platforms can target and break down coronary artery plaques and prevent injuries caused by stenosis or occlusion of arteries. Nanoparticulate systems can also reduce the adverse effects of reperfusion injuries and regenerate/salvage myocardium after MI, through sustained and targeted delivery of cells, biomolecules and paracrine factors. (© Nature Publishing Group) (click on image to enlarge)

Here is a summary of the review, which offers an outline of critical issues and emerging developments in cardiac nanotechnology, which overall represent tremendous opportunities for advancing the field.

Diagnosis and treatment of coronary atherosclerosis

Nanoparticles have demonstrated potential in both detection and removal of atherosclerotic plaques. For instance, nanoparticles can deliver therapeutic biomolecules to the site of coronary atherosclerosis and shrink plaques by reducing inflammation (for example, by activation of pro-resolving pathways), and removing lipids and cholesterol crystals.

"The main limiting issue for design of safe and efficient nanoparticles for both prognosis and treatment of coronary atherosclerosis is our lack of a deep understanding of the biological identity of nanoparticles" the authors write (see our previous Nanowerk Spotlight on this issue: "Pre-coating nanoparticles to better deal with protein coronas"). "More specifically, nanoparticles in contact with biological fluids are quickly surrounded by a layer of proteins that form what is called the protein corona, which has not yet been adequately addressed in the field of cardiac nanotechnology."

Therefore, to accelerate the clinical translation of nanoparticles and nanostructured materials for use in cardiac nanotechnology, their biological identities must be precisely assessed and reported.

Cell therapy for salvage and regeneration of heart tissue

Over the past decade, the majority of efforts in myocardial regeneration have been centred on cell-based cardiac repair (see for instance: "Nanotechnology based stem cell therapies for damaged heart muscles").

However, patient-specific therapeutic cells have limitations and nanoparticles could substantially help overcome them by targeting the injured portion of the myocardium.

Delivery of therapeutic molecules to CMs

Nanoparticles demonstrate great potential for delivering therapeutic agents specifically to the ischemic injured heart, although they accumulate mainly at pre-infarcted areas rather than the diseased tissue.

According to the authors, there are two major issues that should be addressed in future studies: 1) as only a low percentage of the injected nanoparticles can pass through the coronary arteries, the targeting capabilities of these particles to the heart tissue should be precisely defined; and 2) the effect of the protein corona on the in vivo release kinetics of the payloads should be characterized. Addressing these critical issues will help scientists design safe and efficient dosage of nanoparticles for biomolecular delivery applications.

Nanostructured scaffolding strategies for myocardial repair

As a bioartificial extracellular matrix (ECM), cardiac tissue scaffolds are engineered to interact optimally with cardiac cells during their gradual degradation and neotissue formation.

A variety of nanobiomaterials have been used to recapitulate the nanoscale features of the native ECM. In comparison with conventional tissue-engineering scaffolds, nanostructured biomaterials (for example, nanofiber/tube and nanoporous scaffolds) offer more biomimetic structural and physiomechanical cues, enhancing protein (molecular) and cellular interactions.

As the field of tissue engineering evolves, more attention is being given to the development of alternative biofabrication strategies to control the nano-scaffold 3D architecture in a more reproducible and patient/tissue-specific manner. Examples include 3D bioprinting and nanoprinting technologies that use computer-assisted layer-by-layer deposition (that is, additive manufacturing) to create 3D structures with sub-micrometer resolution.

Challenges in designing nanoparticles for clinical applications

Despite the enormously large and rapidly growing arsenal of nanoparticle technologies developed to date, few have reached clinical development and even fewer have been approved for clinical use.

This is in part attributed to the challenges associated with controllable and reproducible synthesis of nanoparticles using processes and unit operations that allow for scalable manufacturing required for clinical development and commercialization.

Nanoparticles also encounter unique physiological barriers in the body as compared with small molecule drugs with regard to systemic circulation, access to tissue and intra-cellular trafficking.

The authors point out that, as nanoparticles are increasingly being used in the diagnosis and treatment of cardiac diseases, their potential cardiotoxicity should be examined in detail. Their potential toxicity for cardiac tissue and heart function is of crucial importance for the safety of such nanoparticles.